This Hormone Drives Hunger & Body Fat | Dr. Zachary Knight & Dr. Andrew Huberman

00:00:00.000 | - As a biologist, as a neuroscientist,

00:00:04.160 | how do you think about this thing

00:00:05.160 | that we call hunger and feeding?

00:00:06.160 | - Absolutely, absolutely.

00:00:07.400 | So I think at a very high level,

00:00:09.600 | a good way to think about the regulation of food intake

00:00:11.920 | by the brain is that there's two systems,

00:00:14.860 | a short-term system and a long-term system

00:00:17.440 | that are primarily localized to different parts of the brain,

00:00:21.000 | operate on different timescales,

00:00:22.280 | one on the timescale of a meal, so 10, 20 minutes,

00:00:25.520 | and the other on the timescale of sort of weeks

00:00:28.920 | to months to years and tracks levels of body fat.

00:00:32.280 | And these two systems sort of interact

00:00:34.720 | so that these short-term behaviors we do eating

00:00:38.040 | are matched to our long-term need for energy.

00:00:41.280 | And so I think one of the initial experiments

00:00:46.280 | that really led to this idea

00:00:47.360 | is this great experiment by Harvey Grill about 50 years ago.

00:00:51.760 | It's called the decerebrate rat.

00:00:53.480 | And so essentially what he did was

00:00:55.440 | he made a cut in the rat brains.

00:00:57.160 | He took these rats in the lab, made a cut

00:00:59.160 | so that he separated the brainstem,

00:01:01.280 | so the most posterior part of the brain,

00:01:03.820 | from the entire forebrain,

00:01:04.840 | basically got rid of 80% of the rat's brain.

00:01:07.600 | So he's basically creating these zombie rats,

00:01:10.000 | all they have is a brainstem,

00:01:11.480 | and asked, what can these rats still do?

00:01:13.800 | And as you might imagine, they can't do a lot of things

00:01:16.680 | because they basically have lost most of their brain.

00:01:19.400 | But he discovered that one thing they can still do

00:01:22.520 | is regulate the size of a meal.

00:01:24.320 | And so--

00:01:26.480 | - Very informative experiment.

00:01:27.880 | - And so, you have to be careful how we talk about this,

00:01:30.920 | 'cause the way this meal works

00:01:31.920 | is you have to actually put food into their mouth,

00:01:33.800 | and then they'll swallow it as you put food into their mouth.

00:01:37.520 | But eventually at some point, they'll start spitting it out.

00:01:40.240 | And that basically is an indication

00:01:41.840 | that in some sense they're becoming sated,

00:01:44.700 | and they're just using the brainstem that they have left,

00:01:48.400 | they're able to sense those signals from the gut

00:01:51.040 | and drive the termination of a meal.

00:01:53.240 | And he did other experiments showing

00:01:54.800 | that many of these signals that come from the gut

00:01:56.420 | like gastric stretch, hormones that come from your intestine

00:01:59.240 | in response to food intake like CCK,

00:02:01.320 | these deserebrate rats just have a brainstem.

00:02:04.280 | If you inject those or manipulate the gut in those ways,

00:02:07.600 | it can in an appropriate way change how much the rat eats.

00:02:10.640 | Now, what can't the rat do when it doesn't have a forebrain?

00:02:14.640 | And the thing it can't do is it can't respond

00:02:17.080 | to longer term changes in energy need.

00:02:19.560 | Meaning, if you fast the rat for a couple days,

00:02:22.240 | this deserebrate rat, then start putting food in its mouth,

00:02:25.920 | the amount that it eats doesn't change.

00:02:27.760 | So basically it doesn't eat a larger meal the way you would

00:02:30.200 | if you were fasted for several days and then refed.

00:02:33.720 | And that experiment along with other evidence

00:02:36.480 | has led to the idea that in the brainstem

00:02:39.120 | and then the most posterior part of your brain,

00:02:40.840 | there are neural circuits that control sort of a meal

00:02:43.520 | and then the timescale of 10 minutes or 20 minutes

00:02:45.800 | deciding when a meal should end.

00:02:47.440 | And in the forebrain, primarily in the hypothalamus,

00:02:50.260 | there are neural circuits that then track

00:02:51.920 | what is my overall level of energy reserves?

00:02:54.560 | What is my level of body fat?

00:02:55.740 | Things that would fluctuate on timescale of say days

00:02:57.680 | when you're fasting.

00:02:58.920 | And those forebrain centers feedback to talk

00:03:01.380 | to the brainstem and modulate those brainstem circuits

00:03:03.800 | that are controlling the size of a meal

00:03:05.280 | to sort of match these two timescales.

00:03:07.460 | So that's at the highest level how I think

00:03:09.040 | about the neural circuitry that controls feeding.

00:03:11.480 | There's obviously a lot more going on underneath that.

00:03:14.440 | - Fascinating.

00:03:15.940 | You mentioned body fat and that somehow the brain

00:03:20.720 | is tracking the amount of body fat.

00:03:23.680 | That caught my ear because while it makes total sense,

00:03:27.800 | I'd like to know how that happens

00:03:29.780 | if we happen to know the mechanism.

00:03:31.740 | And the second question is why body fat

00:03:35.560 | and not body fat and muscular mass

00:03:38.300 | or body fat and overall body weight?

00:03:40.580 | What is being signaled between body fat in the brain

00:03:44.860 | that allows the brain to track body fat?

00:03:46.780 | And why do you think body fat is the critical signal?

00:03:49.220 | I realize it represents an energy reserve,

00:03:51.900 | but certainly there are other things

00:03:53.320 | about the bodily state that are important.

00:03:56.000 | - Yeah, well, there are certainly other things

00:03:57.320 | about the bodily state that are important

00:03:58.600 | and there are other things about physiology

00:03:59.920 | definitely that are regulated other than body fat.

00:04:02.420 | But body fat is unique

00:04:05.080 | because it represents this energy reserve.

00:04:07.120 | So the neural circuitry that regulates eating behavior

00:04:10.440 | is in some ways very unique

00:04:11.800 | because it has this reserve of energy.

00:04:13.480 | So we also study thirst in my lab and drinking

00:04:16.000 | and you don't have a reserve of water in your body, right?

00:04:19.020 | And that's true for basically everything else.

00:04:21.080 | But for fat, we have this reserve of energy.

00:04:24.760 | And so it's very important

00:04:26.100 | that the brain know how much remains

00:04:29.900 | and then adjust behavior in coordinates with that

00:04:33.960 | so that you know how urgent it is to get the next meal.

00:04:38.200 | And so the thought is that the major signal

00:04:40.760 | of the level of body fat that we have is leptin.

00:04:43.560 | It's this hormone.

00:04:45.320 | It was discovered, it was cloned in 1994,

00:04:47.320 | actually by my postdoctoral advisor,

00:04:48.800 | a scientist named Jeff Friedman at Rockefeller University,

00:04:51.240 | although its history goes back way before 1994.

00:04:53.520 | So the sort of story behind leptin

00:04:56.040 | is that there's a facility called Jackson Labs

00:05:00.560 | that you I'm sure are familiar with in Maine

00:05:03.280 | that since the 1920s has been raising mice

00:05:05.920 | and selling them to academics basically

00:05:07.720 | who study physiology and behavior.

00:05:10.800 | And so they breed thousands of mice.

00:05:12.560 | So there's sort of a nonprofit organization

00:05:14.600 | that distributes mice to the scientific community.

00:05:16.920 | And at some point in the 1950s,

00:05:19.480 | they spontaneously,

00:05:20.320 | just because they were breeding so many mice,

00:05:22.320 | they came across some spontaneous mutations,

00:05:24.640 | mutant mice that were extremely fat,

00:05:26.720 | like the fattest mice they had ever seen.

00:05:28.120 | These mice just eat constantly.

00:05:29.280 | They're just enormous,

00:05:30.200 | three times the size of a normal mouse.

00:05:32.500 | And it's all body fats.

00:05:34.480 | They're just these huge fat mice.

00:05:38.920 | And they came across several different mutant strains

00:05:43.000 | that all had the same phenotype

00:05:45.360 | in the sense that they were all extremely fat,

00:05:47.080 | all extremely hyperphagic,

00:05:48.760 | but they could tell even in the 1950s

00:05:50.960 | that these mutations were on different chromosomes.

00:05:53.880 | They didn't know anything about

00:05:54.720 | how to identify the genes at that point.

00:05:55.780 | That was just science fiction,

00:05:56.860 | but they knew that there were chromosomes

00:05:58.040 | and they were on different chromosomes.

00:06:00.040 | And so they labeled one obese,

00:06:02.200 | one of these mouse strains obese,

00:06:03.400 | and the other one diabetes,

00:06:04.600 | but they're basically the same.

00:06:06.360 | As people wonder for a long time,

00:06:07.320 | well, what's going on in these mice?

00:06:09.560 | Then there was a scientist at Jackson Labs, Doug Coleman,

00:06:12.580 | who had the idea, what if we do an experiment

00:06:15.600 | where we connect the circulations

00:06:17.780 | of these two different strains of obese mice

00:06:20.560 | and test the hypothesis

00:06:21.600 | that maybe there's a circulating factor,

00:06:23.480 | a hormone that is produced by one of these strains

00:06:26.240 | and that controls appetite?

00:06:28.400 | Because at that point, insulin was known,

00:06:30.200 | glucagon was known.

00:06:31.040 | There were some hormones that were known

00:06:32.000 | that were involved in metabolism.

00:06:33.000 | So it was logical that there could be a hormone

00:06:35.120 | that perhaps regulates body fat levels.

00:06:38.120 | And what they found, which was remarkable,

00:06:40.560 | when you attach the obese strain to the DB strain,

00:06:43.120 | so you basically connect their circulation,

00:06:44.500 | so hormones are transmitted between the two,

00:06:47.040 | the OB mouse, that strain dramatically loses weight.

00:06:52.700 | In fact, within a couple of weeks,

00:06:54.380 | it looks like a normal mouse.

00:06:55.580 | It just stops eating.

00:06:56.500 | It loses almost all of its body fat.

00:06:58.100 | And it essentially, in all aspects, becomes a normal mouse.

00:07:01.060 | The DB mouse, nothing really happens.

00:07:03.300 | It still remains obese and still remains hyperphagic.

00:07:06.420 | And based on just that piece of data,

00:07:08.060 | Doug Coleman hypothesized that what was going on

00:07:10.180 | is these two mutations were mutations

00:07:12.500 | in a hormone and a receptor.

00:07:14.240 | The OB mouse had a mutation in the hormone

00:07:18.100 | that comes from fat, so it couldn't produce this hormone

00:07:20.300 | that comes from fat and signals to the brain

00:07:22.940 | how much fat you have.

00:07:23.780 | And the DB mouse has a mutation in the receptor,

00:07:26.860 | so it can't sense the hormone.

00:07:28.340 | And that was just an idea.

00:07:30.700 | It was a hypothesis.

00:07:32.440 | But in the 1980s, as technology advanced,

00:07:35.800 | as molecular biology had been invented,

00:07:39.060 | it became possible to clone genes.

00:07:41.780 | A number of people tried to identify

00:07:43.660 | what are the genetic mutations that are occurring

00:07:46.620 | in these mice that make them so obese.

00:07:48.340 | And Jeff basically cloned leptin and showed that,

00:07:50.340 | in fact, Doug was exactly right.

00:07:51.980 | The OB mutation is a mutation in this hormone, leptin.

00:07:56.740 | And later, Millennium Pharmaceuticals showed

00:07:59.660 | that the DB mutation is, in fact, a receptor.

00:08:02.300 | And it was an important discovery for a couple of reasons.

00:08:05.540 | One, because this OB gene is just expressed in fat.

00:08:09.380 | It's exclusively expressed in adipose tissue.

00:08:12.700 | And how much it's expressed is directly proportional

00:08:16.340 | to how much body fat you have.

00:08:18.140 | So as you gain weight, the expression of this hormone

00:08:21.340 | increases in a linear manner,

00:08:22.820 | and then it's secreted into the blood.

00:08:24.340 | So the level of leptin in your blood

00:08:26.100 | is a direct readout of your body fat reserves.

00:08:28.400 | This receptor for leptin, leptin receptor,

00:08:33.560 | the functional form of it is expressed

00:08:35.460 | almost exclusively in the brain.

00:08:37.500 | And it's expressed in all of the brain regions

00:08:39.500 | that we knew from previous work were important for appetite.

00:08:41.840 | So basically, the expression of this receptor

00:08:43.560 | gives you a map in the brain

00:08:44.900 | of the neurons that control hunger.

00:08:46.840 | And so what happens is, basically, when you lose weight,

00:08:50.680 | the levels of leptin in your blood fall,

00:08:52.240 | because basically you've lost adipose tissue.

00:08:54.920 | The absence of that hormone sends a signal

00:08:56.560 | to all these neurons that have leptin receptors

00:08:58.080 | in the brain, they're not getting that signal

00:09:00.020 | that I'm starving.

00:09:01.920 | And it basically, that initiates this entire

00:09:03.860 | homeostatic response to starvation.

00:09:06.340 | So a big part of that is obviously increased hunger,

00:09:10.060 | but it's also decreased energy expenditure,

00:09:12.000 | decreased body temperature, even decreased fertility,

00:09:16.220 | because you don't want to reproduce if you're starving.

00:09:18.340 | - Less spontaneous movement.

00:09:19.900 | - Less spontaneous movement, all of this.

00:09:21.980 | And so the thought is, which I think is absolutely correct,

00:09:26.500 | is that this hormone leptin

00:09:27.860 | is part of this negative feedback loop

00:09:29.820 | from the fat to the brain

00:09:31.620 | that basically tells you about your level

00:09:33.020 | of body fat reserves and how urgent it is

00:09:34.980 | to find the next meal.

00:09:36.260 | - Fascinating.

00:09:37.300 | As I recall, Amgen Pharmaceuticals owned the patent

00:09:41.420 | for leptin in hopes that it would become

00:09:43.500 | the blockbuster diet drug.

00:09:45.420 | The logic being that if you were to take this hormone

00:09:48.620 | somehow, or activate this pathway,

00:09:50.620 | that the brain would be tricked into thinking

00:09:52.200 | that there was more body fat, more energy reserves

00:09:54.700 | than there was, and then people would basically

00:09:58.500 | be less hungry, eat less, and lose body fat.

00:10:01.460 | - Yes.

00:10:02.300 | - What happened with that?

00:10:03.700 | Do we know why it did not work?

00:10:05.300 | - Yeah, so that's a great question.

00:10:07.140 | So there was a lot of excitement when leptin was cloned,

00:10:09.760 | 'cause it was thought basically we've cured obesity.

00:10:12.340 | There was an auction for the patent, Amgen won,

00:10:15.440 | I think it was something like $20 million up front payment,

00:10:17.760 | plus royalties, which at the time was,

00:10:19.800 | I mean, it still is a lot of money, but even more money.

00:10:21.420 | - Nowadays it would be a drop in the ocean

00:10:24.260 | compared to what companies will invest

00:10:25.900 | into potential diet drugs.

00:10:26.940 | - Exactly, but you know, at the time,

00:10:30.260 | and still a lot of money today,

00:10:31.900 | and they did a clinical trial, gave obese people leptin,

00:10:36.100 | subcutaneous injections of this hormone,

00:10:38.340 | and they didn't lose a lot of weight,

00:10:40.100 | and the question was why.

00:10:42.620 | And so what was subsequently revealed

00:10:44.740 | is that the challenge with leptin is that individuals

00:10:47.540 | who are obese do not have low levels of leptin

00:10:50.580 | for the most part, they actually have high levels of leptin.

00:10:53.780 | And so what they have is a state of leptin resistance.

00:10:56.020 | So it's analogous to someone who has type two diabetes.

00:10:58.500 | It's not because they lack insulin,

00:10:59.900 | it's because they actually have, over time,

00:11:01.500 | a high level of insulin,

00:11:03.060 | and so target tissue stopped responding to insulin.

00:11:05.140 | And the thought is that it's the same way

00:11:06.820 | in obesity and leptin.

00:11:08.420 | Now, subsequently, they went back

00:11:11.340 | and did a reanalysis of that clinical trial,

00:11:14.900 | and asked, what if you take all of these people

00:11:16.860 | and stratify them according to their starting leptin level?

00:11:19.460 | So some people have relatively low levels of leptin,

00:11:21.500 | some have higher, some have really high levels of leptin,

00:11:24.140 | and then ask, if we reanalyze the data,

00:11:26.240 | how effective is leptin?

00:11:29.260 | And as you might expect,

00:11:30.140 | the people with the lowest levels of leptin,

00:11:31.420 | they lost the most weight when you gave them this drug,

00:11:34.380 | and the people with the highest levels of leptin

00:11:35.980 | lost the least weight.

00:11:37.300 | So there is a rationale there for why,

00:11:39.780 | for a scenario in which leptin could work,

00:11:41.860 | either among the subset of people

00:11:44.420 | who just have, for some reason, lower levels of leptin,

00:11:47.460 | these aren't people with mutations like the OB-MALS,

00:11:49.180 | they have some leptin,

00:11:50.020 | they just don't have unusually high levels,

00:11:52.060 | or, alternatively, after weight loss.

00:11:54.580 | So after you've lost a lot of weight,

00:11:56.860 | your leptin levels plummet, they become very low,

00:11:59.060 | and that part of the reason,

00:12:00.340 | it's a big part of the reason

00:12:01.620 | it's so difficult to keep weight off,

00:12:02.900 | is because those leptin levels are so low.

00:12:05.020 | And so it's been thought for a long time

00:12:07.020 | that that is a scenario where treating people with leptin

00:12:10.220 | could be really useful to help them keep the weight off.

00:12:14.220 | Why it never made it as a drug for that application,

00:12:17.100 | I really don't understand.

00:12:18.060 | It has something to do, I think,

00:12:19.060 | with the pharmaceutical industry, with the economics,

00:12:20.940 | with a bunch of other issues

00:12:22.740 | that aren't necessarily scientific.

00:12:24.500 | But I think there still, in the future,

00:12:27.140 | is a possibility that it could come back

00:12:28.740 | for that indication,

00:12:29.580 | especially now that we have these GLP-1 drugs,

00:12:31.420 | and now there's just millions of people losing so much weight

00:12:33.900 | and perhaps they want to transition

00:12:35.100 | to a different kind of drug to keep the weight off.

00:12:37.740 | - Thank you for tuning in

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This Hormone Drives Hunger & Body Fat | Dr. Zachary Knight & Dr. Andrew Huberman

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