Dr. Zachary Knight: The Science of Hunger & Medications to Combat Obesity

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.240 | where we discuss science

00:00:03.660 | and science-based tools for everyday life.

00:00:05.880 | I'm Andrew Huberman,

00:00:10.400 | and I'm a professor of neurobiology and ophthalmology

00:00:13.560 | at Stanford School of Medicine.

00:00:15.520 | My guest today is Dr. Zachary Knight.

00:00:18.040 | Dr. Zachary Knight is a professor of physiology

00:00:20.460 | at the University of California, San Francisco,

00:00:23.040 | and an investigator with the Howard Hughes Medical Institute.

00:00:26.600 | For those of you that don't know,

00:00:28.080 | Howard Hughes Medical Investigators are selected

00:00:31.320 | from an extremely competitive pool of applicants

00:00:34.400 | and have to renew in order to maintain

00:00:37.160 | their investigatorship with the Howard Hughes

00:00:39.400 | Medical Institute every five years or so,

00:00:42.380 | placing him in the most elite of categories

00:00:45.680 | with respect to research scientists.

00:00:48.040 | His laboratory focuses on homeostasis,

00:00:50.560 | in particular, what drives our sense of hunger,

00:00:53.760 | what drives our sense of thirst,

00:00:55.560 | and what controls thermoregulation,

00:00:57.680 | which is the ability to maintain body temperature

00:01:00.120 | within a specific safe range.

00:01:02.240 | Today, we mainly focus on hunger.

00:01:04.360 | Dr. Zachary Knight explains the biological mechanisms

00:01:07.000 | for craving food, for consuming food,

00:01:10.080 | and believe it or not, you have brain circuits

00:01:12.440 | that actually determine how much you're likely to eat

00:01:14.520 | even before you take your very first bite.

00:01:16.980 | And he explains the biological mechanisms for satiety,

00:01:20.160 | that is the sense that one has had enough

00:01:22.520 | of a particular food or food group.

00:01:24.560 | Dr. Knight also explains the role of dopamine

00:01:27.120 | in food craving and consumption,

00:01:29.280 | which I think everybody will find very surprising

00:01:32.000 | because it runs countercurrent

00:01:33.280 | to most people's understanding of what dopamine does

00:01:35.760 | in the context of eating and other cravings.

00:01:38.600 | Today's discussion also includes a deep dive

00:01:41.000 | into GLP-1, glucagon-like peptide,

00:01:44.800 | and the novel class of drugs such as Ozempic and Monjaro

00:01:48.120 | and other related compounds that are now widespread in use

00:01:51.500 | for the reduction in body weight.

00:01:53.820 | Dr. Knight explains how GLP-1 was first discovered

00:01:56.680 | and how these drugs were developed, how they work,

00:01:59.360 | and importantly, why they work,

00:02:01.440 | and how that is leading to the next generation

00:02:04.240 | of so-called diet drugs or drugs to treat obesity,

00:02:07.280 | diabetes, and related syndromes.

00:02:09.400 | We also discussed thirst and the intimate relationship

00:02:12.220 | between water consumption and food consumption.

00:02:14.640 | And we also talk about the relationship

00:02:16.060 | between sodium intake, water intake, and food intake.

00:02:19.680 | By the end of today's conversation,

00:02:20.980 | you will have learned a tremendous amount

00:02:22.260 | about the modern understanding

00:02:23.960 | of hunger, thirst, and salt intake,

00:02:26.280 | as well as this modern class of drugs,

00:02:28.380 | such as Ozempic and related compounds,

00:02:30.480 | all from a truly world-class investigator

00:02:33.640 | in the subjects of researching hunger,

00:02:36.080 | thirst, and thermal regulation.

00:02:38.140 | Before we begin, I'd like to emphasize

00:02:39.960 | that this podcast is separate

00:02:41.400 | from my teaching and research roles at Stanford.

00:02:43.640 | It is, however, part of my desire and effort

00:02:45.540 | to bring zero-cost to consumer information

00:02:47.640 | about science and science-related tools

00:02:49.840 | to the general public.

00:02:51.120 | In keeping with that theme,

00:02:52.200 | I'd like to thank the sponsors of today's podcast.

00:02:55.080 | Our first sponsor is BetterHelp.

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00:03:02.860 | I've been doing weekly therapy for well over 30 years.

00:03:06.140 | Initially, I didn't have a choice.

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00:07:04.500 | And now for my discussion with Dr. Zachary Knight.

00:07:07.900 | Dr. Zachary Knight, welcome.

00:07:09.860 | - Great to be here.

00:07:11.420 | - Today, we're going to talk about hunger, appetite, thirst,

00:07:15.580 | other motivated behaviors, the role of dopamine,

00:07:19.100 | the vagus nerve.

00:07:19.940 | These are terms and topics

00:07:21.620 | that a lot of people hear nowadays,

00:07:23.860 | and for which there's a ton of interest.

00:07:26.020 | But just to march us in sequentially,

00:07:29.200 | could you describe some of what's happening in the brain

00:07:32.940 | and/or body as we get hungry, decide what to eat,

00:07:38.660 | and then decide that we've had enough to eat?

00:07:42.500 | I think most people just assume that,

00:07:44.700 | okay, that my stomach's full, is what we say.

00:07:47.180 | I've had enough.

00:07:48.120 | Or we self-regulate it for some other reason,

00:07:52.060 | caloric restriction or monitoring in some cases.

00:07:55.740 | What's happening in the brain in terms of the circuitries?

00:08:00.640 | And what have you discovered

00:08:01.980 | about what that process looks like

00:08:04.220 | in terms of its kind of universality across people?

00:08:08.860 | And then maybe how it sometimes differs between people.

00:08:11.660 | - Okay, well, there's a lot in that that I'll try to unpack.

00:08:13.940 | - And I can remind you of some of the nuances.

00:08:16.420 | In other words, as a biologist, as a neuroscientist,

00:08:18.620 | how do you think about this thing

00:08:19.600 | that we call hunger and feeding?

00:08:20.620 | - Absolutely, absolutely.

00:08:21.860 | So I think at a very high level,

00:08:24.060 | a good way to think about the regulation of food intake

00:08:26.380 | by the brain is that there's two systems,

00:08:29.300 | a short-term system and a long-term system,

00:08:31.900 | that are primarily localized

00:08:33.740 | to different parts of the brain,

00:08:35.460 | operate on different timescales,

00:08:36.740 | one on the timescale of a meal, so 10, 20 minutes,

00:08:40.000 | and the other on the timescale of sort of weeks

00:08:43.380 | to months to years and tracks levels of body fat.

00:08:46.740 | And these two systems sort of interact

00:08:49.180 | so that these short-term behaviors we do eating

00:08:52.500 | are matched to our long-term need for energy.

00:08:55.760 | And so I think one of the initial experiments

00:09:00.780 | that really led to this idea

00:09:01.860 | is this great experiment by Harvey Grill

00:09:04.460 | about 50 years ago.

00:09:06.220 | It's called the decerebrate rat.

00:09:07.940 | And so essentially what he did was he made a cut

00:09:11.000 | in the rat brain.

00:09:11.840 | So he took these rats in the lab,

00:09:12.660 | made a cut so that he separated the brainstem,

00:09:15.740 | so the most posterior part of the brain,

00:09:18.260 | from the entire forebrain.

00:09:19.300 | Basically got rid of 80% of the rat's brain.

00:09:22.060 | So basically creating these zombie rats,

00:09:24.420 | all they have is a brainstem,

00:09:25.980 | and asked what can these rats still do?

00:09:29.340 | And as you might imagine,

00:09:30.180 | they can't do a lot of things, right?

00:09:31.140 | Because they basically have lost most of their brain.

00:09:33.860 | But he discovered that one thing they can still do

00:09:36.980 | is regulate the size of a meal.

00:09:38.780 | And so--

00:09:39.620 | - A very informative experiment.

00:09:42.380 | - And so, and you have to be careful

00:09:44.660 | how we talk about this,

00:09:45.500 | 'cause the way this meal works

00:09:46.340 | is you have to actually put food into their mouth,

00:09:48.260 | and then they'll swallow it as you put food

00:09:50.160 | into their mouth.

00:09:51.000 | But eventually at some point,

00:09:53.340 | they'll start spitting it out.

00:09:54.700 | And that basically is an indication

00:09:56.300 | that in some sense, they're becoming sated.

00:09:59.180 | And they're just using the brainstem that they have left,

00:10:02.900 | they're able to sense those signals from the gut

00:10:05.540 | and drive the termination of a meal.

00:10:07.740 | And he did other experiments showing

00:10:09.300 | that many of these signals that come from the gut,

00:10:10.940 | gastric stretch, hormones that come from your intestine

00:10:13.700 | in response to food intake, like CCK,

00:10:15.780 | these desirabate rats just have a brainstem.

00:10:18.740 | If you inject those or manipulate the gut in those ways,

00:10:22.060 | it can, in an appropriate way,

00:10:23.620 | change how much the rat eats.

00:10:25.120 | Now what can't the rat do when it doesn't have a forebrain?

00:10:29.100 | The thing it can't do is it can't respond

00:10:31.540 | to longer term changes in energy need.

00:10:34.020 | Meaning, if you fast the rat for a couple days,

00:10:36.700 | this desirabate rat, then start putting food in its mouth,

00:10:40.380 | the amount that it eats doesn't change.

00:10:42.220 | So basically, it doesn't eat a larger meal

00:10:43.860 | the way you would if you were fasted for several days

00:10:46.060 | and then refed.

00:10:46.940 | And that experiment along with other evidence

00:10:50.900 | has led to the idea that in the brainstem,

00:10:53.580 | and then the most posterior part of your brain,

00:10:55.300 | there are neural circuits that control sort of a meal.

00:10:57.980 | And then the timescale of 10 minutes or 20 minutes

00:11:00.260 | deciding when a meal should end.

00:11:01.880 | And in the forebrain, primarily in the hypothalamus,

00:11:04.700 | there are neural circuits that then track

00:11:06.380 | what is my overall level of energy reserves?

00:11:09.020 | What is my level of body fat?

00:11:10.180 | Things that would fluctuate on timescales,

00:11:11.700 | say days when you're fasting.

00:11:13.420 | And those forebrain centers feedback

00:11:15.460 | to talk to the brainstem and modulate

00:11:17.300 | those brainstem circuits that are controlling

00:11:18.780 | the size of a meal to sort of match these two timescales.

00:11:21.960 | So that's at the highest level how I think

00:11:23.540 | about the neural circuitry that controls feeding.

00:11:25.960 | There's obviously a lot more going on underneath that.

00:11:28.900 | - Fascinating.

00:11:30.380 | You mentioned body fat and that somehow the brain

00:11:35.180 | is tracking the amount of body fat.

00:11:37.260 | That caught my ear because while it makes total sense,

00:11:42.260 | I'd like to know how that happens

00:11:44.260 | if we happen to know the mechanism.

00:11:46.200 | And the second question is why body fat

00:11:50.020 | and not body fat and muscular mass

00:11:52.780 | or body fat and overall body weight?

00:11:56.000 | What is being signaled between body fat and the brain

00:11:59.320 | that allows the brain to track body fat?

00:12:01.240 | And why do you think body fat is the critical signal?

00:12:03.680 | I realize it represents an energy reserve,

00:12:06.360 | but certainly there are other things

00:12:07.800 | about the bodily state that are important.

00:12:10.480 | - Yeah, well, there are certainly other things

00:12:11.820 | about the bodily state that are important.

00:12:13.080 | And there are other things about physiology

00:12:14.400 | definitely that are regulated other than body fat.

00:12:16.960 | But body fat is unique because it represents

00:12:20.500 | this energy reserve.

00:12:21.620 | So the neural circuitry that regulates eating behavior

00:12:24.960 | is in some ways very unique

00:12:26.320 | because it has this reserve of energy.

00:12:28.000 | So if you, we also study thirst in my lab and drinking

00:12:30.520 | and you don't have a reserve of water in your body, right?

00:12:33.560 | And that's true for basically everything else.

00:12:35.600 | But for fat, we have this reserve of energy.

00:12:39.260 | And so it's very important that the brain know

00:12:42.040 | how much remains and then adjust behavior

00:12:45.800 | in coordinates with that so that, you know,

00:12:49.920 | you know how urgent it is to get the next meal.

00:12:52.680 | And so the thought is that the major signal

00:12:55.240 | of the level of body fat that we have is leptin.

00:12:58.040 | It's this hormone.

00:12:59.800 | It was discovered, it was cloned in 1994,

00:13:01.800 | actually by my postdoctoral advisor,

00:13:03.240 | a scientist named Jeff Friedman at Rockefeller University,

00:13:05.720 | although its history goes back way before 1994.

00:13:08.040 | So the sort of story behind leptin

00:13:10.520 | is that there's a facility called Jackson Labs

00:13:15.040 | that you I'm sure are familiar with in Maine

00:13:17.800 | that since the 1920s has been raising mice

00:13:20.440 | and selling them to academics,

00:13:21.720 | basically who study physiology and behavior.

00:13:25.280 | And so they breed thousands of mice.

00:13:27.040 | So there's sort of a nonprofit organization

00:13:29.080 | that distributes mice to the scientific community.

00:13:31.400 | And at some point in the 1950s,

00:13:33.960 | they spontaneously just because they were breeding

00:13:35.600 | so many mice, they came across some spontaneous mutations,

00:13:39.120 | mutant mice that were extremely fat,

00:13:41.180 | like the fattest mice they had ever seen.

00:13:42.580 | These mice just eat constantly.

00:13:43.760 | They're just enormous, three times the size

00:13:45.520 | of a normal mouse.

00:13:46.960 | And it's all body fats.

00:13:48.920 | They're just these huge fat mice.

00:13:53.360 | And they came across several different mutant strains

00:13:57.440 | that all had the same phenotype

00:13:59.800 | in the sense that they were all extremely fat,

00:14:01.520 | all extremely hyperphagic,

00:14:03.200 | but they could tell even in the 1950s

00:14:05.400 | that these mutations were on different chromosomes.

00:14:08.360 | They didn't know anything about how to identify the genes

00:14:09.840 | at that point, that was just science fiction,

00:14:11.320 | but they knew that there were chromosomes

00:14:12.520 | and they were on different chromosomes.

00:14:14.520 | And so they labeled one obese,

00:14:16.640 | one of these mouse strains obese,

00:14:17.840 | and the other one diabetes,

00:14:19.040 | but they're basically the same.

00:14:20.800 | As people wonder for a long time,

00:14:21.760 | well, what's going on in these mice?

00:14:24.000 | Then there was a scientist at Jackson Labs, Doug Coleman,

00:14:27.040 | who had the idea, what if we do an experiment

00:14:30.040 | where we connect the circulations

00:14:32.240 | of these two different strains of obese mice

00:14:35.000 | and test the hypothesis

00:14:36.040 | that maybe there's a circulating factor,

00:14:37.920 | a hormone that is produced by one of these strains

00:14:40.680 | and that controls appetite.

00:14:42.840 | Because at that point, insulin was known,

00:14:44.640 | glucagon was known, there were some hormones

00:14:46.000 | that were known that were involved in metabolism.

00:14:47.440 | So it was logical that there could be a hormone

00:14:49.560 | that perhaps regulates body fat levels.

00:14:52.600 | And what they found, which was remarkable,

00:14:55.000 | when you attach the OB strain to the DB strains,

00:14:57.600 | you basically connect their circulation,

00:14:58.920 | so hormones are transmitted between the two.

00:15:01.480 | The OB mouse, that strain dramatically loses weight.

00:15:07.160 | In fact, within a couple of weeks,

00:15:08.840 | it looks like a normal mouse.

00:15:10.040 | It just stops eating, it loses almost all of its body fat,

00:15:12.560 | and it essentially in all aspects becomes a normal mouse.

00:15:15.520 | The DB mouse, nothing really happens.

00:15:17.760 | It still remains obese, it still remains hyperphagic.

00:15:20.880 | And based on just that piece of data,

00:15:22.520 | Doug Coleman hypothesized that what was going on

00:15:24.640 | is these two mutations were mutations

00:15:26.960 | in a hormone and a receptor.

00:15:28.700 | The OB mouse had a mutation in the hormone

00:15:32.560 | that comes from fat, so it couldn't produce this hormone

00:15:34.760 | that comes from fat and signals to the brain

00:15:37.400 | how much fat you have.

00:15:38.240 | And the DB mouse has a mutation in the receptor,

00:15:41.320 | so it can't sense the hormone.

00:15:44.320 | And that was just an idea, it was a hypothesis.

00:15:46.920 | But in the 1980s, as technology advanced,

00:15:50.280 | as molecular biology had been invented,

00:15:53.560 | it became possible to clone genes.

00:15:56.240 | A number of people tried to identify

00:15:58.120 | what are the genetic mutations that are occurring

00:16:01.080 | in these mice that make them so obese.

00:16:02.800 | And Jeff basically cloned leptin and showed that in fact,

00:16:05.200 | Doug was exactly right.

00:16:06.440 | The OB mutation is a mutation in this hormone, leptin.

00:16:11.200 | And later, millennium pharmaceuticals showed

00:16:14.160 | that the DB mutation is in fact a receptor.

00:16:16.800 | And it was an important discovery for a couple of reasons.

00:16:20.040 | One, because this OB gene is just expressed in fat.

00:16:23.920 | It's exclusively expressed in adipose tissue.

00:16:27.240 | And how much it's expressed is directly proportional

00:16:30.880 | to how much body fat you have.

00:16:32.680 | So as you gain weight,

00:16:34.760 | the expression of this hormone increases in a linear manner,

00:16:37.360 | and then it's secreted into the blood.

00:16:38.880 | So the level of leptin in your blood

00:16:40.640 | is a direct readout of your body fat reserves.

00:16:42.960 | This receptor for leptin, leptin receptor,

00:16:48.080 | the functional form of it is expressed

00:16:49.960 | almost exclusively in the brain.

00:16:52.000 | And it's expressed in all of the brain regions

00:16:54.000 | that we knew from previous work were important for appetite.

00:16:56.360 | So basically the expression of this receptor

00:16:58.080 | gives you a map in the brain

00:16:59.400 | of the neurons that control hunger.

00:17:01.360 | And so what happens is basically when you lose weight,

00:17:05.200 | the levels of leptin in your blood fall

00:17:06.760 | because basically you've lost adipose tissue.

00:17:09.440 | The absence of that hormone sends a signal

00:17:11.080 | to all these neurons that have leptin receptors in the brain.

00:17:12.960 | They're not getting that signal that I'm starving.

00:17:16.440 | And basically that initiates

00:17:17.800 | this entire homeostatic response to starvation.

00:17:20.880 | So a big part of that is obviously increased hunger,

00:17:24.600 | but it's also decreased energy expenditure,

00:17:26.520 | decreased body temperature, even decreased fertility,

00:17:30.760 | because you don't wanna reproduce if you're starving.

00:17:32.880 | - Less spontaneous movement.

00:17:34.440 | - Less spontaneous movement, all of this.

00:17:39.080 | And so the thought is, which I think is absolutely correct,

00:17:40.960 | is that this hormone leptin

00:17:42.320 | is part of this negative feedback loop

00:17:44.280 | from the fat to the brain

00:17:46.080 | that basically tells you about your level

00:17:47.480 | of body fat reserves and how urgent it is

00:17:49.440 | to find the next meal.

00:17:50.720 | - Fascinating.

00:17:51.760 | As I recall, Amgen Pharmaceuticals

00:17:54.960 | owned the patent for leptin

00:17:56.800 | in hopes that it would become the blockbuster diet drug,

00:17:59.880 | the logic being that if you were to take this hormone

00:18:03.080 | somehow or activate this pathway,

00:18:05.080 | that the brain would be tricked into thinking

00:18:06.640 | that there was more body fat,

00:18:08.160 | more energy reserves than there was,

00:18:09.680 | and then people would basically be less hungry,

00:18:13.640 | eat less, and lose body fat.

00:18:16.720 | What happened with that?

00:18:18.160 | Do we know why it did not work?

00:18:19.760 | - Yeah, so that's a great question.

00:18:21.560 | So there was a lot of excitement when leptin was cloned

00:18:24.200 | 'cause it was thought basically we've cured obesity.

00:18:26.800 | There was an auction for the patent, Amgen won,

00:18:29.900 | I think it was something like $20 million up front payment,

00:18:32.220 | plus royalties, which at the time was,

00:18:34.240 | I mean, it still is a lot of money,

00:18:35.240 | but even more money.

00:18:36.080 | - In other ways, it would be a drop in the ocean

00:18:38.720 | compared to what companies

00:18:39.800 | will invest into a potential diet drug.

00:18:41.400 | - Exactly, but at the time,

00:18:44.720 | and still a lot of money today,

00:18:46.360 | and they did a clinical trial,

00:18:49.320 | gave obese people leptin,

00:18:50.560 | subcutaneous injections of this hormone,

00:18:52.800 | and they didn't lose a lot of weight,

00:18:54.560 | and the question was why.

00:18:57.080 | And so what was subsequently revealed

00:18:59.200 | is that the challenge with leptin

00:19:00.480 | is that individuals who are obese

00:19:03.720 | do not have low levels of leptin for the most part.

00:19:06.400 | They actually have high levels of leptin,

00:19:08.240 | and so what they have is a state of leptin resistance.

00:19:10.440 | So it's analogous to someone who has type 2 diabetes.

00:19:12.920 | It's not because they lack insulin,

00:19:14.320 | it's because they actually have, over time,

00:19:15.940 | a high level of insulin,

00:19:17.440 | and so target tissue stopped responding to insulin,

00:19:19.640 | and the thought is that it's the same way

00:19:21.280 | in obesity and leptin.

00:19:22.880 | Now, subsequently, they went back

00:19:25.800 | and did a reanalysis of that clinical trial

00:19:29.240 | and asked what if you take all of these people

00:19:31.320 | and stratify them according to their starting leptin level.

00:19:33.960 | So some people have relatively low levels of leptin,

00:19:36.000 | some have higher, some have really high levels of leptin,

00:19:38.660 | and then ask, if we reanalyze the data,

00:19:40.760 | how effective is leptin?

00:19:43.760 | And as you might expect,

00:19:44.620 | the people with the lowest levels of leptin,

00:19:45.920 | they lost the most weight when you gave them this drug,

00:19:48.880 | and the people with the highest levels of leptin

00:19:50.480 | lost the least weight.

00:19:51.800 | So there is a rationale there for why,

00:19:54.280 | for a scenario in which leptin could work,

00:19:56.360 | either among the subset of people

00:19:58.900 | who just have, for some reason, lower levels of leptin,

00:20:01.920 | these aren't people with mutations like the OB MALS,

00:20:03.680 | they have some leptin,

00:20:04.520 | they just don't have unusually high levels,

00:20:06.560 | or alternatively, after weight loss.

00:20:09.080 | So after you've lost a lot of weight,

00:20:11.360 | your leptin levels plummet, they become very low,

00:20:13.540 | and that part of the reason,

00:20:14.800 | it's a big part of the reason

00:20:16.080 | it's so difficult to keep weight off

00:20:17.340 | is because those leptin levels are so low.

00:20:19.480 | And so it's been thought for a long time

00:20:21.480 | that that is a scenario where treating people with leptin

00:20:24.680 | could be really useful to help them keep the weight off.

00:20:28.680 | Why it never made it as a drug for that application,

00:20:31.540 | I really don't understand.

00:20:32.520 | It has something to do, I think,

00:20:33.520 | with the pharmaceutical industry, with the economics,

00:20:35.400 | with a bunch of other issues

00:20:37.200 | that aren't necessarily scientific.

00:20:38.960 | But I think there's still, in the future,

00:20:41.600 | is a possibility that it could come back for that indication,

00:20:43.880 | especially now that we have these GLP-1 drugs,

00:20:45.880 | and now there's just millions of people losing so much weight

00:20:48.360 | and perhaps they want to transition

00:20:49.560 | to a different kind of drug to keep the weight off.

00:20:52.040 | - We are definitely going to talk about GLP-1, Ozempic,

00:20:54.760 | and some of the related compounds in a few minutes,

00:20:58.440 | but before we do that,

00:21:00.020 | I'd love to get to this issue

00:21:02.800 | of what's happening in the brain as we get hungry,

00:21:06.240 | approach a meal, decide what to eat,

00:21:09.000 | and decide when we've had enough.

00:21:11.280 | Are there separate circuitries,

00:21:12.640 | or at least separate neurons for each of those steps?

00:21:14.960 | And if you would, could you walk us through

00:21:18.000 | what that process looks like since we do it every day?

00:21:20.940 | Most people do it every day unless they're fasting,

00:21:23.040 | multiple times per day.

00:21:24.640 | What's going on in our brain and body

00:21:26.400 | as we think about and approach a meal,

00:21:30.080 | consume a meal, and decide enough?

00:21:32.280 | - Sure, so there are different neurons

00:21:35.720 | that are preferentially involved

00:21:36.920 | in different aspects of those processes.

00:21:38.840 | So I think we often divide feeding behavior

00:21:42.400 | and many other kinds of motivated behaviors

00:21:44.700 | into appetitive and consummatory phases.

00:21:47.160 | So appetitive is the phase of the behavior

00:21:49.680 | where you're, for example, searching for food.

00:21:52.160 | It's foraging.

00:21:53.040 | It's all the actions that lead up

00:21:55.320 | to the actual behavior itself,

00:21:57.560 | which then we call the consummatory phase.

00:22:00.200 | That's actually putting the food

00:22:01.040 | in your mouth and eating it.

00:22:02.720 | And the general thought is that these four brain circuits

00:22:06.040 | in the hypothalamus are more important,

00:22:08.040 | particularly in the hypothalamus,

00:22:09.180 | but other parts of the forebrain as well,

00:22:11.220 | are more important for the appetitive phase.

00:22:14.160 | And the brainstem circuits are more important

00:22:16.440 | for the consummatory phase,

00:22:17.340 | the actual putting it in your mouth

00:22:18.360 | and licking, chewing, swallowing, and all of that.

00:22:20.420 | Within the hypothalamus, there's a population

00:22:22.140 | of neurons called AGRP neurons.

00:22:24.520 | So it's just an acronym, A-G-R-P,

00:22:26.600 | and it stands for agouti-related peptide,

00:22:28.760 | but it doesn't really matter.

00:22:30.760 | They're absolutely critical for that appetitive phase,

00:22:32.920 | for the searching for food,

00:22:34.360 | for the desire to find food

00:22:36.040 | and consume it when you're hungry.

00:22:37.740 | - Sorry, just to touch on the AGRP neurons

00:22:41.960 | and this appetitive phase,

00:22:43.880 | are they known to connect to areas of the brain and body

00:22:46.800 | that stimulate the desire to move?

00:22:48.800 | Because I think about when I get hungry,

00:22:50.760 | if I'm at my desk or something,

00:22:53.340 | I need to get up and find food.

00:22:55.420 | I need to walk to lunch or go to the refrigerator.

00:22:57.500 | Are they somehow linked to the circuits

00:22:59.160 | that promote locomotion?

00:23:01.760 | - Well, they have to promote those things,

00:23:04.300 | but they're not directly linked to any of those circuits.

00:23:06.460 | They're linked directly to other forebrain circuits

00:23:08.980 | involved in motivation.

00:23:10.020 | So the way we think about what these kinds of neurons,

00:23:14.080 | like AGRP neurons, are doing,

00:23:15.620 | they're not directly talking to the motor circuits

00:23:17.720 | to tell you to move your legs or arms

00:23:19.300 | to pick up the sandwich or whatever.

00:23:21.020 | They're rather creating this general problem

00:23:23.500 | that the animal has to solve,

00:23:24.660 | which is that I'm hungry, I need to get food.

00:23:27.980 | It would be really great if I could have a sandwich.

00:23:29.940 | And then the animal uses all of its mental capacities

00:23:32.740 | to solve that problem.

00:23:33.760 | So they're just there to set the goal,

00:23:35.260 | not so much to direct the solution.

00:23:37.020 | But these AGRP neurons,

00:23:39.740 | there are a few thousand neurons

00:23:41.260 | at the base of the hypothalamus.

00:23:42.500 | So basically the most ventral,

00:23:44.500 | the most bottom part of the forebrain.

00:23:46.740 | So tiny population of cells,

00:23:49.580 | but outsized importance for the control of feeding behavior.

00:23:52.540 | So if you stimulate these cells in a mouse or a rat

00:23:55.300 | that's not hungry,

00:23:56.700 | the animal will voraciously eat like it's starving.

00:23:59.200 | If you silence these cells, animals will starve to death.

00:24:03.140 | So you can basically give them food.

00:24:04.400 | They just won't eat it voluntarily

00:24:05.540 | until basically you have to euthanize them

00:24:07.360 | because they've lost so much weight.

00:24:09.480 | And the activity of these AGRP neurons

00:24:14.380 | is thought to track the body's need for energy.

00:24:18.220 | One reason that's thought

00:24:20.180 | is that they express these receptors for leptin,

00:24:24.220 | this hormone that I was just talking about

00:24:25.620 | that comes from fat

00:24:26.740 | and signals the level of body fat reserves.

00:24:29.160 | And leptin inhibits AGRP neurons.

00:24:31.340 | So as you might expect, if you have lots of body fat,

00:24:33.980 | then a neuron that expresses,

00:24:37.180 | that controls hunger should be less active

00:24:39.000 | than if you have very little body fat.

00:24:40.500 | So that's one mechanism by which leptin controls hunger.

00:24:45.100 | We in my lab have investigated

00:24:46.660 | the role of these AGRP neurons

00:24:48.380 | from a slightly different perspective,

00:24:51.820 | which is, and this relates to your question

00:24:54.060 | about what happens when we approach food,

00:24:56.620 | when we start a meal.

00:24:58.420 | And to ask, what are their activity patterns?

00:25:00.940 | What is the natural sort of firing

00:25:02.640 | of this population of neurons when an animal eats a meal?

00:25:05.260 | It's a very basic question.

00:25:06.900 | Something I think we've wanted to know for a long time

00:25:10.020 | was not really addressable until about 10 years ago

00:25:12.300 | because the technology didn't exist

00:25:13.980 | because these are such a tiny population of cells,

00:25:15.820 | so deep in the brain.

00:25:16.940 | So one of the very first experiments we did in my lab

00:25:20.540 | was to investigate that, to ask for the first time

00:25:22.340 | what happens to these AGRP neurons when an animal eats.

00:25:24.380 | And so one of my first graduate students, Yiming Chen,

00:25:27.820 | he used a technology called fiber photometry,

00:25:31.240 | which allows us to put a fiber optic into the mouse's brain.

00:25:33.940 | So then we could record fluorescence

00:25:35.820 | from these AGRP neurons,

00:25:38.000 | which we could use as a readout of their activity.

00:25:40.100 | It's basically using a calcium sensor.

00:25:41.620 | So calcium is a surrogate for neural activity.

00:25:44.740 | And one of the very first experiments he did,

00:25:46.980 | he said, let's make the animal hungry.

00:25:49.300 | These AGRP neurons will be very active

00:25:50.820 | 'cause the animal's hungry.

00:25:51.640 | And then let's give it some food

00:25:52.480 | and see what happens during a meal.

00:25:54.380 | And our expectation was that these AGRP neurons

00:25:56.940 | would gradually decline in activity as the animal eats

00:25:59.420 | and levels of hormones in the blood start changing,

00:26:02.720 | feeding back to inhibit these neurons.

00:26:04.680 | What we found was really surprising.

00:26:07.060 | I remember that when he made this discovery,

00:26:08.900 | basically him running into my office and saying,

00:26:10.340 | "Zach, I gave the mouse a piece of food,

00:26:12.180 | "but the weirdest thing happened.

00:26:13.520 | "The neurons shut off almost immediately."

00:26:16.220 | And I said, "Yiming, you've made a mistake.

00:26:17.320 | "It's okay.

00:26:18.160 | "You're just starting off in graduate school.

00:26:19.340 | "This happens.

00:26:20.180 | "Go back and repeat the experiment

00:26:21.320 | "and then we'll discuss it."

00:26:22.660 | But he did several times.

00:26:23.500 | He said, "You know, Zach,

00:26:24.320 | "every single time I do this happens,

00:26:25.160 | "I give a hungry mouse food and the AGRP neurons,

00:26:27.020 | "within just a few seconds,

00:26:29.020 | "their activity has greatly diminished

00:26:32.000 | "back to the level it would be in a fed mouse,

00:26:33.640 | "even before they take the first bite of food."

00:26:36.380 | And so Yiming then went to do a series of experiments,

00:26:39.020 | tried to understand what was going on.

00:26:40.500 | And what he basically showed by changing the kind of food

00:26:43.220 | he gave them or the accessibility of the food

00:26:45.220 | or how hungry the mouse was

00:26:46.420 | and measuring the response of these AGRP neurons

00:26:49.420 | was that what the neurons were doing was predicting.

00:26:53.360 | The mouse looks at the food,

00:26:55.060 | it looks at how palatable it is,

00:26:56.420 | imagines how hungry the mouse is, how accessible it is.

00:26:59.180 | And then within a few seconds,

00:27:00.360 | these neurons predict how much food the mouse is going to eat

00:27:03.220 | in the forthcoming meal.

00:27:04.780 | And so essentially these neurons know

00:27:05.780 | how much the mouse is going to eat

00:27:06.860 | before the mouse even takes the first bite.

00:27:08.900 | And you can show this by a very simple analysis

00:27:12.260 | in which you give the mouse different foods

00:27:14.140 | and you look at how much these AGRP neurons drop

00:27:16.660 | when the mouse sees and smells the food.

00:27:18.420 | And then you plot that against,

00:27:20.260 | this drop happens in three seconds, four seconds,

00:27:22.060 | something like that.

00:27:23.020 | Then you look at how much does the mouse go on to eat

00:27:26.060 | in the next 30 minutes.

00:27:27.020 | You can just draw a straight line.

00:27:28.200 | So this was one of the first results from my lab

00:27:29.780 | and it was really surprising to all of us,

00:27:31.100 | and I think everyone.

00:27:32.560 | But it illustrated a theme

00:27:33.900 | that we've now seen again and again,

00:27:35.400 | which is that these circuits that control internal state,

00:27:37.620 | control things like hunger and thirst,

00:27:39.940 | what they're constantly doing is predicting the future.

00:27:42.780 | They can sense these signals from the body

00:27:44.820 | that tell you about what's happened,

00:27:46.020 | but those signals are slow.

00:27:47.220 | And you don't want to wait 20 minutes

00:27:49.980 | from the food that you ingested to reach your stomach

00:27:52.060 | and then slowly start entering your intestine

00:27:53.740 | to figure out what was the nutrient content of the meal.

00:27:56.460 | You want to try to figure that out as soon as you can, right?

00:28:00.260 | And so the animals learn presumably through just experience

00:28:03.020 | that, okay, something that smells like this

00:28:04.380 | and looks like this, it has about this many calories

00:28:06.140 | and I know I'm this hungry,

00:28:06.980 | I'm gonna eat about this much.

00:28:08.260 | And then that information is all transmitted

00:28:10.260 | to these circuits to start the process of satiation

00:28:13.540 | before the meal begins.

00:28:15.300 | - Is it satiation or it's ceasing of foraging

00:28:19.300 | so that the animal, or if I translate to a person,

00:28:23.320 | decides, okay, now I'm going to consume this sandwich,

00:28:25.820 | this package of food.

00:28:27.020 | - That's a great question.

00:28:28.060 | So we don't fully know the answer.

00:28:30.580 | So one interpretation of the data I just showed you

00:28:32.320 | is exactly what you said,

00:28:33.720 | is that what these neurons do

00:28:34.760 | is they control foraging alone.

00:28:36.220 | They don't control eating.

00:28:37.220 | And so this is perfect.

00:28:38.100 | You see the food, you know that it's got enough calories,

00:28:40.900 | the neurons shut off and then you stay there and eat it.

00:28:42.980 | You transition from this appetitive

00:28:44.100 | to this consummatory phase.

00:28:45.420 | But that doesn't seem to be the whole explanation

00:28:48.540 | because if you artificially stimulate these neurons,

00:28:51.420 | so prevent that drop from ever happening,

00:28:53.380 | just stimulate them continually,

00:28:55.000 | the mouse will just sit there and eat.

00:28:56.380 | So you can't fully separate,

00:28:58.100 | although we'd like to make this distinction

00:28:59.400 | between appetitive and consummatory,

00:29:00.740 | and we know that in different parts of the brain

00:29:03.940 | there's more important for one versus the other,

00:29:05.580 | the reality is that the entire behavior is linked

00:29:07.700 | and you can't fully separate them.

00:29:09.780 | So there's a number of ideas about what this means.

00:29:12.280 | So one idea that I just mentioned

00:29:13.940 | is that starting the process of satiety

00:29:16.400 | before the meal begins.

00:29:17.660 | Another idea which you mentioned,

00:29:19.700 | which could be part of the answer,

00:29:22.260 | is that it is reducing this appetitive drive

00:29:24.440 | and allowing the transition to consummatory behavior.

00:29:27.900 | Another idea is that,

00:29:29.740 | and I call these ideas

00:29:30.620 | because we don't really fully know the answer yet

00:29:32.020 | for exactly what the purpose is.

00:29:33.460 | In biology it's always hard to answer why something happens.

00:29:35.520 | You can figure out what does happens,

00:29:36.580 | but then you can,

00:29:37.460 | the reason why it evolved that way is challenging.

00:29:39.860 | Another idea is it's involved in these,

00:29:43.180 | what we call cephalic phase responses

00:29:45.460 | that are necessary to prepare you for a meal, right?

00:29:47.820 | So the famous example, this is Pavlov, right,

00:29:50.020 | basically trains the dog to associate the ringing of the bell

00:29:53.380 | with the presentation of food,

00:29:56.540 | and then eventually the ringing of the bell alone

00:29:58.380 | causes the dog to salivate in the absence of any food.

00:30:01.340 | And salivation is one example of a cephalic phase response.

00:30:04.980 | The purpose of that is to have enzymes in your mouth

00:30:07.540 | that basically are gonna digest the food

00:30:08.860 | and get them there right before you need them.

00:30:10.740 | But there's also some other things,

00:30:11.820 | like basically the secretion of insulin occurs

00:30:13.940 | in response to food cues,

00:30:15.820 | changes in gastric acid, gut motility,

00:30:18.120 | all these things are getting ready for the meal to happen.

00:30:20.460 | And so another idea is it could be part of that,

00:30:23.940 | but probably it's doing all of these things.

00:30:26.260 | - As many of you know,

00:30:27.140 | I've been taking AG1 for more than 10 years now.

00:30:30.020 | So I'm delighted that they're sponsoring this podcast.

00:30:32.500 | To be clear, I don't take AG1

00:30:34.220 | because they're a sponsor,

00:30:35.260 | rather they are a sponsor because I take AG1.

00:30:38.380 | In fact, I take AG1 once and often twice every single day,

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00:30:48.060 | about what proper nutrition is.

00:30:50.260 | But here's what there seems to be a general consensus on.

00:30:53.220 | Whether you're an omnivore, a carnivore,

00:30:55.560 | a vegetarian or a vegan,

00:30:57.260 | I think it's generally agreed

00:30:58.460 | that you should get most of your food

00:30:59.980 | from unprocessed or minimally processed sources,

00:31:03.000 | which allows you to eat enough, but not overeat,

00:31:05.500 | get plenty of vitamins and minerals,

00:31:07.080 | probiotics and micronutrients

00:31:09.100 | that we all need for physical and mental health.

00:31:11.500 | Now, I personally am an omnivore,

00:31:13.300 | and I strive to get most of my food

00:31:14.860 | from unprocessed or minimally processed sources.

00:31:17.660 | But the reason I still take AG1 once

00:31:19.620 | and often twice every day

00:31:21.340 | is that it ensures I get all of those vitamins,

00:31:23.820 | minerals, probiotics, et cetera,

00:31:25.980 | but it also has adaptogens to help me cope with stress.

00:31:28.820 | It's basically a nutritional insurance policy

00:31:31.100 | meant to augment, not replace quality food.

00:31:33.800 | So by drinking a serving of AG1 in the morning,

00:31:36.000 | and again in the afternoon or evening,

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00:32:15.440 | It's so interesting.

00:32:16.400 | I have a number of questions,

00:32:17.540 | but I think the one that I'll put at the top of the list

00:32:20.360 | is the other night we were out to dinner in New York

00:32:22.840 | and I was very hungry.

00:32:25.920 | I hadn't eaten much that day

00:32:27.460 | and I was looking forward to a nice steak.

00:32:30.400 | They brought out bread, French bread.

00:32:32.840 | It was a French restaurant.

00:32:33.720 | I took one bite.

00:32:34.560 | I realized it was absolutely delicious French bread.

00:32:36.540 | The butter was fantastic.

00:32:38.400 | And so I had some bread and butter, which I love.

00:32:41.600 | Then they brought more.

00:32:42.680 | And then they started bringing out,

00:32:44.040 | I don't know who ordered them 'cause I didn't, appetizers.

00:32:46.520 | And I realized that this was going to be

00:32:49.140 | a much more extensive calorically dense meal.

00:32:53.400 | And suddenly my appetite for the appetizers,

00:32:56.280 | it sort of went down

00:32:57.120 | because I knew there was more food coming.

00:32:59.900 | Had I not known that there was more food coming,

00:33:02.360 | I think I would have consumed more of the appetizers,

00:33:04.840 | which also looked great.

00:33:06.160 | So clearly there's something going on

00:33:07.460 | with these AGRP neurons at the moment.

00:33:09.280 | You're sort of integrating based on new information.

00:33:12.600 | - Exactly.

00:33:13.440 | - On the other end of the spectrum,

00:33:16.720 | I did a solo episode about eating disorders

00:33:19.160 | and anorexia nervosa in particular.

00:33:20.920 | And one of the things that I learned from experts

00:33:22.840 | in that field, the psychiatrists who work on this

00:33:26.240 | and the scientists who work on this,

00:33:27.920 | is that people with anorexia are unbelievably tuned

00:33:32.920 | to the caloric content of food.

00:33:38.480 | That their visual system and presumably other systems

00:33:42.400 | have become like almost hyper-accurate calculators

00:33:47.400 | of the amount of calories in food.

00:33:49.340 | They've devoted a lot of cognition to it.

00:33:51.260 | It sometimes can border on

00:33:53.140 | or be placed within the obsessive realm,

00:33:55.420 | but that they see food and they can tell you

00:33:58.560 | a tremendous amount about the caloric amounts

00:34:00.920 | with these foods, even food combinations,

00:34:03.400 | with a very small margin of error.

00:34:06.920 | And that drives in that condition, obviously food avoidance.

00:34:14.360 | So I have to assume that these AGRP neurons

00:34:16.880 | are involved in this kind of thing.

00:34:18.200 | One represents a regulation,

00:34:19.800 | in the case of the example I gave,

00:34:21.080 | and in the other case, let's just call it what it is

00:34:24.000 | because anorexia nervosa is the most deadly

00:34:26.240 | of the psychiatric conditions, sadly,

00:34:28.260 | a pathologic dysregulation, a maladaptive dysregulation.

00:34:32.300 | So what is known about these AGRP neurons in humans?

00:34:35.780 | Meaning, do they exist in humans?

00:34:38.460 | Presumably they express the leptin receptor.

00:34:42.780 | Sounds like they are able to integrate information,

00:34:46.620 | both cognitive, based on immediate experience,

00:34:50.200 | visual, olfactory, but also a lot of prior experience.

00:34:53.820 | A hamburger patty,

00:34:55.940 | I can't tell you how many calories it has.

00:34:57.500 | All I know is that it's mostly protein and some fat.

00:35:00.740 | What are these neurons doing?

00:35:05.140 | What do they have access to?

00:35:06.260 | They sound like, anytime I hear about hypothalamus,

00:35:09.060 | I think very basic drives,

00:35:10.160 | but you're talking about a pretty sophisticated analysis

00:35:12.600 | of a real-time event that is driving

00:35:17.460 | fairly nuanced behavioral decisions and updating that,

00:35:20.760 | which is a big deal.

00:35:22.420 | We're both neuroscientists,

00:35:24.340 | but for everyone listening and watching,

00:35:26.580 | this is a big deal.

00:35:27.440 | This is as nuanced as deciding

00:35:29.360 | whether or not somebody is friend or foe

00:35:30.880 | or deciding whether or not you like a movie or you don't.

00:35:34.160 | I mean, this is some pretty sophisticated processing.

00:35:38.380 | This isn't eat, don't eat, or eat less, eat more.

00:35:41.280 | These aren't switches.

00:35:42.480 | - Exactly.

00:35:43.320 | - These are dials.

00:35:44.240 | - Exactly.

00:35:45.320 | Yeah, so there's a lot there.

00:35:46.480 | I'll try to unpack that.

00:35:48.360 | So the first thing I would say is they are present in humans

00:35:50.620 | and humans have AGRP neurons.

00:35:54.680 | Human AGRP neurons express the leptin receptor

00:35:57.240 | and we think the functions are very similar.

00:35:59.440 | So one of the nice things actually

00:36:01.480 | about studying these kinds of things,

00:36:03.340 | like basic mechanisms of hunger, thirst,

00:36:05.960 | because these things are so important for survival,

00:36:07.920 | they've been under really strong selection, right?

00:36:10.600 | And so many of the components of these systems

00:36:13.040 | are genetically hardwired,

00:36:14.200 | meaning these are cell types that have a single purpose,

00:36:16.760 | in this case, to control hunger.

00:36:18.200 | They're labeled by specific genes

00:36:19.880 | and those are conserved through evolution.

00:36:21.980 | We also know that this pathway, this AGRP neuron pathway,

00:36:27.040 | is important in humans due to human genetics.

00:36:29.960 | So just to add a little bit more information here,

00:36:32.560 | there's a companion set of neurons called POMC neurons

00:36:35.860 | that promotes satiety.

00:36:36.960 | So there's sort of the yin and yang of hunger.

00:36:38.920 | AGRP neurons promote hunger.

00:36:40.400 | POMC neurons promote satiety.

00:36:43.720 | They're intermingled in the same part of the hypothalamus.

00:36:46.800 | They're axons that project

00:36:49.560 | to the exact same downstream brain regions.

00:36:52.640 | Then it's thought that these two neurons

00:36:53.840 | compete with each other to control appetite.

00:36:57.160 | And that competition occurs through neuropeptides

00:36:59.760 | that they release, one of which is an agonist

00:37:02.640 | for a downstream receptor

00:37:03.560 | and the other one of which is an antagonist.

00:37:05.660 | We know from human genetics that among severely obese people

00:37:12.400 | mutations in this pathway, AGRP, POMC neurons,

00:37:15.280 | and their direct downstream targets are quite common.

00:37:18.160 | - Really?

00:37:19.000 | So is it fair to say that some amount of obesity is genetic

00:37:24.000 | in nature at the level of neuronal firing or circuitry?

00:37:29.540 | - I think a lot of body weight regulation is genetic.

00:37:31.640 | It's highly heritable.

00:37:32.760 | There's a question of how much of it is due to single genes.

00:37:36.600 | And the number of people quote,

00:37:38.680 | and this is among people who are severely obese.

00:37:40.520 | So not just people who you've seen someone

00:37:42.320 | who's overweight, but people have sort of syndromes

00:37:44.760 | where they're very obese from a very young age.

00:37:47.200 | Among those people, something on the order of 10%

00:37:49.920 | have mutations in this pathway.

00:37:51.940 | And it can either be this hormone POMC

00:37:56.040 | or an enzyme within those cells that processes POMC

00:38:00.840 | into the right form, or in the downs,

00:38:03.520 | and this is the most common mutation

00:38:04.920 | in the downstream receptor for POMC,

00:38:06.800 | it's called the melanocortin-4 receptor.

00:38:10.240 | And so among the severely obese,

00:38:13.320 | people who have sort of genetically inherited

00:38:14.720 | severe obesity from childhood,

00:38:16.900 | something on the order of 10% have mutations

00:38:18.700 | in this pathway.

00:38:19.540 | So it's very clear that this pathway is involved

00:38:22.800 | in body weight regulation in humans.

00:38:24.720 | Most obesity, although there is a very strong

00:38:26.660 | genetic component, is not associated

00:38:30.440 | with single gene mutations like this,

00:38:32.040 | it's associated with effects of many mutations.

00:38:35.020 | But we know that even in that sort of polygenic obesity

00:38:37.880 | that has many different genetic causes,

00:38:40.160 | that the brain is important.

00:38:44.200 | And one of the reasons we know that,

00:38:45.400 | so if you look at the genes

00:38:46.320 | through genetic association studies

00:38:48.000 | that have been associated with body weight,

00:38:49.320 | and there's been lots of genetic association studies

00:38:50.920 | trying to find mutations that are associated

00:38:52.720 | with whether you're lean or obese.

00:38:54.480 | Something on the order of 1,000 genes

00:38:57.400 | have been linked to body weight regulation.

00:39:00.200 | And the vast majority of those are expressed in the brain.

00:39:02.680 | They're highly enriched for brain processes,

00:39:04.360 | which makes sense because body weight

00:39:06.160 | is controlled by food intake, right?

00:39:07.320 | And the brain controls behavior,

00:39:09.160 | and also the brain controls energy expenditure.

00:39:10.640 | So maybe it's not so surprising,

00:39:12.720 | but it's clear that mutations in genes in the brain

00:39:17.720 | are important for body weight,

00:39:18.760 | which is consistent with the results of twin studies.

00:39:21.080 | So if you look at monozygotic versus dizygotic twins,

00:39:24.240 | the estimates for the heritability of body weight

00:39:26.480 | is something on the order of 80%.

00:39:28.400 | - We should explain monozygotic, dizygotic,

00:39:30.600 | which I've talked about before on the podcast,

00:39:32.000 | just to brush people off.

00:39:33.400 | - Just identical versus fraternal twins, basically.

00:39:35.720 | And so, and by comparing their,

00:39:39.040 | basically their body weight when they become adults,

00:39:42.720 | you can get a sense for how much of this

00:39:43.880 | is genetic versus environmental.

00:39:46.000 | And something on the order of 80% is thought to,

00:39:50.280 | the variation between individuals

00:39:51.720 | is thought to have a genetic component.

00:39:54.160 | - Wow.

00:39:55.440 | I don't think most people appreciate that.

00:39:57.360 | - Yeah, it's- - And a lot of the debate

00:39:58.400 | we hear nowadays is because there are things

00:40:01.200 | that people can do to lose body fat,

00:40:03.960 | exercise, eat differently, et cetera,

00:40:06.400 | maybe embrace pharmacology if that's appropriate.

00:40:10.480 | There seems to be this, to me, silly debate

00:40:14.860 | as to whether or not people should be eating better

00:40:17.680 | and exercising or assuming that all of the obesity

00:40:21.680 | they might have arises through genetic causes

00:40:26.680 | and therefore take a prescription drug.

00:40:28.720 | I mean, why wouldn't it be a combination of things?

00:40:31.480 | Like, to me, it just seems like why wouldn't people embrace

00:40:35.600 | some or all of the tools that they could afford

00:40:37.240 | and that are safe for them?

00:40:38.200 | So, I just want to get that out there

00:40:39.320 | because the moment this comes up,

00:40:40.440 | people start thinking, "Oh, well,

00:40:42.040 | "the moment we assign a genetic source to something,

00:40:44.560 | "we're removing personal responsibility."

00:40:47.640 | But of course, there are people,

00:40:49.320 | I know people who have struggled with their weight

00:40:51.280 | their entire lives, for whom some of these new

00:40:54.120 | pharmaceuticals like Ozempic have provided them

00:40:56.880 | the opportunity to finally be able to lose weight

00:41:00.080 | and feel better and exercise safely, for instance.

00:41:04.240 | - I completely agree with that.

00:41:05.880 | I think there is a misconception out there about this,

00:41:09.000 | about what it means for something

00:41:10.040 | to be genetically heritable.

00:41:11.040 | And I think this gets to the root of why

00:41:12.360 | so many people find this sort of hard to believe

00:41:14.320 | that there's such a strong genetic component to body weight.

00:41:16.640 | And that's the idea that if you look at people,

00:41:19.320 | say, 75 years ago, they were much leaner, right?

00:41:22.280 | And you look at people today and there's been this,

00:41:24.240 | starting sometime around the 1970s,

00:41:26.080 | there was this explosion in body weight

00:41:27.440 | and increase in obesity.

00:41:28.640 | - Is that when, that's when it started, mid '70s?

00:41:30.440 | - Sort of the 1970s is when a lot of that started happening.

00:41:32.880 | - Snacking.

00:41:33.720 | - So there's lots of explanations.

00:41:35.360 | - Seed oil, snacking.

00:41:36.200 | By the way, I don't think that's the reason, folks.

00:41:38.520 | I think there are a lot of reasons,

00:41:39.780 | but the theories that abound right now on social media

00:41:43.600 | are, I have a list of theories

00:41:45.920 | as to why the obesity is increasing.

00:41:47.840 | You get everything from seed oils to snacking

00:41:50.000 | to smartphones to conspiracies to, it's wild.

00:41:55.000 | It's wild.

00:41:56.440 | The range of hypotheses is wild.

00:41:59.160 | - Yeah, I mean, and the challenges,

00:42:00.320 | I mean, some of them could be true,

00:42:01.280 | but it's just very hard to test those things experimentally

00:42:03.520 | 'cause they're happening in the whole population, right?

00:42:05.640 | But so I think the thing that people find hard

00:42:07.100 | to wrap their heads around,

00:42:07.940 | because it is a little bit of a confusing idea,

00:42:09.520 | is that how can it be that in, say, 50 or 75 years,

00:42:13.600 | there's been this explosion in obesity,

00:42:15.440 | which is, the environment has changed,

00:42:17.400 | but human genetics has not changed in that amount of time.

00:42:19.280 | It's just not fast enough for people to evolve.

00:42:20.760 | So it can't be due to mutations in humans.

00:42:22.600 | - What about devolve?

00:42:24.400 | My understanding is that within a species,

00:42:27.200 | evolving new traits is very slow.

00:42:29.160 | - Yes.

00:42:30.000 | - But mutations arise, like the OB mutation,

00:42:33.160 | and then you can get very fat versions

00:42:35.000 | of an animal very quickly, right?

00:42:37.920 | All you need is, if it's a recessive allele,

00:42:42.680 | you need two copies, and the next thing you know,

00:42:44.280 | you've got a mouse that's four times larger

00:42:45.900 | than a typical mouse,

00:42:47.080 | and it's all explained by increased body weight.

00:42:49.080 | So that can happen very quickly within a species.

00:42:52.560 | What's rare to find is an entire new branch of a species

00:42:57.080 | that has a very, a new adaptive function.

00:43:00.800 | That seems more rare.

00:43:02.360 | - So that's true.

00:43:03.200 | So definitely, there's some things

00:43:04.440 | that take longer to evolve than others,

00:43:06.600 | but with humans, we're talking about just two generations.

00:43:08.600 | There just isn't enough time for any evolution

00:43:10.080 | of any significance to happen.

00:43:11.560 | - Baby boomers, right?

00:43:14.000 | Generate X. - Generate X.

00:43:14.840 | - That's new, right?

00:43:15.660 | And then whatever is YZ millennial.

00:43:17.400 | - Exactly. - I lose track after that.

00:43:18.760 | - Exactly.

00:43:19.600 | So I think the thing that people find hard

00:43:21.080 | to wrap their heads around is how can it be

00:43:22.320 | that that increase in body weight

00:43:24.560 | is clearly environmental, right?

00:43:25.920 | 'Cause that's all that's changed is the environment.

00:43:27.800 | Nothing has changed genetically.

00:43:29.160 | Yet it's also true what I said,

00:43:30.480 | that body weight is extremely heritable.

00:43:32.320 | It's one of the most heritable features,

00:43:34.440 | and something on the order of 80%.

00:43:36.280 | One of the only things we know about

00:43:37.200 | that's actually more heritable than body weight is height.

00:43:39.800 | Most diseases are not as heritable as body weight.

00:43:42.560 | How can you explain that?

00:43:43.400 | And the idea is this.

00:43:45.320 | There's a distribution of body weights among people.

00:43:47.720 | So in any given society at any point in time,

00:43:50.200 | some people are gonna be leaner,

00:43:51.560 | some people are gonna be more obese.

00:43:53.720 | That distribution, where you lie on that distribution

00:43:56.200 | is determined primarily by genetics.

00:43:58.280 | So you may be the person who has the thrifty genes,

00:44:00.600 | so that basically cause you to save energy,

00:44:02.280 | and so you would be more on the obese side.

00:44:04.160 | Or you may be a person who has different genes

00:44:06.640 | that cause you to be a little bit less hungry,

00:44:08.080 | so you would be on the leaner side.

00:44:10.640 | What environment does is then it shifts

00:44:12.720 | that whole distribution, so that basically the mean shifts

00:44:15.560 | so that everyone becomes, or most people become heavier.

00:44:19.160 | And so sort of a phrase that people sometimes use

00:44:22.720 | is that genetics loads the gun

00:44:26.320 | and environment pulls the trigger.

00:44:27.960 | So basically genetics sets your propensity,

00:44:30.880 | and then environment can basically unmask that.

00:44:34.400 | And so as we've had this change in environment

00:44:37.300 | where there's all of this,

00:44:38.340 | and we don't know exactly what the things are

00:44:39.680 | that have changed that are important,

00:44:40.840 | but there's all this ultra-processed food,

00:44:42.400 | highly palatable food, just various other things

00:44:45.760 | that you mentioned, seed oils,

00:44:46.780 | who knows if that's important.

00:44:49.160 | Certain people had these latent mutations

00:44:52.520 | that made them, say, very sensitive to palatable food.

00:44:55.320 | And in an earlier time, they may have been lean,

00:44:57.840 | but now because they have that latent capacity

00:44:59.700 | to be sensitive to ultra-processed food,

00:45:02.160 | they now gain tons of weight

00:45:03.120 | in the environment that we're in.

00:45:04.720 | It's still because of genetics,

00:45:06.040 | but it also requires the environmental component.

00:45:08.080 | I mean, just take a step back, right?

00:45:09.480 | You can make anyone lean by just putting them in prison

00:45:13.720 | and just only feeding them 1,500 calories.

00:45:15.240 | I mean, we've done those kinds of experiments.

00:45:16.520 | There's this famous experiment,

00:45:17.560 | the Minnesota starvation experiment, right?

00:45:19.600 | They basically, they didn't put people in prison,

00:45:22.000 | but this is in World War II.

00:45:22.840 | They took a bunch of healthy volunteers,

00:45:25.160 | fed them 1,600 calories a day,

00:45:26.560 | and just asked what would happen

00:45:28.000 | if you basically semi-starved people.

00:45:29.400 | And unsurprisingly, they lose an incredible amount of weight.

00:45:31.280 | All they think about is food.

00:45:32.320 | They basically, their body temperature goes down,

00:45:33.760 | their heart rate goes down.

00:45:34.880 | They just become obsessed with food.

00:45:36.440 | And you could always do that for anyone, right?

00:45:38.160 | But in a given environment where you're not

00:45:41.720 | in that kind of situation,

00:45:43.280 | then your propensity to gain weight

00:45:44.600 | will be determined by genetics.

00:45:46.160 | So that's the idea.

00:45:47.160 | - I very much appreciate that description.

00:45:50.220 | And I know a great number of other people will as well,

00:45:52.880 | because the explanation for the increase in obesity

00:45:57.200 | has not been described with that level of accuracy

00:46:00.640 | and detail with respect to the interactions

00:46:03.360 | between genetics and the environment.

00:46:05.200 | Is it fair to say that what's changed in our environment

00:46:09.120 | is the free availability of food?

00:46:11.520 | You know, I was walking through an airport yesterday

00:46:13.320 | and every 20 meters or so,

00:46:15.680 | there's a vending machine or a restaurant.

00:46:18.240 | The cost of calories is fairly low, right?

00:46:22.720 | Getting high quality nutritious food

00:46:24.640 | that tastes great is expensive, I would argue.

00:46:28.760 | But getting calories is fairly inexpensive.

00:46:32.720 | - Yeah, I think that's a plausible hypothesis.

00:46:36.280 | It's one of several plausible hypotheses

00:46:38.080 | and it would be surprising to me if it didn't contribute.

00:46:41.040 | But the reality is these population level questions

00:46:42.960 | are just so hard to actually know

00:46:44.240 | because you can't do an experiment, right?

00:46:45.880 | We can't create a parallel society

00:46:47.840 | where we manipulate one of these variables

00:46:49.240 | and see if the people become obese.

00:46:51.120 | So I think probably the availability of food,

00:46:53.880 | the free availability, the low cost is one part of it.

00:46:56.920 | Another part of it is probably,

00:46:59.000 | although again, it's not proven,

00:47:01.680 | is that these ultra processed foods

00:47:03.400 | have a number of features

00:47:05.080 | that make people prone to gain weight.

00:47:08.400 | And there's really beautiful work,

00:47:09.480 | I don't know if you know this,

00:47:10.320 | from Kevin Hall at the NIH who's investigated this.

00:47:12.480 | He's really, in my opinion, the best person

00:47:14.240 | doing this kind of human obesity research today.

00:47:16.680 | And he does these experiments

00:47:18.040 | where he takes people into the NIH, into the hospital,

00:47:20.880 | hospitalizes them for several weeks

00:47:22.240 | so he can exactly control what they eat.

00:47:24.040 | And he did this beautiful experiment

00:47:25.600 | where basically he had chefs prepare two kinds of food,

00:47:28.680 | one ultra processed and the other not ultra processed,

00:47:32.200 | sort of more whole foods, more healthier foods,

00:47:34.840 | but had them take a lot of care

00:47:37.080 | so that when they gave the foods to independent raters,

00:47:39.640 | to people to test,

00:47:40.480 | they would say this is about equally palatable.

00:47:41.720 | So I like this ultra processed dish

00:47:43.560 | as much as this non-ultra processed dish.

00:47:46.800 | - What's an example of an ultra processed dish?

00:47:48.440 | Like a out of package macaroni and cheese?

00:47:50.600 | - Exactly, that kind of stuff.

00:47:51.440 | - With bacon kind of thing?

00:47:52.580 | - Exactly.

00:47:53.420 | - Versus some pasta sitting next to a vegetable

00:47:55.960 | and a nice piece of salmon or something?

00:47:58.760 | - Exactly, exactly.

00:48:00.240 | And took people into the hospital,

00:48:05.200 | basically allowed them to eat

00:48:06.720 | just as much as they would like,

00:48:08.360 | first of the ultra processed meals.

00:48:10.640 | So they had the selection of ultra processed meals

00:48:12.760 | for a couple of weeks

00:48:13.840 | and then switch them to the non-ultra processed meals.

00:48:16.880 | And then also did it in the reverse order.

00:48:18.040 | So the other half of the people,

00:48:18.880 | they got the regular food first,

00:48:19.880 | then they got the ultra processed food.

00:48:21.640 | And what he found is that even though

00:48:24.280 | people rated the foods as equally palatable,

00:48:26.320 | they ate much more of the ultra processed food.

00:48:28.320 | And they actually gained weight

00:48:29.560 | during that two week period

00:48:30.640 | when they were being given the ultra processed foods.

00:48:32.600 | And then when you switch them, they lost weight.

00:48:34.660 | So the idea being that you can have two sets of food

00:48:37.720 | that you have equal preferences for,

00:48:40.560 | but something about the ultra processed food

00:48:42.240 | is making you eat more of it when you actually consume it.

00:48:44.640 | And there's a number of ideas about why that could be.

00:48:46.600 | So one idea is that these ultra processed foods

00:48:49.440 | have been optimized to have the right percentage of fat

00:48:52.680 | and sugar and protein to sort of promote more consumption

00:48:55.640 | once you start eating it.

00:48:56.600 | So that could be part of it.

00:48:58.000 | Another idea is that a big thing about whole foods

00:49:01.640 | is that they take more energy to digest

00:49:03.800 | and they have more volume.

00:49:04.640 | So one of the striking things from that study

00:49:06.560 | is if you just look at the pictures of the meals,

00:49:09.080 | they're the same number of calories,

00:49:10.280 | but there's so much more food seemingly

00:49:12.400 | on the non-processed food versus the ultra processed food.

00:49:14.680 | And that's just because whole foods are bigger

00:49:16.400 | because they're not so energy dense.

00:49:18.720 | So, and we know that for example,

00:49:20.520 | volume is a major signal in the short term

00:49:22.600 | for regulating food intake.

00:49:23.640 | So if you just eat more volume, that could be valuable.

00:49:27.040 | And there's lots of things like that.

00:49:28.240 | So I think that's another plausible hypothesis,

00:49:30.800 | but the truth is we don't really know.

00:49:32.760 | - I have a hypothesis

00:49:33.800 | and I don't wanna force you into speculation,

00:49:35.960 | but given that you've studied and discovered

00:49:39.760 | that the neurons and circuits involved in appetitive

00:49:43.520 | and consummatory behaviors can learn

00:49:46.760 | based on experience and expectation,

00:49:48.920 | I think it's fair game to at least ask your thoughts

00:49:51.680 | on this.

00:49:52.520 | So I've been paying a lot of attention to the landscape

00:49:55.240 | of what the general public think about,

00:49:58.380 | let's call them elimination diets,

00:50:00.800 | where people will just eat meat.

00:50:03.000 | - Yes.

00:50:03.840 | - Or will go into a vegan diet

00:50:06.760 | or do some time restricted feeding

00:50:09.080 | or do any number of different things

00:50:10.840 | that have been shown to promote weight loss,

00:50:14.280 | provided people obey the laws of thermodynamics

00:50:16.920 | and consume fewer calories than they burn.

00:50:20.440 | - Yeah.

00:50:21.280 | - Right, I do believe in calories in, calories out.

00:50:23.040 | And there are a number of different routes to get there

00:50:24.880 | and some are more painful, some are less painful,

00:50:27.820 | and it depends on the individual lifestyle exercise

00:50:30.320 | and on and on.

00:50:31.800 | But let's just suppose for a moment,

00:50:34.400 | based on Kevin's work on highly processed foods

00:50:38.720 | versus whole foods,

00:50:40.360 | that there's a learning that takes place when we eat.

00:50:43.960 | - Yes.

00:50:44.800 | - And that this learning takes place over time

00:50:46.400 | such that our brain and appetite

00:50:48.520 | start to link the variables of taste,

00:50:51.720 | macronutrients, proteins, fats, and carbohydrates,

00:50:55.880 | sort of knowledge about macronutrients.

00:50:57.600 | A piece of fish is mostly protein, has some fat.

00:51:00.280 | A bowl of rice is mostly carbohydrate, has some protein.

00:51:04.840 | - Yeah.

00:51:05.920 | - Put a pat of butter on it, has some fat also, right?

00:51:08.280 | It's sort of obvious.

00:51:10.000 | But taste, macronutrient content,

00:51:15.000 | calories, which we already know people with anorexia

00:51:19.280 | are exquisitely good at counting with their eyes.

00:51:23.960 | So it's possible they represent, again,

00:51:25.840 | a pathologic extreme of this.

00:51:27.500 | And micronutrient content, maybe even amino acid content,

00:51:33.380 | like how much leucine is there.

00:51:35.200 | Now, most people aren't thinking about

00:51:36.280 | how much leucine is in a meal,

00:51:38.080 | but we know that leucine is important

00:51:40.720 | for certain aspects of muscle metabolism.

00:51:42.840 | It's present in certain proteins and not others.

00:51:45.460 | You're going to find less of it in a vegetable,

00:51:47.800 | typically, than you would in a piece of chicken and so on.

00:51:51.500 | And that when people eat mostly non-processed

00:51:55.640 | or minimally processed foods and not in combination,

00:51:58.760 | so we're not talking about stewing all this together

00:52:00.880 | or blending all of it together,

00:52:02.260 | which sounds disgusting, right?

00:52:04.000 | Broccoli rice and a chicken breast

00:52:05.440 | blended together just sounds horrible,

00:52:06.800 | but eating them separately, if there's some olive oil

00:52:08.600 | and a little pat of butter involved,

00:52:09.720 | like that sounds pretty good.

00:52:11.520 | But a highly processed food in some ways

00:52:14.160 | is a blending together of macronutrients,

00:52:17.760 | micronutrients, if there are any,

00:52:19.700 | and other features of the food

00:52:23.140 | that neurons in the brain seem to pay attention to,

00:52:25.640 | and then giving it a unified taste, a Dorito, right?

00:52:29.280 | - Yes.

00:52:30.120 | - A candy bar that we attach to the product,

00:52:34.240 | we attach to the name of the processed food,

00:52:36.440 | to the packaging.

00:52:37.940 | But I could imagine, and here's the hypothesis,

00:52:40.360 | that that is quote unquote confusing to our neural circuits

00:52:44.500 | in a way that doesn't match up well

00:52:46.520 | with our thermodynamic requirements

00:52:49.740 | of how much we're burning versus how much we need to eat.

00:52:52.320 | Whereas when I eat a piece of steak and a vegetable,

00:52:57.240 | I actually want less carbohydrate afterwards.

00:52:59.600 | If I eat the carbohydrate first, for me, it's difficult

00:53:02.200 | 'cause I love the taste of carbohydrates,

00:53:03.600 | especially when they're combined with fat.

00:53:05.120 | But there seems to be an easier time regulating food intake

00:53:09.260 | when people step back and say,

00:53:10.840 | "I'm going to consume minimally processed whole foods."

00:53:14.480 | And I'm guessing it's not just because

00:53:17.400 | they're trying to be healthier,

00:53:18.440 | that might be what stimulates the shift,

00:53:21.080 | but that the brain starts to learn the relationship

00:53:23.820 | between food volume, smell, taste,

00:53:27.220 | what these things look like,

00:53:29.600 | and satiation at the level of,

00:53:31.340 | oh, that's enough amino acids because I had a piece of fish.

00:53:33.700 | So maybe I don't need to consume

00:53:34.960 | as much of some other things.

00:53:35.920 | Or the vegetables provide volume and fiber,

00:53:38.800 | and often vegetables can taste really delicious too.

00:53:41.400 | So that there's a linking of nutrients, calories, and taste

00:53:45.920 | in a way that's more appropriately matched

00:53:48.280 | to the energetic demands of the organism,

00:53:51.200 | in this case, us humans,

00:53:53.360 | that highly processed foods bypass.

00:53:56.600 | Okay, now I realize that was long-winded and forgive me,

00:54:00.120 | but my audience is used to that.

00:54:01.720 | Whenever I'm trying to table something for,

00:54:04.220 | no pun intended, for discussion that I would like to think

00:54:07.500 | can at least stimulate some additional thinking

00:54:09.640 | about a landscape, in this case,

00:54:12.060 | nutrition and feeding behavior,

00:54:14.020 | that for a lot of people is just really confusing.

00:54:16.500 | And here's why, and this is the last thing I'll say.

00:54:18.300 | I have several friends who have been very overweight

00:54:21.900 | their entire lives,

00:54:23.420 | for whom the following diet has worked exceptionally well.

00:54:27.000 | I'm not a diet coach, I'm not a nutritionist.

00:54:29.940 | I don't pretend to be one.

00:54:31.720 | I say, eat proteins like meat, fish, eggs,

00:54:34.760 | vegetables, and fruit,

00:54:37.020 | and do that for a couple of months,

00:54:40.040 | and then add back in starches

00:54:41.520 | as you see fit based on your food intake.

00:54:44.840 | And without fail, they all lose a ton of weight.

00:54:47.900 | They're very happy with that.

00:54:49.640 | They add back in a minimum of starches.

00:54:52.060 | They keep the weight off, and they're also exercising,

00:54:56.220 | but not more than they were before in most cases.

00:54:58.920 | And I don't think that it's meat, or fish,

00:55:01.180 | or vegetables per se.

00:55:02.620 | I think it's that they finally develop an appreciation

00:55:06.060 | for what different foods have

00:55:07.640 | in terms of what they actually need.

00:55:09.900 | And without fail, they all say,

00:55:11.600 | "Oh, you know, I went to this party,

00:55:13.620 | "and I had a piece of cake,

00:55:14.460 | "and it didn't taste good to me after three or four bites."

00:55:17.060 | So that's interesting too.

00:55:18.400 | So I just would like your thoughts on this.

00:55:19.860 | We're not defining any new diets.

00:55:21.300 | I don't sell any diets.

00:55:22.560 | I don't do any of that.

00:55:23.680 | But I find it amazing that when people start eating

00:55:26.400 | minimally processed whole foods,

00:55:28.740 | I have to assume that their brain changes

00:55:30.360 | as it relates to appetite, craving,

00:55:32.840 | and just kind of an unconscious understanding

00:55:35.460 | about what food is providing them or not.

00:55:37.540 | And that highly processed foods

00:55:39.580 | basically bypass all of this,

00:55:41.600 | and just get you to consume more,

00:55:43.580 | perhaps in hopes of getting something

00:55:45.300 | that you probably aren't getting at all,

00:55:48.240 | or that you need to consume a lot of this food

00:55:49.820 | in order to get.

00:55:50.660 | - There's several interesting ideas there.

00:55:53.700 | So there's two that come to mind,

00:55:55.020 | just thinking about what you just said.

00:55:56.980 | So the one is the idea of what's going on

00:55:58.940 | when these people consume simpler diets,

00:56:02.460 | more of whole foods.

00:56:03.540 | And one thing I think that's very likely going on

00:56:08.140 | is this phenomenon of sensory-specific satiety

00:56:10.820 | as being engaged.

00:56:11.900 | And so sensory-specific satiety is just the idea

00:56:15.580 | that as you expose yourself repeatedly

00:56:17.740 | to a certain flavor or taste,

00:56:20.020 | you basically lose appetite for that.

00:56:22.880 | You get specific loss of appetite for that flavor or taste.

00:56:25.940 | This is why, as you said,

00:56:27.220 | basically if you start off eating the protein,

00:56:29.100 | after a while you're, "I don't want any more salmon,

00:56:30.540 | "but I would like some carbohydrates now,"

00:56:31.980 | because you have this sensory-specific satiety.

00:56:34.540 | And so it's well-known, actually,

00:56:36.940 | that if you simplify your diet,

00:56:38.220 | make your diet really simple so there's just a few things,

00:56:40.900 | then sensory-specific satiety alone

00:56:42.500 | can cause you to eat less,

00:56:44.820 | basically because there's just less variety in your diet,

00:56:46.640 | and you don't wanna eat more of that same thing.

00:56:48.780 | And so I think a lot of diets actually,

00:56:51.500 | it's not about the specific macronutrient

00:56:53.300 | or the specific food.

00:56:54.440 | It's just that they're reducing the variety in the diet.

00:56:58.420 | Eventually you just get sick of eating the same thing.

00:57:00.480 | And the thought behind that idea

00:57:02.740 | is that it's important evolutionarily

00:57:04.340 | so that you eat a diverse diet.

00:57:05.660 | It's the reason probably that you want sweets

00:57:07.300 | after you've eaten a savory meal and so on.

00:57:09.820 | A second idea, though, that comes to mind

00:57:11.900 | is just, as you mentioned, this idea of learning.

00:57:14.180 | And so much about our preferences for food are,

00:57:18.860 | they're not innate, they're driven by learning, right?

00:57:20.420 | And so there are some things that are innate.

00:57:22.180 | So if you put sugar on a baby's tongue, it'll smile,

00:57:26.340 | indicating that it likes it.

00:57:27.380 | And if you put something bitter, it'll frown.

00:57:29.900 | And a rat will do the same thing, a neonate rat.

00:57:32.860 | But most of flavor and the perception of food

00:57:36.660 | is not just sweet or bitter.

00:57:38.820 | It's this much more complex sensation

00:57:40.600 | that involves smells, it involves tastes,

00:57:43.200 | and then it involves how those tastes and smells interact

00:57:46.940 | with the post-ingestive effects of the nutrients.

00:57:49.300 | So the sensing of those nutrients in your stomach

00:57:52.220 | and in your intestine, primarily in your intestine,

00:57:54.760 | are thought to then feed back

00:57:56.420 | and then change your preference for these foods.

00:57:58.220 | And so there's lots of examples of this

00:58:00.600 | that you can just imagine from everyday experience.

00:58:02.020 | Most people, the first time they had a beer

00:58:03.660 | or the first time they had a glass of coffee

00:58:05.180 | found it repulsive, right?

00:58:06.260 | Because it's extremely bitter.

00:58:07.960 | But then we come to crave these things

00:58:09.420 | because we know what they do to our body,

00:58:10.720 | we like what they do to our body.

00:58:12.080 | And that doesn't just make us take them like they're medicine

00:58:14.660 | we actually somehow change our very perception

00:58:16.840 | of how that flavor is.

00:58:17.740 | We actually come to savor that flavor

00:58:19.580 | we previously found disgusting.

00:58:20.740 | And it's because our sensation of

00:58:22.660 | whether something's good or bad

00:58:25.460 | depends on our internal state.

00:58:26.900 | And so it's an interesting idea.

00:58:28.980 | Perhaps if these ultra-processed foods

00:58:30.860 | that have so many different ingredients

00:58:32.220 | and such an unnatural combination,

00:58:34.260 | perhaps this process of learning about the nutrient content

00:58:37.940 | of different foods and flavors becomes impaired

00:58:41.980 | because it's just the brain is not used,

00:58:43.380 | the brain's used to saying, you know,

00:58:44.500 | this is a piece of chicken and this is primarily protein

00:58:46.980 | and so I can gauge, you know, from this flavor,

00:58:49.220 | I can connect this flavor to an amino acid content

00:58:51.300 | but something that's so diverse, it might be harder to do.

00:58:54.920 | - And isn't it the case that the neurons in the gut

00:58:58.500 | and the hormones that are produced by the gut

00:59:02.260 | as we digest food and that the neurons in the brain

00:59:05.020 | that control appetite and feeding

00:59:07.500 | have to be tuned to macronutrient content

00:59:12.000 | because those are the primary colors of nutrients

00:59:16.840 | and nutrients are the way in which we can persist

00:59:20.820 | on a day-to-day basis, right?

00:59:22.460 | I mean, I'm not trying to sound more sophisticated

00:59:24.380 | where simpler terms would suffice.

00:59:25.860 | What I'm basically saying is that the neurons in our brains

00:59:28.740 | that control these behaviors,

00:59:31.000 | both eating and cessation of eating an ingredient

00:59:34.080 | or an entire meal,

00:59:35.740 | can't be tuned to a particular food product

00:59:38.740 | or to chicken or to an egg or to a steak or to lentils

00:59:44.620 | but rather to amino acid content,

00:59:46.940 | essential amino acid content in particular,

00:59:48.640 | essential fatty acids.

00:59:50.260 | And in the case of carbohydrate,

00:59:51.340 | whatever is going to replace whatever glycogen

00:59:53.580 | we might've depleted, right?

00:59:55.020 | I mean, like if we really break it down into biology,

00:59:57.820 | eating is for a purpose.

00:59:59.140 | And my understanding is that the purpose of eating

01:00:01.240 | is to replace those things as needed

01:00:04.340 | rather than to, you know, taste savory or taste-

01:00:10.240 | - Absolutely, absolutely, absolutely.

01:00:12.260 | Those sensory cues are just markers

01:00:15.820 | that tell the brain what might be in that substance.

01:00:18.220 | I think if you look broadly at this difference

01:00:21.260 | between calories and macronutrients and micronutrients,

01:00:24.740 | I would say what you see is that most of the circuits

01:00:26.860 | that are controlling hunger are primarily calorie specific.

01:00:30.100 | So they can, like for example, an AGRP neuron,

01:00:33.360 | I can put sugar, fat or protein into the stomach of a mouse

01:00:37.900 | and to an equal extent, inhibit an AGRP neuron

01:00:40.380 | as long as they have equal calories.

01:00:41.780 | - Really? - Yeah.

01:00:42.620 | - So a little drop of olive oil into the belly

01:00:45.020 | that has, of an animal that has,

01:00:47.420 | let's drop, let's say a little bit more.

01:00:50.100 | Let's say 120 calories of olive oil

01:00:54.100 | is equal potent to 120 calories of chicken breast?

01:00:59.660 | - At the level of these AGRP neurons, it is.

01:01:01.900 | - So they don't care about the macronutrient?

01:01:04.380 | - No, they're really concerned about,

01:01:06.320 | they're really concerned about energy.

01:01:08.220 | There are circuitries that are more concerned

01:01:11.620 | with macronutrients individually,

01:01:13.180 | although I don't think we know nearly as much

01:01:14.740 | about how that works.

01:01:15.940 | And I think the evidence is clear

01:01:17.180 | that the strongest defended macronutrient by far is protein.

01:01:21.220 | So protein, I don't think really sugar and fat intake

01:01:25.660 | are strongly defended in the sense that you're fine

01:01:29.200 | if you go without eating sugar, right?

01:01:30.700 | Basically you can synthesize sugar from other,

01:01:32.340 | from amino acids, for example.

01:01:34.220 | And you don't develop a specific sugar appetite

01:01:38.380 | in the same way you do, for example,

01:01:39.900 | if you deprive yourself of hunger

01:01:41.060 | you develop a protein hunger or essential.

01:01:43.060 | I think the difference is that proteins

01:01:44.700 | consist of essential amino acids.

01:01:46.020 | There's just this, I forget if it's nine amino acids

01:01:49.220 | that your body cannot synthesize.

01:01:51.680 | You absolutely need them or you will die.

01:01:53.720 | And so, whereas sugar and fat can be interchanged

01:01:57.100 | with other macronutrients.

01:01:58.380 | And there's other things also

01:02:01.260 | that you absolutely need to ingest

01:02:02.460 | like sodium chloride, right?

01:02:03.740 | So sodium, so there's very few,

01:02:07.060 | deprive an animal of sodium,

01:02:08.840 | they will develop this salt appetite

01:02:10.180 | that's incredible basically,

01:02:11.260 | and that's completely innate.

01:02:12.700 | But that's, I think salt appetite

01:02:16.540 | and protein appetite are the things

01:02:18.820 | that are probably the most strongly regulated

01:02:20.340 | at the level of the macro and micronutrients.

01:02:23.300 | - I'd like to take a brief break

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01:03:59.080 | If we could talk about body weight homeostasis

01:04:02.840 | for a moment, I think that would be useful.

01:04:05.600 | So let's say somebody decides they want to lose some weight.

01:04:09.000 | They caloric restrict slightly,

01:04:12.600 | either by exercising more or eating less or both.

01:04:15.440 | Their body weight drops by a bit.

01:04:16.760 | Let's say they lose 10 pounds,

01:04:19.240 | eight of which are body fat.

01:04:20.660 | They lose a little bit of lean mass also.

01:04:23.160 | They're now at a new lower body weight.

01:04:25.760 | Are the AGRP neurons motivated

01:04:27.940 | to have them seek out more food?

01:04:29.340 | In other words, are they hungrier

01:04:30.640 | and more motivated to find and eat food?

01:04:33.160 | Or do these AGRP neurons learn,

01:04:35.520 | "Hey, body weight is lower

01:04:37.840 | and I don't need to push to find so much food so often."

01:04:42.640 | - No, I mean, the idea is that the AGRP neurons

01:04:44.400 | are more active when you lose weight

01:04:46.120 | and that chronic activation of those neurons,

01:04:48.800 | in part because leptin levels are lower in the blood

01:04:51.120 | because you've lost weight,

01:04:52.520 | is that drive, that counter-regulatory drive

01:04:55.240 | that drives you to then consume more food.

01:04:57.200 | - But then how do people ever keep weight off?

01:04:59.600 | - Well, so part of the answer is they don't.

01:05:02.140 | I mean, so there's so-

01:05:03.800 | - Really?

01:05:04.640 | 'Cause I would argue like I have these friends

01:05:06.520 | who were very heavy.

01:05:09.520 | Most of the excess weight was body fat for a long time.

01:05:12.680 | They seem to be doing great

01:05:14.520 | eating the way that I described before.

01:05:15.840 | And by the way, I'm not a proponent

01:05:17.040 | of any one particular diet.

01:05:18.960 | I have vegan friends, carnivore friends, et cetera,

01:05:20.520 | but that pattern of eating I described before

01:05:22.420 | has been enormously successful for them.

01:05:24.800 | I haven't run a randomized controlled trial.

01:05:27.400 | It's not my job to do that in the realm of nutrition,

01:05:29.920 | but they're doing great.

01:05:31.480 | They claim to be sated.

01:05:32.760 | They are so happy with the way things are going.

01:05:36.160 | And I don't hear that they're constantly hungry.

01:05:39.980 | I hear that they're constantly sated.

01:05:41.440 | - Well, so I would say that there have been efforts

01:05:46.440 | for a long time to develop diets

01:05:48.560 | that would help people consistently lose weight.

01:05:50.800 | And it has been very unsuccessful.

01:05:53.300 | There are some people who, for various reasons,

01:05:55.480 | can successfully lose weight and keep it off.

01:05:57.280 | And I don't know that I have a good answer

01:05:59.360 | for what's going on in those individual cases,

01:06:01.520 | how they are the exceptions to the rule.

01:06:02.920 | What about them is different that makes sense.

01:06:04.200 | - Some also quit drinking alcohol.

01:06:06.040 | - Yeah, so there's other things.

01:06:07.080 | So, you know, I think-

01:06:07.920 | - So behavioral regulation is better

01:06:09.400 | when you're sober as opposed to-

01:06:11.040 | - You can change your environment.

01:06:12.380 | But, you know, so what this is sort of getting at

01:06:15.120 | is what is the counter-regulatory response to weight loss?

01:06:18.320 | And so this has been studied.

01:06:20.560 | It was first studied in the context of energy expenditure.

01:06:24.760 | And because energy expenditure

01:06:26.780 | is actually surprisingly easier to measure in humans

01:06:28.880 | than food intake, because people don't tell you accurately

01:06:30.980 | what food they eat.

01:06:31.820 | If they're free living humans,

01:06:32.880 | they have to fill out a questionnaire.

01:06:34.540 | But, and the idea is that

01:06:37.480 | for every kilogram of weight you lose,

01:06:39.760 | so it's about 2.2 pounds, I think,

01:06:42.580 | your energy expenditure decreases

01:06:45.120 | by about 30 kilocalories a day.

01:06:46.720 | Now, so not a ton, but that is significant, right?

01:06:51.460 | 30 calories.

01:06:52.300 | And then if you lose, as you said, 10 pounds,

01:06:54.580 | then that's 150 calories, and that adds up over time.

01:06:58.580 | One interesting thing about that

01:07:00.420 | is that if you take people who were obese

01:07:03.380 | and then they've lost a ton of weight.

01:07:04.700 | So there's a study by Rudy Liebel

01:07:06.180 | about 25 years ago that did this.

01:07:07.820 | Take people who lost like 100 pounds

01:07:11.340 | and then take a control group

01:07:12.660 | that has the same height, weight,

01:07:15.220 | basically the same body composition

01:07:16.580 | as those people who've now lost 100 pounds.

01:07:19.140 | Compare their energy expenditure.

01:07:21.300 | The energy expenditure in the people

01:07:22.900 | that lost all the weight is about 25% lower

01:07:25.220 | than the people who never were obese.

01:07:27.900 | And so those people who lost the weight,

01:07:30.060 | we call them the reduced obese,

01:07:31.180 | or that's what they were called in those studies.

01:07:33.020 | And the idea is that there's now this chronic deficit.

01:07:36.460 | They have to eat 25% less than someone

01:07:38.300 | who looks the same as them, is the same height as them,

01:07:40.460 | the same weight as them,

01:07:41.420 | in order to maintain that body weight.

01:07:43.340 | What's unclear is whether that's because those people

01:07:45.880 | simply always had a slower metabolism,

01:07:47.500 | they were always destined to be obese,

01:07:48.720 | and then you're just basically,

01:07:49.560 | you're comparing two different groups,

01:07:50.580 | or whether something about the process

01:07:52.740 | of gaining weight and being at a higher weight

01:07:54.100 | for a longer period of time changes the brain

01:07:55.940 | so that then once you lose the weight, it's irreversible.

01:07:58.780 | But there have been studies looking at at least a year,

01:08:01.680 | and it doesn't seem to come back within a year,

01:08:03.220 | that difference in energy expenditure.

01:08:05.500 | Now, the question is, is that really the big effect?

01:08:08.020 | Is that why it's so hard to lose weight, energy expenditure,

01:08:09.700 | or is it because you're hungrier?

01:08:11.860 | And that's actually much harder to measure.

01:08:14.300 | But there was another really nice study,

01:08:15.980 | again, by Kevin Hall, investigating this.

01:08:18.500 | He used a really clever approach, this drug.

01:08:21.540 | So basically what he wanted to do was,

01:08:23.260 | is he reasoned that you can measure people's body weight,

01:08:26.580 | and you can measure people's energy expenditure.

01:08:30.220 | And because calories in, calories out,

01:08:32.480 | if we can measure body weight

01:08:33.460 | and energy expenditure accurately,

01:08:35.260 | we can then back-calculate

01:08:36.860 | how much that person was actually eating.

01:08:38.900 | So let's see what happens when you have people lose weight.

01:08:43.600 | How does their food intake change?

01:08:45.340 | But the trick to this is, you need to do it in such a way

01:08:48.460 | that you don't just tell them to go run on a treadmill,

01:08:49.940 | because if you tell someone to go run on a treadmill

01:08:51.140 | and lose weight, then basically,

01:08:52.220 | they're thinking about the fact that they're doing this.

01:08:54.460 | So you need to do it in some way covertly,

01:08:55.980 | so that you increase their energy expenditure,

01:08:57.460 | cause them to lose weight,

01:08:58.660 | but without them realizing that's what's happening.

01:09:00.740 | So they gave them these drugs, these SGLT2 inhibitors.

01:09:05.220 | And it's a pill you can take.

01:09:06.780 | They're used for diabetes.

01:09:08.300 | They block this protein, SGLT2, in the kidney

01:09:11.940 | that is necessary for glucose

01:09:13.380 | to be reabsorbed into the blood.

01:09:14.860 | And so basically what happens is you pee out

01:09:16.340 | about like 90 grams of glucose a day.

01:09:18.780 | But you don't know that you're doing that.

01:09:20.140 | And that causes you to lose energy.

01:09:21.540 | So these people would lose some weight.

01:09:23.620 | And then measure how their food intake changes.

01:09:25.940 | And what that showed is that for every two pounds or so

01:09:29.260 | of weight you lose, your hunger goes up

01:09:31.140 | by a hundred calories per day.

01:09:33.440 | So basically you've got a 30 kilocalorie decrease

01:09:35.900 | in energy expenditure,

01:09:36.980 | a hundred kilocalorie decrease in appetite

01:09:38.880 | for every two pounds you lose, on average.

01:09:40.620 | Some people will be exceptions, right?

01:09:41.620 | And they won't experience that at all

01:09:42.500 | for aspects of their physiology we don't understand.

01:09:45.060 | And so the increased hunger seems to be the main reason

01:09:48.060 | people find it so difficult to keep weight off.

01:09:50.620 | - That seems the perfect segue to talk about GLP-1,

01:09:54.420 | glucagon-like peptide one,

01:09:56.540 | ozempic, monjaro, and similar drugs.

01:09:59.080 | My understanding of the back history on these

01:10:02.940 | is that a biologist obsessed with Gila monsters,

01:10:06.440 | a reptile that doesn't need to eat very often

01:10:11.700 | discovered a peptide within their bloodstream

01:10:14.140 | called Xtendin that allowed them to eat very seldom.

01:10:20.140 | It curbed appetite in the Gila monster of all things.

01:10:24.300 | And it has a analog homologue, you know, we don't know.

01:10:30.100 | I don't know the sequence homology exactly,

01:10:31.980 | but there's a similar peptide made in mice and in humans

01:10:36.620 | that suppresses appetite.

01:10:38.940 | If you would, could you tell us what is known

01:10:41.020 | about how GLP-1 works to suppress appetite,

01:10:44.060 | where in the body and/or brain?

01:10:45.980 | And your sort of read of these drugs

01:10:50.180 | and what's happening there, good, bad, exciting, ugly.

01:10:55.180 | - Sure, I'd be happy to.

01:10:57.420 | - Anything else?

01:10:58.240 | - So the story of GLP-1,

01:11:00.740 | so the Gila monster is an important turn,

01:11:02.240 | and I'll talk about that.

01:11:03.080 | It actually goes back before that quite a ways.

01:11:05.120 | So I should take a step back and say, you know,

01:11:07.080 | these were developed as drugs for diabetes, right?

01:11:09.900 | And so, and diabetes is a condition

01:11:11.780 | where basically you have elevated blood glucose,

01:11:13.700 | either because you don't produce enough insulin

01:11:15.700 | or because your insulin is not effective.

01:11:18.280 | And so back in sort of the 1920s,

01:11:21.580 | right around the time insulin was discovered,

01:11:24.300 | there was this phenomenon discovered

01:11:25.620 | known as the incretin effect.

01:11:27.120 | And what it was- - Incretin?

01:11:29.980 | - Incretin, yeah. - Not the cretin effect.

01:11:31.820 | - Not the cretin effect.

01:11:32.660 | - You can observe the cretin effect

01:11:34.020 | in numerous places in daily life and online, just kidding.

01:11:36.980 | - So it's called the incretin effect.

01:11:39.260 | You can think of it as increase insulin

01:11:41.220 | 'cause that's what the effect is.

01:11:43.140 | And the idea was that if you take glucose by mouth,

01:11:45.860 | if you consume glucose orally,

01:11:47.380 | versus if you have the same amount of glucose

01:11:50.180 | injected intravenously, more insulin is produced

01:11:54.420 | when you take the glucose orally

01:11:56.620 | versus if it's delivered intravenously.

01:11:58.460 | Suggesting something about the process

01:11:59.660 | of ingesting the glucose causes more insulin to be released

01:12:03.780 | and causes you to lower your body sugar more accurately

01:12:06.980 | and more strongly. - Interesting.

01:12:09.720 | - Which is a little bit counterintuitive

01:12:11.000 | because in the pancreas, right?

01:12:12.460 | So insulin is released from the pancreas,

01:12:13.700 | from the beta cell.

01:12:15.020 | The pancreas senses the glucose concentration

01:12:17.180 | in the blood directly.

01:12:18.020 | And so it suggests that insulin is being released

01:12:20.140 | not just in response to changes in blood glucose,

01:12:21.820 | but in response to a second factor.

01:12:23.380 | And so they call that an incretin.

01:12:25.820 | And through various experiments it was shown

01:12:29.420 | that this incretin effect comes from the intestine,

01:12:31.780 | that there's some substance being produced by the intestine

01:12:34.820 | that when you eat a meal,

01:12:36.980 | sugar goes through your intestine

01:12:38.660 | that boosts this insulin response to glucose in the blood.

01:12:42.340 | And people immediately realized

01:12:43.740 | this could potentially be very valuable.

01:12:45.180 | And the reason is that you can treat diabetes

01:12:47.300 | with insulin injections, but insulin is dangerous, right?

01:12:49.420 | 'Cause if you inject too much insulin,

01:12:50.540 | you can kill yourself by making yourself hypoglycemic, right?

01:12:52.660 | So you have to be very careful.

01:12:54.700 | But the thing about the incretin effect

01:12:56.500 | is it's not causing insulin release directly,

01:12:59.020 | but it's rather boosting the natural insulin release

01:13:01.740 | that comes when your glucose is higher in your blood.

01:13:03.700 | So it's sort of an amplifier

01:13:04.820 | on the natural insulin release.

01:13:06.980 | So basically in the years that followed,

01:13:08.180 | whenever someone would find a new hormone,

01:13:10.060 | they would test it, is it this incretin?

01:13:11.620 | And there's lots of failures, they weren't the incretin.

01:13:14.940 | But then, so there's this other hormone

01:13:16.700 | that comes from the pancreas called glucagon, right?

01:13:20.580 | And so glucagon, it was also discovered in the 1920s,

01:13:23.340 | glucagon is kind of the anti-insulin.

01:13:25.500 | So when blood sugar goes low,

01:13:28.140 | glucagon is released in order to cause your liver

01:13:30.140 | to release glucose into the blood.

01:13:32.180 | So glucagon and insulin are these two opposing hormones.

01:13:35.820 | Glucagon was known for a long time,

01:13:36.980 | but people discovered in sort of the 1980s

01:13:39.820 | that the glucagon gene is expressed in other tissues

01:13:42.980 | other than the pancreas.

01:13:44.620 | And it's differentially processed,

01:13:46.380 | the protein is differentially processed

01:13:47.940 | to produce different hormones,

01:13:49.060 | hormones other than glucagon.

01:13:51.060 | And they discovered there was one in the intestine,

01:13:52.740 | and so they called it glucagon-like peptide

01:13:54.660 | because it comes from the same gene,

01:13:56.420 | but it's just slightly different,

01:13:57.620 | it's cut up slightly differently.

01:14:00.060 | And this hormone wasn't incretin.

01:14:01.500 | So basically if you put it on beta cells,

01:14:05.100 | you get this increased response of insulin

01:14:06.900 | in response to glucose.

01:14:08.100 | And so there was the idea,

01:14:10.860 | okay, this could be a great diabetes drug, right?

01:14:12.540 | And I should say there was one other incretin

01:14:14.660 | that's been found, it's called GIP, G-I-P,

01:14:17.460 | and that will be important

01:14:18.780 | in talking about some of these other drugs,

01:14:20.900 | also a hormone that comes from the intestine.

01:14:23.660 | And so the challenge with making GLP-1 into a drug

01:14:28.420 | is that it has an extremely short half-life.

01:14:30.740 | So it has a half-life of about two minutes in the blood.

01:14:33.760 | And so even if you inject people with GLP-1,

01:14:36.740 | it won't really be useful for anything.

01:14:38.140 | You don't decrease appetite,

01:14:39.060 | you don't affect blood sugar 'cause it's just degraded

01:14:41.140 | too fast.

01:14:42.660 | And the reason it's degraded is because there's an enzyme,

01:14:44.540 | DPP-4 is what it's called, that degrades GLP-1.

01:14:49.540 | So the first thing people tried was,

01:14:50.620 | let's make inhibitors of that enzyme

01:14:51.940 | so we can boost this natural GLP-1 signal.

01:14:53.780 | And those are approved diabetes drugs,

01:14:57.500 | they're called gliptins.

01:14:58.340 | You've probably heard about them.

01:14:59.160 | Genuvia is the most common one.

01:15:01.100 | And those boost the level of GLP-1,

01:15:02.780 | the natural GLP-1 produced from the intestine

01:15:06.060 | by about three-fold.

01:15:07.380 | And they're effective in treating diabetes.

01:15:09.180 | - Do people lose weight?

01:15:10.420 | - People do not lose weight.

01:15:12.500 | And that's one of the key reasons that we know

01:15:14.900 | that the natural function of GLP-1

01:15:16.620 | is not really to control body weight

01:15:18.140 | because you can boost the level three-fold

01:15:19.940 | with these DPP-4 drugs.

01:15:21.940 | Millions of people have taken them,

01:15:22.980 | they do not lose weight.

01:15:24.260 | That's a great question.

01:15:25.800 | So, but a three-fold is great,

01:15:28.080 | but you'd like to increase it even more, right?

01:15:29.740 | And to do that, you can't block this enzyme.

01:15:31.780 | You have to actually produce a GLP-1

01:15:34.340 | that is more stable in the blood.

01:15:36.580 | And that's where this lizard that you mentioned

01:15:39.140 | comes into play.

01:15:40.580 | It produces a stabilized form of GLP-1 and it's a venom.

01:15:44.440 | No one knows why.

01:15:45.340 | One hypothesis is that it's something to do with the lizard,

01:15:48.860 | as you said, basically having this long time period

01:15:51.240 | between meals and it needs to regulate its blood glucose.

01:15:53.560 | Who knows if that is true,

01:15:54.940 | but it turned out to be fortuitous

01:15:56.360 | because then this GLP-1 from this lizard,

01:15:59.220 | it has a half-life of like two hours.

01:16:01.500 | And so the first GLP-1 drug that was approved

01:16:03.740 | was just this molecule from this lizard, basically.

01:16:06.220 | And it's called Xenotide and it was approved in 2005.

01:16:11.220 | Works well for diabetes, has a half-life of two hours.

01:16:15.700 | You inject it and it doesn't cause a ton of weight loss.

01:16:19.940 | But two hours is good, but it's not so great.

01:16:22.660 | So then the pharmaceutical industry said,

01:16:24.860 | "Can we basically improve this even further?"

01:16:26.820 | And so they start engineering this hormone,

01:16:28.620 | making mutations, attaching lipid tails

01:16:30.900 | to make it bind to proteins in the blood

01:16:33.080 | that would stabilize it.

01:16:34.740 | - Chemistry jockey stuff.

01:16:36.060 | - Yeah, exactly.

01:16:37.060 | And I think the next big advance

01:16:39.100 | was this compound liraglutide.

01:16:40.660 | And liraglutide was approved for diabetes in 2010

01:16:45.300 | and then for weight loss in 2014.

01:16:47.740 | And so liraglutide has a half-life

01:16:49.860 | of about 13 hours in the blood.

01:16:51.700 | Now you're getting up to something serious.

01:16:52.700 | We've gone from two minutes, two hours, 13 hours.

01:16:56.260 | And you get better effects on aspects of blood glucose

01:16:59.980 | and diabetes control.

01:17:00.900 | And they started to see that some people were losing weight.

01:17:04.360 | Very variable responses.

01:17:05.400 | Not everyone loses weight on liraglutide.

01:17:08.000 | And one of the things they noticed

01:17:09.280 | that I think is just as fascinating

01:17:10.520 | just sort of example of how drug discovery works

01:17:12.160 | in the real world.

01:17:13.060 | You know, a lot of these people would take liraglutide.

01:17:15.640 | Now it has this longer half-life.

01:17:17.280 | They'll start to get nauseous.

01:17:18.660 | And that would limit

01:17:19.500 | how much of the liraglutide they could take.

01:17:20.800 | And it's a known side effect of these GLP-1 drugs.

01:17:22.680 | It causes nausea and sort of this gastrointestinal distress.

01:17:26.280 | But they noticed that over time,

01:17:28.120 | the nausea would just sort of go away.

01:17:29.760 | And so they would start dose escalating,

01:17:31.540 | sort of raising the dose that the person would take.

01:17:33.620 | So you would go, you know, a month at this dose,

01:17:36.820 | and then a month at a slightly higher dose,

01:17:38.540 | and then a month at a slightly higher dose.

01:17:39.820 | And you could work your way up.

01:17:41.220 | And these side effects would reappear,

01:17:42.820 | but then they'd go away.

01:17:44.280 | And then once you got up to the highest doses,

01:17:45.660 | then people really started losing weight.

01:17:47.020 | And so there's a couple of things

01:17:48.660 | that our pharmaceutical industry realized,

01:17:49.820 | wow, these are potentially

01:17:50.660 | really effective weight loss drugs.

01:17:52.540 | And also this nausea, which we thought was, you know,

01:17:55.580 | a killer, people are able to just get used to it.

01:17:58.500 | And then it just goes away.

01:17:59.420 | It undergoes, the word is tachyphylaxis.

01:18:01.800 | So the idea is that the receptor that's affecting,

01:18:05.460 | in the gut that's causing these effects,

01:18:08.020 | it undergoes some sort of downregulation

01:18:09.940 | with chronic exposure.

01:18:12.380 | So liraglutide, you know, it's been around,

01:18:14.580 | you know, it's been on the market for 14 years now,

01:18:17.060 | was used, but still you're only getting

01:18:18.460 | sort of like seven to 10% weight loss,

01:18:21.620 | which is good, but not like, you know, amazing, impressive.

01:18:25.300 | But then semaglutide came along.

01:18:28.180 | And that was approved for diabetes in 2017.

01:18:31.220 | And semaglutide is Ozempic,

01:18:32.900 | or also marketed as Wigovi for weight loss.

01:18:37.900 | And semaglutide now has a half-life of seven days.

01:18:41.020 | So now we've gone from two minutes,

01:18:42.980 | two hours, 13 hours, seven days.

01:18:46.200 | And you can really jack up the concentration

01:18:47.940 | with a seven-day half-life.

01:18:50.880 | And then they saw people started really losing weight.

01:18:53.140 | And so in some of those trials,

01:18:54.860 | people lost, you know, 16% of their body weight,

01:18:56.980 | which previously had been unattainable.

01:18:59.700 | - In what timeframe?

01:19:01.260 | - Typically takes about a year.

01:19:02.980 | - Okay, and most of the loss in body weight

01:19:05.980 | is from body fat or from other compartments?

01:19:09.100 | - The typical number is that if you lose weight,

01:19:12.260 | either through dieting or through taking one of these drugs,

01:19:14.220 | and you don't do anything like eat a high-protein diet

01:19:16.140 | or do resistance training,

01:19:17.860 | somewhere between 25 and 33% of what you lose

01:19:21.020 | is gonna be muscle.

01:19:22.140 | The rest is gonna be fat.

01:19:23.300 | - But as you said, some of that could be offset

01:19:25.300 | by resistance training and/or consuming

01:19:27.860 | a higher-protein diet.

01:19:30.180 | - Yeah, you can almost completely eliminate that

01:19:32.060 | if you eat enough protein and do serious weightlifting.

01:19:35.140 | Obviously not the whole population

01:19:37.700 | is interested in doing that.

01:19:38.660 | And there's been a lot of discussion

01:19:40.420 | of how serious a side effect this is.

01:19:42.420 | You know, among elderly people,

01:19:44.700 | you don't wanna be losing muscle mass

01:19:46.220 | because you're already losing so much muscle mass.

01:19:48.380 | On the other hand, the counterargument that has been made,

01:19:50.900 | which I think is also kind of convincing,

01:19:52.340 | is that, true, you're losing some muscle,

01:19:55.260 | but you're also losing all this fat,

01:19:56.940 | and you no longer need as much muscle

01:19:59.140 | when you're not carrying around as much body fat.

01:20:01.060 | So people who are heavier naturally have more muscle

01:20:03.100 | because they need to to move their body, right?

01:20:04.660 | And so--

01:20:05.500 | - Yeah, the calves on very obese people are often enormous.

01:20:10.460 | - Exactly.

01:20:11.300 | - And then they lose weight and--

01:20:12.300 | - Exactly.

01:20:13.460 | - And I mentioned the calves in particular

01:20:15.140 | because they're carrying a lot of the body load.

01:20:18.620 | - Exactly, exactly.

01:20:19.500 | So it's still an open question as to whether,

01:20:21.420 | as to how serious a problem this lean muscle mass loss is,

01:20:24.780 | although the pharmaceutical industry

01:20:26.660 | is all in now on making drugs

01:20:28.100 | that basically are gonna prevent that.

01:20:29.220 | So that's something that will be happening

01:20:31.100 | probably in the future.

01:20:32.180 | - Is it a, sorry to interrupt,

01:20:33.500 | but is the weight loss on these drugs

01:20:37.140 | the consequence of reduced appetite

01:20:39.700 | or some other aspect of metabolism?

01:20:41.700 | And if it's the consequence of reduced appetite,

01:20:44.740 | is that occurring at the level of the brain and gut

01:20:47.300 | or a combination?

01:20:50.220 | - So it's almost entirely reduced appetite,

01:20:52.660 | and it's almost entirely occurring

01:20:54.220 | at the level of the brain.

01:20:55.380 | - Which neurons?

01:20:56.260 | - It's thought that the key targets of these drugs

01:20:59.860 | are neurons in these two regions.

01:21:01.100 | One's called the nucleus of the solitary tract,

01:21:03.740 | and the other one's called the area posteroma.

01:21:05.500 | - So we're back in the brainstem.

01:21:06.780 | - Back in the brainstem.

01:21:07.900 | So these are actually the neurons

01:21:09.420 | in that decerebrate rat story I was telling earlier.

01:21:12.220 | These are the brain regions that are preserved

01:21:13.940 | in the decerebrate rat.

01:21:14.820 | The decerebrate rat still has these

01:21:16.300 | very caudal brainstem structures.

01:21:19.100 | They're two very special brain regions

01:21:20.580 | because they get direct input from the vagus nerve.

01:21:23.700 | So the vagus nerve is the nerve that innervates your stomach

01:21:26.020 | and intestines and heart and lungs,

01:21:28.060 | and is sort of the major pathway from gut to brain.

01:21:30.300 | It provides most of the neural input from gut to brain,

01:21:33.940 | telling you about things like your stomach distention,

01:21:36.820 | how many nutrients are in your intestine,

01:21:38.780 | breathing, all that stuff.

01:21:40.580 | And almost all of those vagal nerves

01:21:42.460 | terminate on these two structures in the brainstem.

01:21:45.620 | - When I hear posteroma, I think about nausea

01:21:48.060 | because I was taught that posteroma contains neurons

01:21:51.180 | that can stimulate vomiting.

01:21:52.900 | And this seems to link up well,

01:21:55.220 | at least in the logical sense,

01:21:56.420 | with the idea that stimulating, activating receptors

01:22:00.000 | in these neurons within posteroma

01:22:01.940 | might explain part of the transient nausea side effect

01:22:05.300 | of ozempic and related drugs.

01:22:07.660 | - Yeah, so the current thought is that

01:22:09.220 | a lot of the nausea is coming from activating the neurons

01:22:11.620 | in the area of posteroma,

01:22:12.700 | and that a lot of the sort of physiologic satiety

01:22:15.340 | is coming from activating the neurons

01:22:16.940 | in the nucleus of the solitary tract.

01:22:18.680 | Now, the whole brain is connected to each other,

01:22:20.060 | and so if you really turn on these neurons

01:22:21.660 | in the NTS and the AP,

01:22:22.700 | they're gonna talk to the hypothalamus

01:22:24.060 | and all these other brain regions,

01:22:24.900 | it's gonna change the whole brain.

01:22:26.380 | So it's not just those regions,

01:22:27.640 | but these drugs don't have great access to the brain.

01:22:31.100 | They can penetrate a little bit into the brain,

01:22:32.480 | but they don't penetrate into the whole brain.

01:22:34.380 | And it's thought that if you take

01:22:36.380 | fluorescently labeled versions of these drugs

01:22:38.740 | and see where they, so you can visualize

01:22:40.380 | where do they actually go,

01:22:41.620 | they're enriched in these structures in the brainstem.

01:22:43.540 | So that's why people think

01:22:44.500 | that this is probably where they're acting.

01:22:46.300 | - Is that because there's an abundance of the receptors

01:22:50.300 | for these compounds in post-trauma and NTS,

01:22:55.300 | or is it because the blood-brain barrier

01:22:57.180 | is somehow weaker at that location?

01:22:59.620 | - It's because the blood-brain barrier is weaker.

01:23:01.140 | So basically it's a region,

01:23:02.720 | what's known as a circumventricular organ,

01:23:06.140 | meaning it's one of these rare places in the brain

01:23:08.420 | where the blood-brain barrier is weakened,

01:23:09.940 | and so substances can come from the outside into the brain.

01:23:13.180 | And that's important for these big peptides,

01:23:16.060 | 'cause these are not small molecules,

01:23:17.180 | these are big peptides with lipid chains on them

01:23:19.020 | and other things.

01:23:19.860 | So they can really only get into areas of the brain

01:23:22.340 | where the blood-brain barrier is weakened.

01:23:24.780 | - I really appreciate that you mentioned

01:23:26.340 | the half-life issue with GLP-1

01:23:29.380 | and the fact that these DPP-4 antagonists

01:23:33.340 | did not lead to weight loss despite increasing,

01:23:36.260 | circulating GLP by threefold.

01:23:40.260 | This is relevant to a number of different claims

01:23:43.820 | that people make that a given food or a given drink

01:23:47.260 | increases GLP-1.

01:23:49.540 | I've actually said before,

01:23:51.140 | I'm a big consumer of Yerba Mate,

01:23:52.580 | my father's side is Argentine

01:23:54.940 | and it's a known appetite suppressant,

01:23:56.820 | but it contains caffeine and other stimulants

01:23:58.700 | that might explain some of that.

01:24:00.100 | And it's not a robust appetite suppressant

01:24:02.260 | to the point where most people would rely on it

01:24:05.340 | as a weight loss compound.

01:24:07.060 | But anyway, it's my preferred source of caffeine,

01:24:09.220 | but I've said before,

01:24:11.020 | there's some evidence that it can increase GLP-1,

01:24:13.940 | but based on what you've said,

01:24:15.400 | the increases in GLP-1 that it creates

01:24:17.240 | are very unlikely to produce

01:24:18.920 | the kind of appetite suppressive effect

01:24:21.080 | that would lead to any significant weight loss

01:24:22.640 | in somebody that's obese,

01:24:23.880 | presumably that are separate

01:24:25.740 | from any caffeine stimulatory effects.

01:24:29.000 | So you can't separate 'cause it's a complex compound,

01:24:31.520 | this Yerba Mate thing, it's got lots of things in it.

01:24:33.880 | But also, I've observed you being vocal on social media

01:24:38.880 | when people have said, "Hey, this thing increases GLP-1."

01:24:44.120 | You, quite appropriately, I think, said, "Wait."

01:24:49.120 | Ozempic and drugs like that increase GLP-1 thousandfold.

01:24:55.060 | When you talk about a food or drink

01:24:57.440 | or maybe a supplement increasing GLP-1,

01:24:59.360 | it's very unlikely to increase its GLP-1 to that level.

01:25:02.980 | Meaning, unless you're getting into the hundredfold

01:25:06.520 | or thousandfold increases,

01:25:09.100 | probably not right to talk about GLP-1

01:25:12.440 | being the source of any appetite suppressive effect.

01:25:14.680 | - Yeah, that's all correct.

01:25:16.240 | So, I mean, I think it's important sometimes

01:25:18.240 | to distinguish between pharmacologic and physiologic effects.

01:25:21.520 | So physiologic is what the hormone naturally does

01:25:24.180 | in your body and what can be modulated by natural things

01:25:27.080 | like eating a different food.

01:25:28.800 | And you might get a twofold change in your GLP-1

01:25:31.200 | by eating a different food, one food versus the other.

01:25:34.240 | But as we know from those DPP-4 inhibitors,

01:25:35.680 | it's not gonna really change your appetite

01:25:37.240 | because the drugs increase it threefold.

01:25:40.080 | These GLP-1 agonists are really a pharmacologic effect,

01:25:43.880 | effect that only happens with drugs.

01:25:45.000 | So you get a thousand to 10,000 fold higher concentrations

01:25:48.080 | of these drugs in your blood than the natural hormone.

01:25:51.800 | And so it's just,

01:25:53.560 | there's no diet that's ever gonna give you that.

01:25:55.520 | - And there's no precedent for it either.

01:25:57.320 | So should we be at all concerned about that?

01:26:00.000 | I mean, they run clinical trials and address safety,

01:26:02.680 | but when you're talking about a thousandfold increase

01:26:05.240 | in essentially a peptide hormone,

01:26:08.640 | if we were talking about a different peptide hormone,

01:26:11.880 | not, you know, pick one, you know,

01:26:14.000 | oxytocin or estrogen, testosterone,

01:26:16.800 | they're not really, you know, broadly speaking,

01:26:20.040 | most people would be concerned about thousandfold dosing

01:26:23.460 | of something like that.

01:26:24.560 | And obviously there are clinical indications

01:26:26.240 | where that's important.

01:26:27.600 | However, my observation of the ever-expanding literature

01:26:31.480 | on GLP-1 agonists is that there seems to be improvements

01:26:38.320 | in like reduction in alcohol consumption.

01:26:42.460 | And by the way, why would increasing GLP-1

01:26:46.120 | reduce craving for alcohol?

01:26:49.080 | It seems like there's an ever-expanding list of things

01:26:51.500 | that GLP-1 agonism is good for.

01:26:54.360 | But we are talking about,

01:26:55.680 | I would say supra-physiological levels when one takes it.

01:26:59.320 | And again, I'm not against it, nor for it,

01:27:02.160 | I'm just paying attention to the literature.

01:27:04.280 | - So I would say that that's absolutely right.

01:27:06.440 | When you're increasing the level of hormone a thousandfold,

01:27:08.800 | you need to be careful, see what's happening.

01:27:11.680 | But at the end, it's an empirical question.

01:27:13.120 | What does it actually do to a person?

01:27:14.920 | And it can only be answered through experiments.

01:27:16.540 | And I think the nice thing about these GLP-1 drugs

01:27:18.940 | that a lot of people don't realize is

01:27:20.640 | they've been around and approved since 2005,

01:27:22.840 | the earliest ones.

01:27:23.920 | And even something like Ozempic,

01:27:25.480 | which maybe only entered the public consciousness

01:27:27.360 | in the last year or two, right?

01:27:28.500 | It's been around for seven-ish years, I think.

01:27:30.920 | And so, and big clinical trials with these drugs.

01:27:34.260 | And so, and the evidence so far

01:27:36.920 | is that they seem to be incredibly safe.

01:27:38.680 | And as you said, not just incredibly safe,

01:27:40.440 | but they seem to have all these unexpected health benefits

01:27:44.280 | that seem to be, in some cases,

01:27:46.720 | even unrelated to weight loss.

01:27:48.120 | And so, because of the reasons you mentioned,

01:27:51.320 | one of the things the FDA requires

01:27:52.600 | from these pharmaceutical companies for diabetes drugs

01:27:54.960 | is these large cardiac outcome trials.

01:27:58.160 | So basically where you measure stroke

01:27:59.800 | and where you measure heart attacks

01:28:01.960 | and death from any cardiac cause,

01:28:04.180 | big trials, like 20,000 people, four years,

01:28:07.460 | cost like a billion dollars to run.

01:28:09.500 | And the data from the semaglutide, the Ozempic trial,

01:28:12.620 | came out last year and, as expected,

01:28:16.420 | reduced the rate of heart attacks, strokes,

01:28:18.900 | all-cause mortality according to cardiac,

01:28:20.940 | for cardiac reasons.

01:28:23.260 | But what's really surprising was

01:28:25.060 | a lot of that seemed to happen

01:28:26.100 | before the people even lost weight.

01:28:27.780 | So there was already a difference

01:28:28.860 | between the placebo group and the semaglutide group

01:28:31.180 | before the people on the drug

01:28:32.240 | had lost a significant amount of weight.

01:28:34.160 | And there was no correlation

01:28:35.440 | between the amount of weight they lost

01:28:37.520 | and how well they were protected from heart disease.

01:28:40.320 | And that's led many people to think

01:28:41.440 | that some of these effects actually could be due

01:28:43.460 | to other things the GLP-1s are doing that we didn't expect.

01:28:46.200 | And so one thing is there's an idea emerging

01:28:49.040 | that they are anti-inflammatory.

01:28:51.760 | So these brain regions, the areoposteum and the NTS,

01:28:55.640 | are also really important for this reflex

01:28:58.200 | known as the inflammatory reflex

01:29:00.200 | that basically acts, starts with the vagus nerve,

01:29:02.920 | goes to these brain regions of the brainstem,

01:29:04.540 | and then goes back down to the body

01:29:06.920 | to basically suppress,

01:29:08.240 | to prevent out-of-control inflammation.

01:29:10.520 | And so it's thought that these drugs

01:29:12.080 | perhaps have an anti-inflammatory effect

01:29:13.880 | that explains some of that.

01:29:15.240 | - Sounds like the patent on these drugs

01:29:18.000 | just got extended by another 100 years.

01:29:20.480 | That's a biopharma joke.

01:29:24.200 | I mean, just to put context on it,

01:29:26.760 | drugs can be patented and sold as a commercial version

01:29:30.520 | and not as generic versions until the patent runs out,

01:29:32.980 | unless companies are able to find

01:29:34.300 | another approved clinical use,

01:29:36.680 | in which case it can be remarketed

01:29:38.720 | only as a brand name, not generic version.

01:29:42.720 | So a lot of companies, once they do the safety testing

01:29:45.920 | and given everything they put into the R&D,

01:29:49.120 | into the research and development,

01:29:50.280 | there's a very big incentive

01:29:52.240 | to not necessarily finding new drugs,

01:29:54.880 | but finding new uses for the same drugs

01:29:57.560 | and not allowing generic versions into the picture.

01:30:01.080 | And that's why it's likely to be,

01:30:03.160 | based on these what sounds like additional uses

01:30:07.680 | of ozempic-related compounds,

01:30:10.640 | a long time before there's generic ozempic available.

01:30:14.120 | - I think it will be a while.

01:30:15.240 | I don't know the exact status of the patents,

01:30:17.160 | but I'm guessing it's gonna be a while

01:30:18.640 | before there are generic versions,

01:30:19.840 | but there's a lot of competition coming.

01:30:21.960 | So every major pharmaceutical company

01:30:24.000 | or almost every major pharmaceutical company

01:30:25.680 | now has a GLP-1 program.

01:30:27.280 | - Really?

01:30:28.120 | - And some of them are really exciting, actually.

01:30:31.920 | So, I mean, the general trend in this area

01:30:34.360 | is what people call GLP-1+,

01:30:36.640 | which means you take the GLP-1 agonist,

01:30:39.120 | which is already giving you 15% weight loss or so,

01:30:42.200 | and then you add additional things to that

01:30:43.640 | to give it additional properties.

01:30:46.000 | So one compound is from Eli Lilly,

01:30:47.720 | which makes this other,

01:30:48.820 | so there's this other drug on the market

01:30:50.200 | that we haven't talked about,

01:30:51.180 | but terzepatide, which is known as Moonjaro,

01:30:53.120 | for diabetes and Zep-Bound for obesity,

01:30:56.040 | which is even better, really, in almost every respect,

01:30:57.840 | a better drug than ozempic.

01:31:00.120 | So people lose more weight,

01:31:01.480 | so it's about 21% weight loss at a year.

01:31:04.460 | Fewer side effects, at least at comparable doses.

01:31:10.060 | That seems to be because this other drug, terzepatide,

01:31:14.440 | it has two targets, not one.

01:31:15.680 | So whereas ozempic is just a GLP-1 receptor agonist,

01:31:20.840 | terzepatide is a dual agonist of GLP-1

01:31:23.280 | and this other incretin that we talked about, GIP, G-I-P.

01:31:27.240 | And it seems like having that GIP agonism

01:31:30.760 | actually acts as an anti-nausea effect,

01:31:32.840 | that sort of counteracts some of the nausea

01:31:34.600 | caused by the GLP-1 in the area post-treatment.

01:31:36.440 | There are GIP receptor neurons in the area post-treatment,

01:31:38.240 | this nausea center.

01:31:39.440 | Just sort of, it allows you to crank up the dose

01:31:41.580 | of the GLP-1 agonism even further

01:31:43.560 | while you're suppressing the nausea

01:31:44.880 | and just get even more weight loss.

01:31:47.440 | So now, talking about the future,

01:31:49.400 | things that aren't available yet

01:31:50.320 | but will be in the next couple of years.

01:31:52.360 | So Eli Lilly, the company that makes this drug,

01:31:54.800 | terzepatide/Mujaro, they have a triple agonist

01:31:59.160 | that's in phase three clinical trials now.

01:32:00.720 | So this is now three hormones in one.

01:32:03.220 | It's the GLP-1, which all these drugs have,

01:32:06.480 | the GIP, which is the anti-nausea component,

01:32:09.480 | and then glucagon itself.

01:32:11.320 | And so there's these three hormones all combined in one pill.

01:32:14.240 | And what the glucagon does

01:32:16.640 | is it increases energy expenditure.

01:32:18.600 | And this is a well-known effect of glucagon.

01:32:20.880 | And so you're basically eating less,

01:32:23.240 | your nausea isn't as bad,

01:32:24.520 | and now you're just burning more calories at baseline.

01:32:27.440 | And the results from this drug are incredible.

01:32:28.660 | So basically, there's been one phase two trial published

01:32:32.120 | and people lost 25% of their body weight

01:32:34.080 | at the end of the, I think it was 48-week period,

01:32:38.440 | and they were still losing weight.

01:32:39.460 | So we don't know where the end point,

01:32:41.000 | we don't know what the maximum is.

01:32:42.560 | So there are bigger, longer trials going on now

01:32:44.480 | to figure that out.

01:32:45.880 | But at that point, when you get beyond 25% body weight,

01:32:49.200 | you're talking about basically bariatric surgery, right?

01:32:51.040 | Which is currently the best thing we have,

01:32:52.480 | you know, like these surgeries people do to--

01:32:54.720 | - Stomach staples. - Stomach, yeah.

01:32:55.840 | - Removing a portion of the stomach.

01:32:56.960 | - Removing a portion of the gut.

01:32:58.360 | So really, it's a pharmacologic version

01:33:00.720 | of bariatric surgery.

01:33:02.560 | The other one that I think is really exciting,

01:33:04.620 | there's this compound from Amgen,

01:33:06.000 | it's called, it's just right now, it's just a code,

01:33:07.560 | it's like AMG-133.

01:33:09.760 | But it's like terzapatide

01:33:13.160 | in the sense that it targets both GLP-1 and GYP.

01:33:15.320 | So it's a dual-targeted.

01:33:19.000 | But unlike terzapatide, which activates the GYP receptor,

01:33:22.480 | this Amgen compound inhibits it.

01:33:24.480 | And for reasons that people don't understand,

01:33:26.680 | either activating or inhibiting this receptor

01:33:28.960 | causes you to lose weight.

01:33:30.220 | So it's still a mystery,

01:33:31.560 | but a lot of debate about what's going on there.

01:33:33.840 | But the way this Amgen compound activates the GYP receptor,

01:33:38.840 | or inhibits the GYP receptor, rather,

01:33:41.680 | is that it's an antibody.

01:33:43.560 | So all these other things were peptides,

01:33:44.780 | but this is a much bigger, it's actual protein,

01:33:46.200 | this is an antibody.

01:33:47.960 | And because it's an antibody, it has a much longer lifetime,

01:33:50.840 | even than something like semaglutide, which is seven days,

01:33:53.080 | so it lasts like a month in the blood or something.

01:33:55.500 | And so you can give people monthly injections of this,

01:33:57.800 | and they lose dramatic amounts of weight.

01:34:00.440 | And then, at least in this initial trial,

01:34:02.940 | at the end of this, they stopped,

01:34:04.400 | and people maintained the weight loss for six months.

01:34:06.800 | - That's impressive.

01:34:07.640 | - Potentially because of the long-lasting effects

01:34:09.680 | of this antibody, or potentially because of other things

01:34:11.560 | that we don't understand.

01:34:12.840 | So, and those are just two,

01:34:13.920 | there's all sorts of other crazy things happening.

01:34:15.500 | So really, I think it's just created this explosion

01:34:18.120 | of interest in pharma once.

01:34:20.280 | Basically, it's one of these things,

01:34:22.260 | once you see that something can be done,

01:34:23.960 | all of a sudden, that changes everyone's perspective.

01:34:26.120 | And so now, obesity drug discovery has gone from something

01:34:29.120 | that 10 years ago, everyone wanted to stay away from,

01:34:31.280 | because there were so many nightmare stories

01:34:33.000 | about drugs that turned out to be not safe.

01:34:34.960 | 'Til now, everybody's sort of all in on this.

01:34:37.640 | - Yeah, I remember in college, the fen-fen debacle,

01:34:40.320 | where a diet drug was released,

01:34:42.440 | and people had cardiac issues, started dying,

01:34:44.200 | so it was pulled from market,

01:34:45.200 | and then it was essentially a quiet field for a long time.

01:34:49.160 | In part, to bring us back into the brain,

01:34:51.600 | and in part because it's directly relevant

01:34:53.920 | to what we've been discussing about Ozempic and GLP-1,

01:34:58.920 | there are other neurons in the brain that regulate feeding,

01:35:04.320 | and there are other peptides involved in appetite control,

01:35:09.440 | for which I would say niche communities

01:35:11.360 | have started to indulge in.

01:35:13.320 | And by the way, people were taking GLP-1 analogs

01:35:16.080 | long before they were FDA-approved

01:35:17.800 | in kind of niche communities.

01:35:19.000 | These aren't communities I'm a part of,

01:35:20.260 | but every once in a while,

01:35:21.560 | I'll stick an ear into one of these communities

01:35:23.120 | and hear what people are taking.

01:35:24.040 | And a big thing right now in these communities

01:35:29.040 | is the use of other peptides

01:35:31.640 | that are in the melanocyte-simulating hormone pathway.

01:35:36.040 | And you mentioned melanocortican receptor-containing neurons.

01:35:41.040 | Could you tell us a little bit about what these neurons do

01:35:45.800 | in the absence of any pharmacologic stimulation,

01:35:48.360 | and then why it would be that people would perhaps

01:35:52.800 | stimulate these pathways with these drugs?

01:35:56.640 | Not that we're recommending that,

01:35:57.800 | but I do think that given that some of these neurons

01:36:01.440 | are also involved in sexual behavior

01:36:02.840 | and are FDA-approved for the treatment

01:36:04.560 | of hyposexual function in women, things like that,

01:36:08.920 | there is FDA approval for some of these compounds,

01:36:11.160 | that they're interesting hypothalamic neurons

01:36:13.520 | that are starting to gain more attention,

01:36:15.600 | and that I predict, based on their potential involvement

01:36:18.640 | in feeding appetite and weight control,

01:36:21.360 | are likely to enter the picture with more prominence

01:36:24.600 | in the not-too-distant future.

01:36:25.920 | - So alpha-MSH, as scientists call it,

01:36:28.600 | the hormone you were just referring to,

01:36:30.240 | is a product of the POMC gene.

01:36:34.400 | So in the same way that we just talked about,

01:36:35.440 | glucagon can be processed into different things,

01:36:37.560 | and some cells, it's made into the glucagon hormone,

01:36:40.840 | and other cells, it's made into GLP-1.

01:36:42.960 | POMC, that gene can be processed

01:36:45.320 | to produce different hormones.

01:36:46.160 | And one is alpha-MSH,

01:36:47.200 | which is very important for feeding control.

01:36:49.080 | And so these POMC neurons,

01:36:51.240 | they're in the arcuate nucleus of the hypothalamus,

01:36:53.520 | the same region where these AGRP neurons

01:36:55.760 | I talked about earlier are located.

01:36:57.400 | And there's sort of these two sets of neurons

01:37:02.320 | that have opposing effects on body weight regulation.

01:37:04.160 | And so alpha-MSH inhibits food intake,

01:37:07.240 | and AGRP neurons promote food intake.

01:37:09.360 | And where they converge is at this receptor,

01:37:13.680 | the melanocortin-4 receptor,

01:37:15.480 | which is important for body weight regulation.

01:37:19.120 | And so alpha-MSH is an agonist.

01:37:20.960 | It turns on that receptor,

01:37:22.440 | and the AGRP peptide is an antagonist.

01:37:24.360 | It turns it off.

01:37:26.280 | And so there's a lot of human genetics,

01:37:29.240 | as I mentioned earlier,

01:37:30.520 | implicating this pathway in body weight regulation.

01:37:34.320 | There've been a lot of efforts over many years

01:37:36.880 | to turn alpha-MSH into a drug.

01:37:40.440 | And it's been very difficult.

01:37:41.920 | There is one drug that's now approved.

01:37:44.800 | It's called, I think, I'm gonna get the name wrong,

01:37:46.720 | it's like setmelanotide or something like this.

01:37:49.720 | It's an MC4 receptor agonist.

01:37:51.520 | It's mainly used in relatively small populations of people

01:37:55.320 | that, for example, have mutations in this pathway.

01:37:57.960 | It's not used as a widespread, as a drug.

01:38:00.520 | And the challenge has been really side effects.

01:38:04.200 | So there's an increase in blood pressure that happens

01:38:07.560 | sometimes with these medicines,

01:38:08.520 | partly because this pathway controls not only appetite,

01:38:12.240 | but also autonomic tone

01:38:14.000 | and sympathetic nervous system activation.

01:38:16.100 | So it's just taking a step back

01:38:21.880 | from everything we've talked about today.

01:38:24.160 | I talked about this short-term system

01:38:26.080 | and the long-term system

01:38:27.080 | that controls energy balance and body weight.

01:38:28.960 | The long short-term system in the brainstem,

01:38:30.760 | the long-term system in the hypothalamus,

01:38:32.840 | the long-term system being leptin and alpha-MSH and AGRP.

01:38:36.440 | When I was coming up, learning about this stuff

01:38:38.760 | 15 years ago or 20 years ago,

01:38:40.240 | the dogma was you could only affect body weight

01:38:46.040 | through the long-term system,

01:38:47.780 | by manipulating the long-term system.

01:38:49.360 | Because any manipulation you did

01:38:51.080 | of the short-term system in the brainstem,

01:38:53.000 | the animal would just compensate.

01:38:54.640 | And there were these famous experiments

01:38:55.900 | where they would take CCK,

01:38:56.960 | which is a hormone just like GLP-1,

01:38:59.040 | inject it into rats, inject it several times a day.

01:39:01.880 | And CCK is known to decrease the size of meals.

01:39:04.520 | And it would decrease the size of meals,

01:39:05.980 | but the rats would never lose any weight

01:39:07.080 | because they would just eat more meals to compensate.

01:39:08.720 | And they would just perfectly compensate

01:39:09.720 | by eating more meals.

01:39:10.800 | And so the lore was, it's just impossible.

01:39:13.120 | The animal will always compensate

01:39:14.240 | unless you hit this body weight set point regulating area,

01:39:17.080 | which is the hypothalamus, the long-term system.

01:39:19.480 | But then what the pharmaceutical industry discovered,

01:39:22.200 | which I guess maybe shouldn't be so surprising,

01:39:23.440 | but I guess it was to some people,

01:39:25.400 | is that if you just hit that receptor,

01:39:27.360 | that short-term system 24 hours a day, seven days a week,

01:39:29.960 | and never let it stop, then you will lose weight, right?

01:39:32.680 | And so the short-term system alone

01:39:33.800 | is enough to cause body weight regulation.

01:39:36.360 | On the other hand, the long-term system

01:39:38.320 | with alpha MSH and AGRP neurons and POMC

01:39:41.240 | and all this stuff has been a challenge

01:39:42.720 | to pharmaceutically target.

01:39:44.080 | As you know, leptin we discussed didn't really work.

01:39:48.120 | And so I think there's gonna be, as you mentioned,

01:39:51.900 | a re-emergence of interest

01:39:53.200 | in considering this other pathway

01:39:54.480 | now that we've seen the success of the GLP-1s.

01:39:58.480 | And I think one area where it may emerge

01:40:00.680 | is in considering their combination,

01:40:03.320 | perhaps at different stages of weight loss.

01:40:05.480 | So perhaps, what would make a lot of sense scientifically,

01:40:08.680 | I don't know if it'll work in practice,

01:40:10.340 | is that you would take a GLP-1 drug to lose the weight.

01:40:13.040 | And then at some point you might stop that drug

01:40:15.400 | and switch to a more hypothalamus-centered

01:40:17.840 | leptin-based drug to keep the weight off.

01:40:20.320 | So basically, use the GLP-1 drug

01:40:22.540 | to force yourself to lose the weight

01:40:24.460 | and then use the leptin hypothalamus-based drug

01:40:27.180 | to sort of say, okay, this is our new body weight set point,

01:40:29.380 | let's not resist this weight loss that's happened.

01:40:32.540 | Whether that will actually make sense practically

01:40:33.780 | is hard to say because the GLP-1 drugs

01:40:35.260 | have just a lot of benefits, even beyond weight loss,

01:40:37.060 | so people might not wanna stop taking them.

01:40:39.140 | But that's one idea.

01:40:41.620 | - Very interesting.

01:40:42.620 | I'd love to talk about dopamine.

01:40:45.580 | - Sure.

01:40:46.860 | - We hear so much about dopamine,

01:40:48.540 | being involved in pleasure.

01:40:50.060 | I like to think I've had at least a small level of impact

01:40:53.940 | in convincing people that it's also involved in,

01:40:56.980 | perhaps mostly involved in things like motivation,

01:40:59.860 | different forms of learning,

01:41:00.920 | and lots of other things too, folks.

01:41:02.980 | Dopamine does lots of things.

01:41:04.060 | It's even expressed in the eye,

01:41:06.180 | controls adaptation to light.

01:41:07.580 | So it does lots of things.

01:41:08.860 | But it certainly is believed that dopamine is involved

01:41:13.420 | in our either craving for food or pleasure from food.

01:41:17.620 | What's the real story on dopamine

01:41:19.900 | as it relates to food and eating behavior?

01:41:22.340 | You had a beautiful paper published in "Nature" entitled,

01:41:25.460 | and we'll put a link to this in the show note captions,

01:41:27.860 | "Dopamine Subsystems That Track Internal States."

01:41:31.660 | And I love this paper for a variety of reasons.

01:41:34.220 | But if you could give us the high points

01:41:36.100 | of your discoveries on dopamine as it relates to feeding,

01:41:39.060 | I think I know, in fact,

01:41:41.260 | that people would find it very illuminating.

01:41:43.380 | - Sure, fantastic.

01:41:44.740 | So, yeah, the question of what dopamine does

01:41:48.580 | with respect to feeding is a great question

01:41:50.380 | and a difficult question, I think, to answer.

01:41:52.580 | There's a lot of misconceptions.

01:41:54.420 | I think the evidence is dopamine

01:41:56.500 | probably isn't so much involved in the pleasure of food,

01:41:59.140 | that taste, the hedonic experience.

01:42:01.680 | One reason we think this is because you can make mice,

01:42:06.140 | that Richard Palminer did this decades ago,

01:42:08.340 | that don't have any dopamine,

01:42:09.580 | and they still show the same sort of effective responses

01:42:12.540 | to food.

01:42:13.380 | So you put something sweet in their mouth,

01:42:14.200 | psh, they like it, right?

01:42:15.680 | What dopamine seems to be important for

01:42:19.140 | with respect to food is two things.

01:42:21.540 | One is the motivation to engage in work to get food,

01:42:25.140 | particularly when it's high levels of effort.

01:42:27.460 | So if you ask a mouse to press a lever

01:42:31.540 | to get a pellet of food,

01:42:32.860 | if it doesn't have any dopamine, it won't do it.

01:42:35.620 | And if it has low levels of dopamine,

01:42:36.900 | it'll just work a little bit.

01:42:37.860 | So dopamine is important for sort of energizing action

01:42:40.620 | and motivating you to engage in hard tasks.

01:42:43.860 | The other thing that dopamine

01:42:44.700 | is really important for is learning.

01:42:46.220 | And it's important for learning about

01:42:48.100 | which cues predict something useful for the body.

01:42:51.340 | And feeding is a central example of that.

01:42:54.500 | And what that paper of ours is about

01:42:57.260 | is the idea that this learning actually happens

01:42:59.540 | on two different timescales for two different kinds of cues.

01:43:02.980 | So what we almost always talk about with dopamine

01:43:05.900 | and learning, which is important,

01:43:07.500 | is learning about how external cues in the environment

01:43:10.340 | predict something like food availability, right?

01:43:12.600 | So you see a McDonald's sign and you know

01:43:14.700 | that that means there's some tasty food in there.

01:43:18.340 | And so dopamine is involved in that process

01:43:21.300 | of sort of learning what that external cue means.

01:43:24.740 | And that's a very fast timescale process.

01:43:26.740 | So in the laboratory, for example, we will play a tone

01:43:31.740 | and then give an animal a sip of a solution

01:43:35.120 | that has calories in it, for example.

01:43:37.180 | And it can learn the association between that tone

01:43:39.860 | and that the food is going to be available

01:43:41.540 | if they're separated by a few seconds, but that's all.

01:43:43.900 | And that's a dopamine-dependent process.

01:43:46.100 | But there's a second sort of much slower timescale

01:43:50.580 | learning about food, which isn't about where I go

01:43:52.380 | to get a hamburger, but rather about what the experience

01:43:55.140 | of eating the food, the aural sensory experience,

01:43:57.060 | its taste, its flavor, its texture,

01:43:59.260 | how that relates to the post-ingestive effects.

01:44:01.380 | - And I should say that this seems extremely relevant

01:44:03.580 | to the McDonald's example,

01:44:05.080 | because in your experimental situation,

01:44:08.740 | the tone is analogous to the golden arches

01:44:10.860 | of the McDonald's sign. - Exactly.

01:44:12.220 | - But in my experience, and forgive me,

01:44:15.440 | but most of the food that I've consumed from McDonald's

01:44:18.220 | does not taste good relative to other

01:44:21.700 | like really delicious hamburgers or French fries

01:44:24.080 | or something like that.

01:44:25.380 | I mean, it's, so you're saying dopamine is required

01:44:29.540 | to link the signal, the golden arches or the tone

01:44:32.620 | to the presence of food at a particular location.

01:44:35.540 | - Exactly.

01:44:36.380 | - But not to the experience of pleasure from that food.

01:44:39.500 | - Exactly.

01:44:40.340 | - Which wears very well with my experience of McDonald's.

01:44:42.180 | And I probably haven't had a bite of McDonald's

01:44:44.020 | in 20 plus years.

01:44:47.100 | - Yeah.

01:44:47.940 | - I would have to be pretty hungry.

01:44:49.060 | - I haven't either.

01:44:49.880 | And it's funny, the golden arches thing

01:44:52.460 | is just something that people in neuroscience talks

01:44:54.140 | about dopamine use.

01:44:55.100 | And so now I've started subconsciously

01:44:56.540 | just talking about golden arches,

01:44:57.660 | even though I also haven't eaten McDonald's in decades.

01:44:59.780 | - In and out burgers, better tasting,

01:45:02.300 | from what I understand, probably better sourcing.

01:45:04.160 | We're not gonna get into all of this in detail,

01:45:05.740 | but everyone has their preferences.

01:45:07.380 | But I do think it's interesting

01:45:09.520 | because what we're talking about here is related,

01:45:12.500 | I think, to this notion of highly processed food,

01:45:14.980 | packaging, the commoditization of food,

01:45:17.540 | just the idea that we are drawn to food for things

01:45:20.260 | other than the taste that we expect for it.

01:45:23.580 | There's all this context.

01:45:24.740 | - That's right.

01:45:25.580 | So I think an important distinction that people make

01:45:28.920 | is the distinction between wanting and liking.

01:45:31.160 | I don't know if you've talked about this previously

01:45:32.420 | on the podcast.

01:45:33.260 | - Anna Lembke, my colleague at Stanford

01:45:34.740 | came on the podcast, talked about dopamine

01:45:36.580 | is about wanting as opposed to enjoying.

01:45:38.900 | - Exactly.

01:45:39.740 | - In most cases.

01:45:40.560 | - Yeah, so liking is the subjective hedonic pleasure

01:45:43.160 | in the moment of eating it,

01:45:44.220 | but wanting is just what's what you want.

01:45:46.340 | And this can be uncoupled all the time.

01:45:48.520 | You can want things that at the end of the day,

01:45:50.180 | you don't actually enjoy it when you get it.

01:45:51.460 | I feel like a lot of life is like that.

01:45:52.940 | - Indeed.

01:45:53.780 | - And so dopamine is very powerful

01:45:58.780 | at making you want something, but not necessarily like it.

01:46:02.360 | So that's one element.

01:46:03.200 | But then there's this other element that is important,

01:46:05.380 | but very much less studied,

01:46:06.900 | but I find much more interesting,

01:46:08.840 | which is how you connect the sensory cues

01:46:12.260 | associated with food, its taste, its flavor, its smell,

01:46:16.060 | with the consequences for the body.

01:46:18.380 | And this is so important because so much of whether we like

01:46:22.340 | or dislike a particular food or drink

01:46:24.940 | is related to its post-ingestive effects.

01:46:26.820 | You come to like things, for example, that have calories.

01:46:29.260 | So this is one of the reasons that adults will eat vegetables

01:46:31.620 | and other savory foods that children find disgusting.

01:46:34.200 | Even though they're a little bit bitter,

01:46:35.500 | you learn through experience,

01:46:36.340 | this makes me feel good to eat this.

01:46:37.480 | And even maybe at a completely subconscious level,

01:46:40.100 | there's also a level of learning that occurs.

01:46:43.120 | And this, of course, happens with other things like coffee

01:46:45.100 | and beer and other things like that.

01:46:47.500 | And so there's been an idea

01:46:49.280 | that this other much slower learning occurs.

01:46:51.620 | And the reason I say it's slower

01:46:52.580 | is because the time between when you taste the food

01:46:55.020 | and when it actually gets into your intestine

01:46:56.420 | and releases the hormones that might drive this

01:46:58.540 | is quite slow, separated by tens of minutes.

01:47:01.260 | But how that works hasn't been clear.

01:47:02.980 | There's been an idea that dopamine might be involved,

01:47:06.360 | but it hadn't really received a lot of attention.

01:47:08.580 | And so we set out to investigate

01:47:10.300 | what is the role of dopamine

01:47:11.400 | in these post-ingestive responses

01:47:12.940 | and sort of map out for the dopamine system,

01:47:15.100 | how does the dopamine system respond,

01:47:16.460 | not when you see the golden arches,

01:47:18.720 | which is usually the kinds of experiments

01:47:20.340 | that have been performed,

01:47:21.180 | but rather when you deliver nutrients

01:47:22.620 | directly to your stomach,

01:47:23.820 | or when you deliver water directly to your stomach

01:47:25.780 | if you're thirsty and so on.

01:47:27.940 | And what we saw was that there are these different

01:47:30.020 | populations of dopamine neurons

01:47:31.780 | that are tuned to respond to signals from inside the body.

01:47:35.200 | And so there are some that respond when nutrients

01:47:37.580 | are in the stomach and intestine.

01:47:39.220 | There are others that respond in a thirsty mouse

01:47:43.540 | when the blood is rehydrated,

01:47:45.180 | when you basically satiate your thirst.

01:47:47.140 | And we showed that the purpose,

01:47:51.340 | or at least a purpose of that activation

01:47:53.420 | is to cause you to learn about the effects

01:47:56.740 | of what you just ate,

01:47:57.580 | basically to create this connection

01:47:58.940 | between the flavor of something

01:48:00.500 | and its post-ingestive effects.

01:48:01.860 | So that sort of, that delayed dopamine signal

01:48:04.920 | after ingested food and fluids

01:48:06.380 | is sort of reinforcing this connection

01:48:08.000 | between the flavor of what I just ate

01:48:09.400 | and that it was something good for me.

01:48:11.200 | One of the sort of interesting things about that paper

01:48:13.400 | that was not the direction we initially expected to go in

01:48:16.120 | is that for food, I think it's kind of intuitive.

01:48:19.240 | There are lots of flavors to food.

01:48:20.440 | You have to learn what all these different flavors mean.

01:48:24.280 | For thirst, people find it a little less obvious

01:48:26.200 | because thirst is just water.

01:48:27.960 | Aren't you just born knowing what water is?

01:48:30.780 | Like how do you have to learn anything

01:48:32.040 | to do with drinking a glass of water?

01:48:34.560 | But it actually is a learning question in part

01:48:37.760 | because for many animals, probably most animals,

01:48:41.000 | thirst is something that's associated with eating,

01:48:43.680 | not drinking.

01:48:44.840 | There's this study I love of rabbits in New Zealand.

01:48:48.840 | So there's not a lot of people studying what animals,

01:48:51.300 | how they get their fluids in the wild,

01:48:52.400 | 'cause who cares, but it's kind of interesting.

01:48:54.380 | And so in New Zealand, there's this huge rabbit problem

01:48:57.160 | 'cause they're an invasive pest species

01:48:58.720 | that was introduced in the 1800s

01:49:00.560 | and they're just eating all the land.

01:49:02.120 | And so there's lots of money to study rabbits,

01:49:04.480 | to understand their ecology.

01:49:06.480 | And so a group of researchers did this experiment

01:49:08.640 | where they made this big pen outside

01:49:10.520 | where they put a bunch of rabbits in this.

01:49:11.640 | The rabbits couldn't escape,

01:49:12.480 | but they had all their natural food.

01:49:13.520 | It was like an outdoor area.

01:49:15.200 | And they also put a trough of water.

01:49:17.020 | So the rats always had access to water,

01:49:18.840 | which is a clean water,

01:49:19.880 | and they could measure how much water the rabbits drank.

01:49:22.840 | And what they basically found is that nine months

01:49:24.320 | out of a year, rabbits drink zero water.

01:49:26.600 | They drink absolutely zero

01:49:27.720 | because they get all of their water from food.

01:49:30.280 | The only time they drink is during the winter

01:49:32.680 | when all of the greenery has sort of become shriveled

01:49:35.220 | and then they can't get water from that anymore.

01:49:38.280 | And so it's just kind of interesting aspect

01:49:39.880 | of how many animals are very different

01:49:41.920 | from the way we think about ingestive behavior.

01:49:43.560 | But that fact that animals have to get water from food

01:49:47.240 | raises this question,

01:49:48.120 | how do they know which foods are rehydrating?

01:49:50.800 | Presumably they have to learn that

01:49:52.200 | because you can't just look at a food

01:49:53.520 | and say if you've never had any experience,

01:49:55.480 | oh yeah, this is something that's very water rich

01:49:57.440 | and this will rehydrate me when I'm thirsty

01:49:58.880 | and this one is not.

01:50:00.640 | And so James, the graduate student who led this project,

01:50:03.440 | basically investigated this by giving mice different fluids

01:50:09.000 | and then measuring the dopamine response.

01:50:11.360 | And he showed there was this delayed dopamine response

01:50:13.440 | after the mice had drank the fluids

01:50:15.560 | that correlated with rehydration of the blood.

01:50:18.920 | So a whole bunch of dopamine neurons

01:50:20.120 | get strongly activated when the blood is rehydrated.

01:50:23.240 | And he hypothesized this might be a signal,

01:50:25.560 | this delayed activation of dopamine neurons

01:50:28.240 | that allows animals in the wild to learn

01:50:30.200 | that food I just ate is rehydrating.

01:50:34.480 | And so he did an experiment

01:50:36.080 | where he basically gave them two different flavors,

01:50:38.380 | mimicking sort of the flavors of two different foods,

01:50:41.260 | one of which was hydrating and one of which was not.

01:50:43.160 | And the animals couldn't tell

01:50:44.000 | because he infused the water directly into their stomach.

01:50:46.620 | And he showed that basically these dopamine neurons

01:50:49.920 | are critical for them learning that association.

01:50:52.520 | So that's the story of that.

01:50:54.040 | - I love it and I'll tell you why.

01:50:56.640 | When I was in college, for reasons that I don't recall,

01:50:59.760 | I decided to run an experiment on myself

01:51:01.760 | where I would eat one meal

01:51:05.480 | that was fairly low water content,

01:51:08.800 | like a piece of meat or something with some cheese,

01:51:11.640 | you know, what some people call a keto meal,

01:51:13.360 | but I wasn't ketogenic.

01:51:14.740 | I don't even think I knew

01:51:15.580 | what a ketogenic diet was at that point.

01:51:18.040 | And then the next meal,

01:51:18.860 | I would have like a salad and some fruits.

01:51:21.960 | And then I would switch back and forth.

01:51:23.960 | And I generally would only eat two or three times a day.

01:51:27.160 | You know, anyway, there's only so many hours in the day.

01:51:30.000 | And I found it to be incredibly satiating.

01:51:32.940 | And I found that I felt great.

01:51:35.840 | And I can imagine any number of different reasons for that.

01:51:39.260 | And there are these theories that you probably recall

01:51:41.160 | that the diet that was being promoted in the '90s

01:51:45.660 | where people would either eat carbohydrates

01:51:47.440 | or protein separately.

01:51:48.640 | Like there was some wackiness out there.

01:51:50.120 | And as I say that,

01:51:51.080 | I'm sure I'll get assaulted in the comments.

01:51:52.520 | It's probably not wacky.

01:51:53.400 | I'm sure there's some enzymatic basis

01:51:55.640 | for why that would be useful.

01:51:56.560 | If you enjoy it, go for it.

01:51:58.200 | You know, I don't have a feeling about it

01:52:01.560 | one way or the other.

01:52:02.400 | But one thing I noticed was that

01:52:04.700 | low water content containing meals,

01:52:09.540 | either by virtue of the foods that they include

01:52:13.120 | or by virtue of the fact that they're not diluted,

01:52:15.560 | so to speak,

01:52:16.400 | it's a different taste experience to eat those foods

01:52:21.560 | than it is to eat like a big salad

01:52:23.360 | or something of that sort.

01:52:25.220 | In any event, I don't do that any longer.

01:52:27.320 | I just sort of stopped, but it was a fun experiment.

01:52:30.040 | And I think it was efficient

01:52:32.160 | because at the time I had very low money as a student.

01:52:34.200 | So, you know, generally fruits and vegetables

01:52:36.380 | were less costly than meats and things of that sort.

01:52:38.180 | But in all seriousness,

01:52:40.500 | to what extent do you think humans overeat or undereat

01:52:46.340 | depending on the water content of the food?

01:52:48.340 | - It's an interesting question.

01:52:49.580 | So, you know, there is this advice

01:52:51.500 | that you should, if you're hungry,

01:52:53.340 | first drink something, drink some water

01:52:55.540 | and see if you're still hungry.

01:52:57.060 | And the idea is that perhaps humans can't always,

01:53:02.060 | I mean, our interoceptive sense,

01:53:04.700 | our ability to sense what our body needs is not perfect.

01:53:07.020 | And sometimes we could be confused

01:53:08.500 | and we could really be thirsty when we're hungry

01:53:10.180 | and hungry when we're thirsty.

01:53:11.860 | And there's some evidence that that could help.

01:53:14.260 | I would say it's probably not a huge effect

01:53:17.660 | in most of modern day life,

01:53:19.080 | but it's an interesting idea, yeah.

01:53:23.820 | - This brings us to the topic of thirst,

01:53:25.700 | something that your laboratory has worked on extensively

01:53:27.980 | and the topic of osmolarity of salt consumption

01:53:32.780 | and things of that sort.

01:53:33.980 | In broad terms, how do these things link up?

01:53:38.500 | Meaning, are there instances in which

01:53:41.880 | what we really need is salt

01:53:43.420 | and we end up eating a bunch of Parmesan cheese?

01:53:46.300 | I got teased yesterday by my team

01:53:47.620 | because occasionally when I'm on the road,

01:53:48.940 | I don't like most of the foods available

01:53:50.560 | in most airports and stuff.

01:53:51.500 | So I'll bring a chunk of really nice Parmesan cheese.

01:53:53.820 | I just break off a piece and eat it.

01:53:55.380 | I'll have half a cucumber and I'll have a can of,

01:53:58.580 | not a can of tuna,

01:53:59.460 | but there are these wonderful jarred filet of tunas

01:54:02.420 | that are available that are in olive oil.

01:54:03.920 | They taste really good.

01:54:05.040 | This is not canned tuna, it's really good.

01:54:07.220 | And I'd rather eat that in most cases

01:54:10.580 | until I can get to a decent meal

01:54:13.660 | than like what's put in front of me on an airplane,

01:54:16.660 | most of the time.

01:54:18.180 | So I get teased about this,

01:54:19.180 | but I notice that for instance,

01:54:21.200 | sometimes I'll eat the cheese and I think,

01:54:23.060 | oh, actually what I really just want is the salt.

01:54:25.460 | - Yeah.

01:54:26.300 | - I really want the salt.

01:54:27.120 | I've been drinking a lot of coffee today.

01:54:28.820 | I've had a couple extra glasses of water.

01:54:30.500 | Maybe I'm just craving salt and I'm confused

01:54:32.900 | and I'm over consuming this cheese.

01:54:35.220 | - Yes.

01:54:36.060 | - When in fact, what I'm going for is the salt.

01:54:38.140 | As you point out,

01:54:39.980 | our understanding of exactly what we need is fairly crude

01:54:44.100 | and oftentimes we overshoot the margin,

01:54:46.420 | especially when foods are in combination.

01:54:48.780 | So salt, water, and let's just say calories.

01:54:53.780 | How do we accurately or inaccurately pursue those

01:54:59.540 | at the level of biology?

01:55:01.100 | - Okay.

01:55:02.220 | So I was-

01:55:03.060 | - You're throwing tough questions at me.

01:55:03.900 | - I know, this feels-

01:55:04.740 | - But you're-

01:55:05.780 | - Feels like my qualifying exam.

01:55:07.380 | So, well, there are separate systems.

01:55:11.300 | There's thought to be separate systems

01:55:12.500 | that control salt appetite, thirst for water

01:55:15.620 | and hunger for calories.

01:55:17.460 | And so they involve different brain regions

01:55:19.540 | for the most part, different neurons,

01:55:21.100 | different signals from the body.

01:55:22.740 | In general, hunger and thirst are pretty separable.

01:55:28.380 | I would say the instance where they interact

01:55:31.060 | is in phenomena such as dehydration anorexia.

01:55:34.500 | This is the idea that if I give you some dry food

01:55:37.340 | but I don't give you any water,

01:55:38.860 | you're gonna eat less food

01:55:40.940 | because basically you're gonna get dehydrated

01:55:42.540 | and you're gonna decide I need to preserve

01:55:44.660 | my fluid balance even if I eat less calories.

01:55:47.860 | - So we prioritize hydration.

01:55:51.500 | - Yes, you will at some point-

01:55:52.780 | - The level of survival.

01:55:53.620 | - At some point you will prioritize hydration.

01:55:56.340 | That's related also to the concept of prandial drinking.

01:55:58.660 | So many animals, including humans,

01:55:59.940 | drink most of their water during meals

01:56:01.380 | because you basically wanna counteract

01:56:02.740 | the osmolites that are in your food.

01:56:04.540 | Salt balance though, and then thirst,

01:56:08.780 | so the thirst for water and the desire for salt

01:56:11.460 | are much more tightly linked

01:56:12.740 | because the purpose of both systems

01:56:15.780 | is to maintain the composition of the blood

01:56:18.540 | at its right concentration.

01:56:19.820 | So you want to have the right osmolality of the blood,

01:56:22.780 | which you can just think of in simple terms

01:56:24.420 | as sort of the total concentration of all the salts.

01:56:27.740 | It's a little more complicated than that,

01:56:30.300 | but it doesn't really matter.

01:56:31.500 | And you also specifically need to maintain

01:56:35.220 | the sodium concentration at the right level.

01:56:37.460 | And there are really powerful innate mechanisms

01:56:42.300 | that drive both.

01:56:43.140 | I think thirst is very intuitive to people.

01:56:45.260 | You get dehydrated, you lose water, you become thirsty.

01:56:48.580 | And we know now that there are a very small set of neurons

01:56:53.980 | in a few brain regions that control that.

01:56:56.540 | And the way they're thought to work

01:57:01.100 | is they contain osmosensors.

01:57:02.980 | So they contain basically,

01:57:05.020 | these neurons are sensors for the osmolality of the blood,

01:57:07.500 | and they're activated when the blood osmolality

01:57:09.300 | gets too high.

01:57:10.140 | And it's an incredibly sensitive system.

01:57:11.820 | So you can perceive an increase in your blood osmolality

01:57:15.420 | of 1% as the sensation of thirst.

01:57:17.860 | So remarkable, yeah.

01:57:20.020 | - That's how critical it is to maintain salt balance.

01:57:22.060 | - Exactly, exactly.

01:57:23.340 | And so you get to 10% increase in blood osmolality,

01:57:26.700 | and you're in extreme discomfort,

01:57:28.020 | and 20% you're like in the hospital.

01:57:29.540 | - So if I took, let's just say a half an ounce sip

01:57:34.540 | of seawater inadvertently, it's extremely aversive.

01:57:41.340 | - It is.

01:57:42.180 | - It's like, like you just,

01:57:43.740 | you want to drink some non-salty water,

01:57:47.260 | some nice clean water.

01:57:48.580 | - Yes, exactly.

01:57:49.500 | - Immediately.

01:57:50.380 | - Yeah.

01:57:51.220 | So I should emphasize that there's two components

01:57:53.960 | to the fluid homeostasis system,

01:57:55.180 | to the water homeostasis system.

01:57:56.780 | One is this desire to drink.

01:57:58.180 | But the other is, of course, the kidney.

01:58:01.140 | And so the reason that drinking the salt water

01:58:03.260 | won't put you in a really bad situation

01:58:05.180 | is your kidney would then filter out a lot of that salt

01:58:07.260 | and cause you just to pee it out, and then you'd be fine.

01:58:10.340 | And so those two work in balance.

01:58:11.500 | The kidney's controlling how much of the salt

01:58:13.060 | gets reabsorbed into the blood,

01:58:14.580 | and then this desire for thirst, this desire to drink,

01:58:17.780 | allowing you to replenish the blood with water

01:58:19.700 | at various intervals.

01:58:21.040 | And so, yeah, I mean, the experiments led to the discovery

01:58:25.580 | of this thirst circuitry are amazing.

01:58:26.700 | It was this guy, Bengt Andersen, working in the 1950s,

01:58:29.540 | and he just had this hypothesis

01:58:31.180 | that there was an osmosensor in the brain, right?

01:58:33.420 | Which is very, I think, you know,

01:58:35.500 | there was some evidence to suggest it,

01:58:36.580 | but it was not really, really strongly supported

01:58:38.980 | at the time by the data.

01:58:40.380 | And so he took these goats,

01:58:41.740 | and he just started infusing small amounts of salt

01:58:44.820 | into various places in their brain,

01:58:46.340 | reasoning that if there was an osmosensor-

01:58:48.260 | - Sorry to chuckle, I was wild.

01:58:50.220 | I mean, I wasn't chuckling in jest,

01:58:53.020 | like, you know, I feel for the goats,

01:58:54.820 | I feel for everyone involved in that experiment,

01:58:56.460 | but what a wild experiment,

01:58:57.780 | just to put salt directly into the brain?

01:58:59.980 | - Concentrated saline solution, yeah.

01:59:02.020 | And he found this tiny region in and around

01:59:03.920 | the hypothalamus that if you infuse salt in this region,

01:59:07.980 | the goats will drink like eight liters of water

01:59:10.500 | in five minutes, just crazy, right?

01:59:12.860 | And so he reasoned, okay, this must be the osmosensor.

01:59:15.580 | And then he went back and stimulated those neurons.

01:59:18.380 | It's just the same thing.

01:59:19.220 | The goat just drinks like crazy.

01:59:20.980 | And so now we know there's this couple small regions

01:59:23.260 | in and around the hypothalamus.

01:59:24.420 | One's called the subfornicle organ,

01:59:26.100 | another one's called, well, it doesn't really matter,

01:59:27.940 | but basically, that have these osmosensors.

01:59:31.940 | One of the interesting things

01:59:32.940 | about the regulation of fluid balance

01:59:34.440 | is you face some of the same challenges

01:59:35.980 | we just talked about with the regulation

01:59:37.260 | of food consumption, which is that you have this behavior,

01:59:39.700 | this ingestive behavior, that leads to replenishment

01:59:44.660 | of the body, but there are these delays, right?

01:59:46.660 | So if you're thirsty and you drink a glass of water,

01:59:48.600 | it can take on the order of sort of 20 to 30 minutes

01:59:51.140 | for the water to be absorbed into your blood,

01:59:53.300 | for the blood to be rehydrated,

01:59:54.820 | and then for these osmosensors that Bank to Anderson

01:59:56.980 | discovered in your brain to be sort of sense that

02:00:01.620 | and return to normal activity.

02:00:03.500 | But of course, if you had the experience

02:00:04.580 | of drinking a glass of water,

02:00:05.520 | you know that you can quench your thirst within minutes,

02:00:08.020 | right, and so how does that work within seconds even?

02:00:11.100 | So one of the other sort of experiments

02:00:13.360 | we did early in my lab was to ask that question,

02:00:17.060 | by basically recording for the first time

02:00:18.660 | the activity of these neurons that Bank had discovered

02:00:20.580 | by putting the salt in the ghost.

02:00:21.700 | We went back into them now in mice,

02:00:22.860 | mice have the same neurons, you have the same neurons,

02:00:24.940 | and recording their activity when a thirsty mice drinks,

02:00:26.960 | it asks what happens.

02:00:28.020 | And what we saw was that the neurons don't wait

02:00:31.880 | until the blood is rehydrated.

02:00:34.900 | They also don't do what the AGRP neurons do,

02:00:36.700 | is meaning they don't look at the water

02:00:38.140 | and predict how much water they're gonna drink.

02:00:40.200 | But instead, they get a signal from the mouth,

02:00:42.500 | which every time the mouse takes a lick of water,

02:00:44.300 | their activity goes down a little bit.

02:00:46.140 | And basically, they track in that way

02:00:48.060 | the volume of water that's passed through the mouth.

02:00:51.140 | They also get the signal from the blood,

02:00:53.380 | really relaying the osmolarity of the blood,

02:00:54.740 | and they compare these two.

02:00:55.780 | And basically, when the mouse has drank enough

02:00:57.820 | in order for the animal to predict

02:01:00.840 | that the blood osmolality is going to return to normal,

02:01:03.020 | then the animal stops drinking.

02:01:04.260 | - Beautiful.

02:01:05.540 | - Yeah.

02:01:06.380 | - It's just beautiful, right?

02:01:07.200 | - It's incredible.

02:01:08.040 | - I was like, the brain is essentially predicting

02:01:09.940 | with, it sounds like a high degree of accuracy,

02:01:11.940 | how much water one needs to drink,

02:01:13.700 | linking it to the pleasure of ingesting good, clean water

02:01:18.700 | under conditions where we're thirsty,

02:01:21.340 | in anticipation of adjusting blood osmolarity in 20 minutes.

02:01:24.900 | - Exactly.

02:01:25.740 | - I mean, it's, yeah, I mean,

02:01:28.460 | this is the kind of thing that just, it delights me,

02:01:30.700 | because it just means that the brain, as a predictive organ,

02:01:33.620 | is just, is so accurate.

02:01:37.020 | - It also explains some sort of funny aspects of thirst

02:01:40.620 | that you may have noticed from everyday experience.

02:01:42.140 | So, you know, one idea is that just cooling your mouth

02:01:46.140 | can sort of quench your thirst, right?

02:01:48.500 | So if you're in the hospital

02:01:49.420 | and you're not allowed to drink any fluids,

02:01:50.740 | they'll give you ice chips to suck on

02:01:52.140 | to sort of quench your thirst.

02:01:52.980 | So why is that?

02:01:54.580 | And so one idea is that perhaps,

02:01:56.660 | because water is usually cooler than your body,

02:01:59.060 | that sensation of water passing,

02:02:00.540 | it always cools your mouth, and so you learn,

02:02:02.160 | or maybe it's innate, that just cooling of my mouth

02:02:04.340 | means that basically I'm gonna be rehydrated.

02:02:07.460 | So Chris, this was an experiment done by a graduate student,

02:02:09.220 | Chris Zimmerman, Chris did the same thing

02:02:11.260 | where he was recording these thirst neurons,

02:02:13.260 | but he put a cold piece of metal on the mouse's tongue.

02:02:15.540 | And you can see when you do that,

02:02:16.500 | these thirst neurons go down in activity,

02:02:18.060 | and then you remove the cold piece of metal

02:02:19.340 | and they go back up.

02:02:20.180 | - Amazing.

02:02:21.000 | - So a lot of these sort of oddities of everyday experience

02:02:23.740 | have to do with how the system has evolved

02:02:25.820 | to make the prediction

02:02:26.980 | about what's going to happen to the body.

02:02:29.220 | - I mean, few things are as rewarding

02:02:32.140 | as the sensation of drinking really nice, clean, cold water

02:02:36.820 | when one is very thirsty.

02:02:38.540 | When my lab was in San Diego,

02:02:39.900 | I used to take my dog hiking in Palomar Mountain,

02:02:42.580 | and one day, you know, I really screwed up.

02:02:44.500 | He was a bulldog mastiff, they overheat easily,

02:02:47.140 | and it was a lot warmer than we thought.

02:02:49.700 | We ran out of water.

02:02:50.700 | It was a actually dangerous situation for him.

02:02:53.200 | We got down to the bottom of the hill,

02:02:54.580 | thankfully, with him still alive,

02:02:55.980 | and there's this pump that pumps

02:02:58.340 | what I was told was spring water,

02:03:00.740 | and it came out, you know, really cold,

02:03:02.740 | and you could just see him fill back up with life.

02:03:07.060 | I filled back up with life

02:03:08.280 | knowing he was filling back up with life,

02:03:09.940 | and it was unlike the kind of reward

02:03:12.700 | that one experiences with food when you're hungry.

02:03:14.820 | - Absolutely.

02:03:15.660 | - It's like that basic critical need for water

02:03:18.900 | - Absolutely.

02:03:19.900 | - under conditions where you're clearly dehydrated

02:03:22.340 | is like nothing else.

02:03:23.620 | It's delicious in a way that no food is delicious.

02:03:27.180 | - I would like to actually say something about this.

02:03:28.340 | So that distinction you made is really interesting

02:03:30.340 | between hunger and thirst.

02:03:32.100 | So when you stimulate these neurons

02:03:34.340 | that make an animal thirsty, the mice hate it.

02:03:36.580 | They will do anything to avoid something

02:03:38.500 | that artificially makes them thirsty.

02:03:40.060 | So we can artificially stimulate these thirst neurons,

02:03:41.660 | create a state of virtual thirst.

02:03:43.860 | They'll lever press hundreds of times to make it stop.

02:03:46.780 | The same neurons, the neurons I talked about

02:03:48.900 | that control hunger, the AGRP neurons,

02:03:51.180 | they actually don't care so much.

02:03:52.940 | They won't really do much of anything to shut them off.

02:03:55.500 | That raises the question, well,

02:03:56.340 | why do the animals eat then

02:03:58.140 | when you stimulate the hunger neurons?

02:03:59.420 | And we think the primary thing

02:04:00.500 | that the hunger neuron stimulation does

02:04:02.380 | is it make food itself more attractive.

02:04:04.020 | It makes the food more delicious,

02:04:05.380 | more of an attractive motivational magnet.

02:04:08.140 | It makes the experience of eating more pleasurable,

02:04:10.260 | but it is not itself the most unpleasant state.

02:04:12.820 | At least the mice aren't willing to do that much.

02:04:14.900 | Whereas for thirst, I think dehydration and thirst

02:04:17.580 | is really just unpleasant,

02:04:18.660 | and animals just want to avoid that.

02:04:20.100 | And so I think that distinction is very real.

02:04:22.900 | I think there are two different motivational mechanisms

02:04:24.900 | for hunger and thirst.

02:04:25.740 | Hunger is mostly about the reward of food.

02:04:27.980 | Thirst is mostly about, this is just really unpleasant.

02:04:30.900 | - And removing that unpleasant.

02:04:32.460 | - Exactly.

02:04:33.300 | - And you had a paper, which I was going to ask you about,

02:04:35.300 | so I will, entitled "The Forebrain Thirst Circuit

02:04:37.680 | "Drives Drinking Through Negative Reinforcement."

02:04:40.060 | - Yes.

02:04:41.120 | - And I'm guessing that paper

02:04:43.020 | illustrates exactly the point you just made.

02:04:44.940 | So it's a forebrain circuit.

02:04:47.160 | So does that mean that there's some elements

02:04:48.820 | of learning and cognition around this?

02:04:50.620 | Or are we broadly speaking about the forebrain,

02:04:52.340 | for instance, the hypothalamus being in the forebrain?

02:04:55.060 | - So, yeah, it's interesting.

02:04:56.220 | So the thirst circuit, for whatever reason,

02:04:59.000 | is mostly in the forebrain.

02:05:00.500 | So the neurons that,

02:05:02.420 | so we talked about the NTS and the areopostrema

02:05:05.000 | being important for hunger and signals from the gut.

02:05:07.840 | Those are, the areopostrema is a circumventricular organ,

02:05:11.900 | meaning it's outside the blood-brain barrier.

02:05:13.220 | There's only a couple of these in the brain.

02:05:15.260 | The neurons that control thirst

02:05:16.780 | are located in the two circumventricular organs

02:05:19.220 | in the forebrain.

02:05:20.440 | One is called the subfornical organ,

02:05:22.140 | the other one is called the OVLT,

02:05:23.660 | but they're just acronyms.

02:05:25.100 | But so why it evolved to have the thirst neurons

02:05:28.780 | more in the forebrain

02:05:29.820 | and the neurons that sense nutrients more in the hindbrain

02:05:32.860 | is a little bit unclear.

02:05:34.460 | And so there is definitely an element of learning,

02:05:37.020 | but a lot of this is those neurons

02:05:38.840 | are also just directly sensing the blood

02:05:40.380 | and sensing changes in both the concentration of salt

02:05:43.020 | in the blood and then also hormones like angiotensin

02:05:45.100 | that drive thirst.

02:05:46.620 | - I was going to ask you this earlier,

02:05:48.160 | but it seems appropriate to ask now.

02:05:49.940 | A colleague of mine at Stanford in the psychology department,

02:05:53.140 | Dr. Allie Crum, who studies mindsets,

02:05:56.420 | has done some interesting experiments

02:05:58.340 | where people are told that a given milkshake

02:06:00.860 | is calorically dense.

02:06:03.320 | Other people are told that a milkshake is calorically sparse.

02:06:06.680 | Both groups independently consume the milkshake

02:06:10.980 | and then they measure things like hormone responses

02:06:15.140 | in the bloodstream that are associated with satiety.

02:06:17.340 | And what she finds is that even hormone responses

02:06:22.480 | to the same shake, meaning the same amount of calories,

02:06:26.140 | fat, sugar, et cetera, can be significantly modulated

02:06:30.260 | based on what we're told.

02:06:32.240 | And it extends into some other,

02:06:35.740 | perhaps even more interesting areas in my opinion,

02:06:38.980 | whereby if people are told that,

02:06:41.180 | let's say a given meal that has a small piece of fish,

02:06:44.980 | serving of vegetables and a carbohydrate is yes,

02:06:49.100 | perhaps a little bit calorically sparse

02:06:50.900 | compared to what one would normally eat at a given meal,

02:06:53.820 | but they're told this is a highly nutritious meal.

02:06:56.500 | This is good for you.

02:06:57.820 | Then just that mere knowledge can drive more satiety,

02:07:02.820 | better feelings about the meal.

02:07:05.160 | Even, I believe, I have to double check on this,

02:07:08.060 | but as I recall, a heightened sense

02:07:10.720 | of it tasting really good.

02:07:12.360 | So humans are very susceptible to the,

02:07:17.360 | in this case, the either inaccurate,

02:07:19.820 | in the case of the milkshake experiment,

02:07:21.540 | or accurate descriptions of food,

02:07:24.220 | meaning they shape our perception

02:07:26.460 | of whether or not something is good for us,

02:07:29.100 | tastes good or not, and whether or not

02:07:32.340 | it leads to more or less satiety.

02:07:35.380 | And I think this is important given the obesity crisis,

02:07:38.620 | you know, to say nothing of these drugs that are coming out,

02:07:41.620 | whereby people often associate dieting

02:07:43.940 | with deprivation and pain,

02:07:45.840 | but if they understand that certain foods are nutritious,

02:07:49.300 | that can at least partially offset

02:07:51.340 | some of the pain of caloric restriction.

02:07:54.580 | What are your thoughts on that?

02:07:56.860 | - Yeah, well, one thing I've been talking about

02:08:00.260 | is how a lot of these circuits are anticipatory.

02:08:02.740 | They're making predictions.

02:08:03.960 | They're trying to estimate what's happening in the future.

02:08:06.740 | And I talked about how these AGRP hunger neurons,

02:08:09.280 | how they can sort of see the food

02:08:11.060 | or get input about the sight, smell of food,

02:08:13.820 | and that way predict how many calories

02:08:15.420 | the mouse is going to eat.

02:08:16.700 | But, I mean, this is a mouse, right?

02:08:18.780 | This is all based on a mouse.

02:08:19.660 | A mouse has, you know, 1,000 times fewer neurons

02:08:21.780 | than you do as a person, right?

02:08:23.380 | So the computational capacity that the human brain has

02:08:25.900 | to make these predictions is just vast

02:08:28.500 | compared to these mice.

02:08:29.340 | And these mice are already doing amazing things, right?

02:08:31.260 | So when you think about then,

02:08:32.980 | what is the human brain able to do

02:08:34.540 | in terms of anticipating changes in nutritional state

02:08:36.680 | and how information that you're given

02:08:39.500 | can change the expected physiologic outcomes?

02:08:42.880 | I mean, you're right.

02:08:44.260 | I mean, there's just this whole other element

02:08:46.320 | that it's very hard to study

02:08:48.320 | because it's happening in the brains of humans

02:08:49.680 | and we can't do these kinds of experiments.

02:08:52.200 | But I'm sure that's very important.

02:08:53.940 | I mean, so I talked a little bit

02:08:55.320 | about these flavor nutrient conditioning experiments.

02:08:58.600 | These are the experiments where, essentially,

02:09:00.720 | an animal learns to consume a certain flavor

02:09:04.680 | because it learns it's gonna be associated

02:09:06.180 | with nutrients later.

02:09:07.240 | Sort of the paradigm for how you learn

02:09:08.640 | to consume bitter vegetables because they're good for you

02:09:10.600 | and you get nutrients.

02:09:12.140 | So people have also done those experiments in humans.

02:09:15.420 | And that does work, but what they've discovered is

02:09:18.240 | it's very sensitive to what you tell the humans

02:09:20.760 | about the thing that they're going to consume.

02:09:22.960 | So if you put nutritional labels

02:09:24.440 | where you show the different numbers of calories,

02:09:26.240 | then basically they sort of adjust their expectations

02:09:28.880 | and nothing happens.

02:09:29.700 | So it really has to be that sort of,

02:09:31.360 | it's very sensitive to what information you give them

02:09:33.640 | before the experiment happens.

02:09:35.080 | So I think that's an example of that kind of thing.

02:09:38.600 | - Without any pressure for it to be prescriptive,

02:09:43.800 | how do you approach eating given the knowledge

02:09:47.280 | that you have about food?

02:09:48.900 | I like to assume that you can sit down to a meal

02:09:52.140 | and not think about your AGRP neurons too much

02:09:54.380 | or any of that.

02:09:55.200 | But given that you have deep knowledge in this,

02:09:57.880 | has it shaped kind of how you think

02:10:00.340 | about food cravings your own?

02:10:02.380 | You don't have to reveal what those are,

02:10:03.620 | even if they exist.

02:10:05.180 | How you observe the eating behavior of others.

02:10:10.260 | And yeah, how has knowledge shaped your feeding behavior?

02:10:15.260 | - Well, I try not to think too much

02:10:17.760 | about my AGRP neurons when I'm eating.

02:10:19.920 | - I would hope, I would hope.

02:10:21.320 | - I think it gets, I think, you know,

02:10:24.640 | the circuitry is so complex

02:10:25.880 | and we're just beginning to see what's happening.

02:10:27.440 | So I wouldn't use that kind of information at this stage

02:10:30.900 | and we're just beginning to prescriptively.

02:10:32.980 | But I think there is a set of, you know,

02:10:36.920 | basic recommendations from physiology and neuroscience.

02:10:40.660 | Very simple things.

02:10:41.500 | You've probably talked about people on your podcast before,

02:10:44.700 | for sort of shaping your diet to be healthier,

02:10:47.460 | to limit food intake.

02:10:48.620 | So one we've already talked about

02:10:50.780 | is limiting consumption of ultra processed food,

02:10:52.900 | eating more whole foods for lots of different reasons.

02:10:56.120 | Because they're more satiating,

02:10:57.780 | because they don't have this sort of engineered palatability

02:11:00.420 | that causes you to overeat.

02:11:02.500 | Another big one, which I'm sure you've talked about

02:11:04.300 | with some of your guests is protein consumption.

02:11:06.740 | Making sure you get adequate protein consumption,

02:11:09.180 | both because there's this concept of protein leveraging.

02:11:11.660 | So if you don't eat a minimum amount of protein,

02:11:13.540 | that's gonna cause you to eat more calories

02:11:15.100 | just to try to achieve that minimum amount of protein.

02:11:17.640 | Also just because protein's more satiating

02:11:19.220 | and also because there's this idea

02:11:21.020 | of thermic effect of food.

02:11:22.260 | And so you basically burn more calories

02:11:23.700 | metabolizing protein than sugar or fat.

02:11:25.740 | - How about consumption of fluids during meals?

02:11:29.060 | You know, I've heard it said before that, you know,

02:11:32.540 | we're not supposed to consume too many fluids

02:11:34.100 | because it's going to dilute the enzymes

02:11:36.340 | that allow us to digest our food.

02:11:37.900 | I've heard other people say that's a complete--

02:11:40.280 | - I think that's-- - Myth.

02:11:41.740 | - That's a myth, I think.

02:11:42.900 | I mean, I think drinking water,

02:11:45.900 | I mean, so humans don't have a perfect capacity

02:11:48.620 | to determine whether they're hungry or thirsty.

02:11:50.020 | And so drinking water will ensure you're not eating

02:11:51.740 | because you're hungry, because you're thirsty.

02:11:54.040 | And so, and there's no idea of diluting it.

02:11:58.180 | I don't think that, and distention itself,

02:12:00.180 | even though water provides a very limited distention signal,

02:12:02.820 | the expansion of your stomach and intestines

02:12:04.700 | is one important way-- - Interesting.

02:12:07.020 | - That you terminate feeding.

02:12:09.260 | And so there is some component of that

02:12:12.100 | where you can get distention just from drinking water.

02:12:14.100 | I say it's-- - Sorry, I blurted out.

02:12:15.300 | Interesting, because I didn't realize

02:12:16.580 | that fluid consumption only provides

02:12:19.640 | a limited signal for distention.

02:12:21.900 | - Well, it's not fluids, it's water.

02:12:23.180 | And so the idea is that you can fill your stomach up

02:12:26.460 | with fluids, but the rate at which fluids empty out

02:12:29.420 | of your stomach depends on their calorie content.

02:12:32.180 | So basically, if you drink water,

02:12:33.820 | it empties very rapidly into your intestine,

02:12:35.900 | and then it goes through your intestine

02:12:36.980 | and is gradually absorbed.

02:12:38.580 | If you drink something like a glass of orange juice,

02:12:40.620 | it will empty much more slowly.

02:12:42.180 | And if you drink something that's really high in fat,

02:12:43.900 | really high in calories, it'll empty

02:12:44.940 | extremely slowly over hours.

02:12:47.180 | And that's because there's a negative feedback loop

02:12:49.020 | from the intestine that controls gastric emptying.

02:12:51.220 | So as those first nutrients leave your stomach

02:12:56.060 | and enter your intestine, that produces hormones

02:12:58.700 | that go back and then slow down

02:12:59.980 | the rate of gastric emptying.

02:13:01.100 | And the purpose for this is that you don't want nutrients

02:13:03.900 | entering the intestine too fast.

02:13:05.380 | That's really unsafe.

02:13:06.340 | It feels very unpleasant and it's just,

02:13:09.220 | your intestine can only metabolize nutrients so fast.

02:13:12.060 | And so if there's calories,

02:13:14.340 | then it slows down gastric emptying a lot,

02:13:15.820 | but water just kind of goes through.

02:13:18.060 | - What a beautiful system.

02:13:20.220 | There's regulation at every point.

02:13:22.660 | Hypothalamus, brainstem, gut, the rate of emptying

02:13:27.960 | based on the difference between water and orange juice.

02:13:32.220 | It's just awesome.

02:13:34.340 | - Yeah, and that's part of the reason I think it's so hard

02:13:36.020 | to outsmart the system, right?

02:13:37.140 | Because these neurons are making predictions

02:13:40.740 | based on the sight and smell of food,

02:13:42.180 | but then the gut is doing its own thing.

02:13:44.020 | It's calculating it separately

02:13:45.280 | and relaying that information.

02:13:46.380 | So at every step, there are these checks.

02:13:47.740 | Basically, they're just confirming

02:13:49.500 | that what you thought happened the first time

02:13:50.860 | is actually what's really going on.

02:13:52.460 | And so, which just makes sense

02:13:54.540 | because it's so important for survival,

02:13:55.940 | these homeostatic systems.

02:13:56.780 | They're the product of so much natural selection.

02:13:59.620 | - Which I think at least partially explains

02:14:01.220 | why thousand-fold increases in peptide hormones like GLP-1

02:14:05.380 | are required to see significant long-lasting changes

02:14:08.680 | in weight because the system is so strongly regulated.

02:14:13.580 | - Exactly, exactly.

02:14:15.060 | - It's hard to beat homeostasis and hard to beat it safely,

02:14:19.060 | but it sounds like you're more or less optimistic

02:14:22.840 | about where that whole field of, let's call it,

02:14:26.160 | anti-obesity drugs is headed.

02:14:28.940 | - I'm very optimistic.

02:14:29.980 | I mean, look, I think that you couldn't have asked for more

02:14:34.500 | so far at this stage with these GLP-1 drugs.

02:14:37.500 | Incredible weight loss, unexpected health benefits,

02:14:42.500 | really safe as far as we can tell.

02:14:44.460 | I mean, it's always possible

02:14:45.940 | that some new side effect will emerge,

02:14:49.360 | but these drugs are in millions of people

02:14:51.180 | and they've been in a lot of people for a long time now

02:14:53.180 | and nothing seems to have shown up.

02:14:55.160 | So I'm very optimistic.

02:14:57.300 | And I think even beyond that,

02:14:58.400 | just now that the pharmaceutical industry is reinvigorated

02:15:01.260 | to investigate this question, there's so many different,

02:15:03.500 | people are gonna, in five years,

02:15:04.400 | people have so many different options.

02:15:05.900 | It won't just be Ozempic or Rojaro.

02:15:07.380 | There'll be five different, 10 different drugs

02:15:09.380 | that they can choose from

02:15:11.220 | that have slightly different side effect profiles,

02:15:12.940 | slightly different efficacy,

02:15:14.580 | perhaps used for people

02:15:15.460 | with slightly different metabolic conditions.

02:15:17.680 | And so it'll really be a whole palette of medicines

02:15:19.900 | you can take that will adjust your physiology and hunger.

02:15:23.340 | - And it's amazing how well it squares

02:15:27.180 | with the understanding of the basic biology, you know?

02:15:31.060 | And that's a perfect opportunity for me

02:15:34.260 | to really just say what is in my mind

02:15:38.700 | and clearly in the minds of everyone listening

02:15:40.380 | and watching, which is thank you so much

02:15:43.100 | for this absolutely encyclopedic

02:15:45.980 | and exceptionally clear explanation

02:15:49.140 | of feeding and thirst and salt regulation

02:15:52.820 | and these new drugs that are, you know,

02:15:55.860 | in everyone's minds and everyone's hearing about.

02:15:58.780 | I've learned so much today.

02:15:59.880 | I know everyone else has.

02:16:01.420 | You run a incredible laboratory.

02:16:04.400 | I've tracked your career for a very long time.

02:16:06.380 | Every paper is spectacular

02:16:08.860 | and you're in a very competitive field

02:16:10.580 | and you've contributed in enormous ways

02:16:13.140 | to our understanding of these important processes.

02:16:15.500 | And I don't just say that as a formality.

02:16:17.500 | I know that to be true given that we, you know,

02:16:20.660 | are from the same field

02:16:22.360 | and have known each other for a long time

02:16:24.980 | and I'm familiar with your work at a deep level.

02:16:28.540 | Today has just been an absolute privilege

02:16:31.300 | and a gift to learn from you.

02:16:32.660 | And I know everyone feels the same way.

02:16:35.560 | So thank you for taking time

02:16:36.840 | out of your busy research schedule

02:16:38.900 | and the other important areas of your life

02:16:40.340 | to come here and educate us all.

02:16:41.900 | I learned so much basic and practical knowledge

02:16:45.100 | and I know everyone else did as well.

02:16:47.380 | Thank you so much.

02:16:48.220 | - Thank you, this has been really fun.

02:16:49.440 | I'm really glad we had a chance to do this.

02:16:51.060 | We talked about some of my favorite topics,

02:16:52.900 | so it's always a pleasure.

02:16:53.940 | And to talk with another neuroscientist

02:16:55.540 | about these things is fantastic.

02:16:57.060 | - All right, well, please come back again.

02:16:59.140 | Meanwhile, thanks for everything you do.

02:17:01.820 | - All right, thanks.

02:17:03.020 | - Thank you for joining me for today's discussion

02:17:04.760 | with Dr. Zachary Knight.

02:17:06.160 | To learn more about his research

02:17:07.620 | or to support his laboratory's work,

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Dr. Zachary Knight: The Science of Hunger & Medications to Combat Obesity

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