back to indexDr. Zachary Knight: The Science of Hunger & Medications to Combat Obesity
Chapters
0:0 Dr. Zachary Knight
2:38 Sponsors: BetterHelp, Helix Sleep & Waking Up
7:7 Hunger & Timescales
11:28 Body Fat, Leptin, Hunger
17:51 Leptin Resistance & Obesity
20:52 Hunger, Food Foraging & Feeding Behaviors, AgRP Neurons
30:26 Sponsor: AG1
32:15 Body Weight & Obesity, Genes & POMC Neurons
39:54 Obesity, Genetics & Environmental Factors
46:5 Whole Foods, Ultra-Processed Foods & Palatability
49:32 Increasing Whole Food Consumption, Sensory Specific Satiety & Learning
58:55 Calories vs. Macronutrients, Protein & Salt
62:23 Sponsor: LMNT
63:58 Challenges of Weight Loss: Hunger & Energy Expenditure
69:50 GLP-1 Drug Development, Semaglutide, Ozempic, Wegovy
79:3 GLP-1 Drugs: Muscle Loss, Appetite Reduction, Nausea
83:24 Pharmacologic & Physiologic Effects; GLP-1 Drugs, Additional Positive Effects
90:14 GLP-1-Plus Development, Tirzepatide, Mounjaro, AMG 133
94:49 Alpha-MSH & Pharmacology
100:41 Dopamine, Eating & Context
106:1 Dopamine & Learning, Water Content & Food
113:23 Salt, Water & Thirst
123:27 Hunger vs. Thirst
125:46 Dieting, Nutrition & Mindset
129:39 Tools: Improving Diet & Limiting Food Intake
134:15 Anti-Obesity Drug Development
137:3 Zero-Cost Support, Spotify & Apple Follow & Reviews, YouTube Feedback, Social Media, Neural Network Newsletter
00:00:10.400 |
and I'm a professor of neurobiology and ophthalmology 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. 00:00:28.080 |
Howard Hughes Medical Investigators are selected 00:00:31.320 |
from an extremely competitive pool of applicants 00:00:37.160 |
their investigatorship with the Howard Hughes 00:00:50.560 |
in particular, what drives our sense of hunger, 00:00:57.680 |
which is the ability to maintain body temperature 00:01:04.360 |
Dr. Zachary Knight explains the biological mechanisms 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 00:01:16.980 |
And he explains the biological mechanisms for satiety, 00:01:24.560 |
Dr. Knight also explains the role of dopamine 00:01:29.280 |
which I think everybody will find very surprising 00:01:33.280 |
to most people's understanding of what dopamine does 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 00:01:53.820 |
Dr. Knight explains how GLP-1 was first discovered 00:01:56.680 |
and how these drugs were developed, how they work, 00:02:01.440 |
and how that is leading to the next generation 00:02:04.240 |
of so-called diet drugs or drugs to treat obesity, 00:02:09.400 |
We also discussed thirst and the intimate relationship 00:02:12.220 |
between water consumption and food consumption. 00:02:16.060 |
between sodium intake, water intake, and food intake. 00:02:41.400 |
from my teaching and research roles at Stanford. 00:02:52.200 |
I'd like to thank the sponsors of today's podcast. 00:02:59.260 |
with a licensed therapist carried out entirely online. 00:03:02.860 |
I've been doing weekly therapy for well over 30 years. 00:03:07.700 |
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Today's episode is also brought to us by Eight Sleep. 00:04:12.140 |
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Today's episode is also brought to us by Waking Up. 00:05:34.980 |
that offers hundreds of guided meditation programs, 00:05:37.420 |
mindfulness trainings, yoga nidra sessions, and more. 00:05:40.800 |
I started practicing meditation when I was about 15 years 00:05:43.660 |
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for improving our focus, managing stress and anxiety, 00:05:57.960 |
In recent years, I started using the Waking Up app 00:06:00.260 |
for my meditations because I find it to be a terrific 00:06:02.720 |
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and those meditations are of different durations. 00:06:33.620 |
And you can always fit meditation into your schedule, 00:06:36.300 |
even if you only have two or three minutes per day 00:06:41.860 |
or what is sometimes called non-sleep deep rest 00:06:50.260 |
that some people experience when they wake up 00:07:04.500 |
And now for my discussion with Dr. Zachary Knight. 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, 00:07:29.200 |
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? 00:07:44.700 |
okay, that my stomach's full, is what we say. 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? 00:08:04.220 |
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, 00:08:24.060 |
a good way to think about the regulation of food intake 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. 00:08:49.180 |
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 00:09:07.940 |
And so essentially what he did was he made a cut 00:09:12.660 |
made a cut so that he separated the brainstem, 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 00:09:46.340 |
is you have to actually put food into their mouth, 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 00:10:09.300 |
that many of these signals that come from the gut, 00:10:10.940 |
gastric stretch, hormones that come from your intestine 00:10:18.740 |
If you inject those or manipulate the gut in those ways, 00:10:25.120 |
Now what can't the rat do when it doesn't have a forebrain? 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, 00:10:43.860 |
the way you would if you were fasted for several days 00:10:46.940 |
And that experiment along with other evidence 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 00:11:01.880 |
And in the forebrain, primarily in the hypothalamus, 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. 00:11:23.540 |
about the neural circuitry that controls feeding. 00:11:25.960 |
There's obviously a lot more going on underneath that. 00:11:30.380 |
You mentioned body fat and that somehow the brain 00:11:37.260 |
That caught my ear because while it makes total sense, 00:11:56.000 |
What is being signaled between body fat and the brain 00:12:01.240 |
And why do you think body fat is the critical signal? 00:12:10.480 |
- Yeah, well, there are certainly other things 00:12:14.400 |
definitely that are regulated other than body fat. 00:12:21.620 |
So the neural circuitry that regulates eating behavior 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. 00:12:39.260 |
And so it's very important that the brain know 00:12:49.920 |
you know how urgent it is to get the next meal. 00:12:55.240 |
of the level of body fat that we have is leptin. 00:13:03.240 |
a scientist named Jeff Friedman at Rockefeller University, 00:13:05.720 |
although its history goes back way before 1994. 00:13:10.520 |
is that there's a facility called Jackson Labs 00:13:29.080 |
that distributes mice to the scientific community. 00:13:33.960 |
they spontaneously just because they were breeding 00:13:35.600 |
so many mice, they came across some spontaneous mutations, 00:13:53.360 |
And they came across several different mutant strains 00:13:59.800 |
in the sense that they were all extremely fat, 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, 00:14:24.000 |
Then there was a scientist at Jackson Labs, Doug Coleman, 00:14:27.040 |
who had the idea, what if we do an experiment 00:14:37.920 |
a hormone that is produced by one of these strains 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 00:14:55.000 |
when you attach the OB strain to the DB strains, 00:15:01.480 |
The OB mouse, that strain dramatically loses weight. 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. 00:15:17.760 |
It still remains obese, it still remains hyperphagic. 00:15:22.520 |
Doug Coleman hypothesized that what was going on 00:15:32.560 |
that comes from fat, so it couldn't produce this hormone 00:15:38.240 |
And the DB mouse has a mutation in the receptor, 00:15:44.320 |
And that was just an idea, it was a hypothesis. 00:15:58.120 |
what are the genetic mutations that are occurring 00:16:02.800 |
And Jeff basically cloned leptin and showed that in fact, 00:16:06.440 |
The OB mutation is a mutation in this hormone, leptin. 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 00:16:34.760 |
the expression of this hormone increases in a linear manner, 00:16:40.640 |
is a direct readout of your body fat reserves. 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. 00:17:01.360 |
And so what happens is basically when you lose weight, 00:17:06.760 |
because basically you've lost adipose tissue. 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. 00:17:17.800 |
this entire homeostatic response to starvation. 00:17:20.880 |
So a big part of that is obviously increased hunger, 00:17:26.520 |
decreased body temperature, even decreased fertility, 00:17:30.760 |
because you don't wanna reproduce if you're starving. 00:17:39.080 |
And so the thought is, which I think is absolutely correct, 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 00:18:05.080 |
that the brain would be tricked into thinking 00:18:09.680 |
and then people would basically be less hungry, 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, 00:18:36.080 |
- In other ways, it would be a drop in the ocean 00:19:03.720 |
do not have low levels of leptin for the most part. 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. 00:19:17.440 |
and so target tissue stopped responding to insulin, 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, 00:19:45.920 |
they lost the most weight when you gave them this drug, 00:19:48.880 |
and the people with the highest levels of leptin 00:19:58.900 |
who just have, for some reason, lower levels of leptin, 00:20:01.920 |
these aren't people with mutations like the OB MALS, 00:20:11.360 |
your leptin levels plummet, they become very low, 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, 00:20:33.520 |
with the pharmaceutical industry, with the economics, 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 00:20:49.560 |
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, 00:21:02.800 |
of what's happening in the brain as we get hungry, 00:21:12.640 |
or at least separate neurons for each of those steps? 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, 00:21:49.680 |
where you're, for example, searching for food. 00:22:02.720 |
And the general thought is that these four brain circuits 00:22:14.160 |
And the brainstem circuits are more important 00:22:18.360 |
and licking, chewing, swallowing, and all of that. 00:22:20.420 |
Within the hypothalamus, there's a population 00:22:30.760 |
They're absolutely critical for that appetitive phase, 00:22:43.880 |
are they known to connect to areas of the brain and body 00:22:55.420 |
I need to walk to lunch or go to the refrigerator. 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 00:23:10.020 |
So the way we think about what these kinds of neurons, 00:23:15.620 |
they're not directly talking to the motor circuits 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 00:23:49.580 |
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 00:23:56.700 |
the animal will voraciously eat like it's starving. 00:23:59.200 |
If you silence these cells, animals will starve to death. 00:24:14.380 |
is thought to track the body's need for energy. 00:24:20.180 |
is that they express these receptors for leptin, 00:24:31.340 |
So as you might expect, if you have lots of body fat, 00:24:40.500 |
So that's one mechanism by which leptin controls hunger. 00:24:58.420 |
And to ask, what are their activity patterns? 00:25:02.640 |
of this population of neurons when an animal eats a meal? 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 00:25:13.980 |
because these are such a tiny population of cells, 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. 00:25:38.000 |
which we could use as a readout of their activity. 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, 00:25:54.380 |
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, 00:26:08.900 |
basically him running into my office and saying, 00:26:18.160 |
"You're just starting off in graduate school. 00:26:25.160 |
"I give a hungry mouse food and the AGRP neurons, 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, 00:26:40.500 |
And what he basically showed by changing the kind of food 00:26:43.220 |
he gave them or the accessibility of the food 00:26:46.420 |
and measuring the response of these AGRP neurons 00:26:49.420 |
was that what the neurons were doing was predicting. 00:26:56.420 |
imagines how hungry the mouse is, how accessible it is. 00:27:00.360 |
these neurons predict how much food the mouse is going to eat 00:27:08.900 |
And you can show this by a very simple analysis 00:27:14.140 |
and you look at how much these AGRP neurons drop 00:27:20.260 |
this drop happens in three seconds, four seconds, 00:27:23.020 |
Then you look at how much does the mouse go on to eat 00:27:28.200 |
So this was one of the first results from my lab 00:27:35.400 |
which is that these circuits that control internal state, 00:27:39.940 |
what they're constantly doing is predicting the future. 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 00:28:04.380 |
and looks like this, it has about this many calories 00:28:10.260 |
to these circuits to start the process of satiation 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, 00:28:30.580 |
So one interpretation of the data I just showed you 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. 00:28:45.420 |
But that doesn't seem to be the whole explanation 00:28:48.540 |
because if you artificially stimulate these neurons, 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 00:29:09.780 |
So there's a number of ideas about what this means. 00:29:24.440 |
and allowing the transition to consummatory behavior. 00:29:30.620 |
because we don't really fully know the answer yet 00:29:33.460 |
In biology it's always hard to answer why something happens. 00:29:37.460 |
the reason why it evolved that way is challenging. 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 00:29:56.540 |
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 00:30:08.860 |
and get them there right before you need them. 00:30:11.820 |
like basically the secretion of insulin occurs 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, 00:30:27.140 |
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. 00:30:35.260 |
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, 00:30:41.780 |
and I've done that since starting way back in 2012. 00:30:45.500 |
There is so much conflicting information out there nowadays 00:30:50.260 |
But here's what there seems to be a general consensus on. 00:30:59.980 |
from unprocessed or minimally processed sources, 00:31:03.000 |
which allows you to eat enough, but not overeat, 00:31:09.100 |
that we all need for physical and mental health. 00:31:14.860 |
from unprocessed or minimally processed sources. 00:31:21.340 |
is that it ensures I get all of those vitamins, 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 00:31:33.800 |
So by drinking a serving of AG1 in the morning, 00:31:38.040 |
I cover all of my foundational nutritional needs. 00:31:40.680 |
And I, like so many other people that take AG1, 00:31:43.380 |
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such as energy levels, digestion, sleep, and more. 00:31:51.000 |
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related to mental health and physical health. 00:32:06.860 |
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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 00:32:34.560 |
I realized it was absolutely delicious French bread. 00:32:38.400 |
And so I had some bread and butter, which I love. 00:32:44.040 |
I don't know who ordered them 'cause I didn't, appetizers. 00:32:49.140 |
a much more extensive calorically dense meal. 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, 00:33:09.280 |
You're sort of integrating based on new information. 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 00:33:27.920 |
is that people with anorexia are unbelievably tuned 00:33:38.480 |
That their visual system and presumably other systems 00:33:42.400 |
have become like almost hyper-accurate calculators 00:33:58.560 |
a tremendous amount about the caloric amounts 00:34:06.920 |
And that drives in that condition, obviously food avoidance. 00:34:21.080 |
and in the other case, let's just call it what it is 00:34:28.260 |
a pathologic dysregulation, a maladaptive dysregulation. 00:34:32.300 |
So what is known about these AGRP neurons in humans? 00:34:42.780 |
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. 00:34:57.500 |
All I know is that it's mostly protein and some fat. 00:35:06.260 |
They sound like, anytime I hear about hypothalamus, 00:35:10.160 |
but you're talking about a pretty sophisticated analysis 00:35:17.460 |
fairly nuanced behavioral decisions and updating that, 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. 00:35:48.360 |
So the first thing I would say is they are present in humans 00:35:54.680 |
Human AGRP neurons express the leptin receptor 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 00:36:14.200 |
meaning these are cell types that have a single purpose, 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 00:36:36.960 |
So there's sort of the yin and yang of hunger. 00:36:43.720 |
They're intermingled in the same part of the hypothalamus. 00:36:57.160 |
And that competition occurs through neuropeptides 00:36:59.760 |
that they release, one of which is an agonist 00:37:05.660 |
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. 00:37:19.000 |
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. 00:37:32.760 |
There's a question of how much of it is due to single genes. 00:37:38.680 |
and this is among people who are severely obese. 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% 00:37:56.040 |
or an enzyme within those cells that processes POMC 00:38:13.320 |
people who have sort of genetically inherited 00:38:19.540 |
So it's very clear that this pathway is involved 00:38:24.720 |
Most obesity, although there is a very strong 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 00:38:49.320 |
and there's been lots of genetic association studies 00:39:00.200 |
And the vast majority of those are expressed in the brain. 00:39:09.160 |
and also the brain controls energy expenditure. 00:39:12.720 |
but it's clear that mutations in genes in the brain 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 00:39:30.600 |
which I've talked about before on the podcast, 00:39:33.400 |
- Just identical versus fraternal twins, basically. 00:39:39.040 |
basically their body weight when they become adults, 00:39:46.000 |
And something on the order of 80% is thought to, 00:40:06.400 |
maybe embrace pharmacology if that's appropriate. 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 00:40:28.720 |
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 00:40:42.040 |
"the moment we assign a genetic source to something, 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. 00:41:05.880 |
I think there is a misconception out there about this, 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, 00:41:28.640 |
- 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. 00:41:36.200 |
By the way, I don't think that's the reason, folks. 00:41:39.780 |
but the theories that abound right now on social media 00:41:47.840 |
You get everything from seed oils to snacking 00:41:50.000 |
to smartphones to conspiracies to, it's wild. 00:42:01.280 |
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 00:42:07.940 |
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, 00:42:17.400 |
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. 00:42:42.680 |
you need two copies, and the next thing you know, 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 00:43:06.600 |
but with humans, we're talking about just two generations. 00:43:08.600 |
There just isn't enough time for any evolution 00:43:25.920 |
'Cause that's all that's changed is the environment. 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. 00:43:45.320 |
There's a distribution of body weights among people. 00:43:47.720 |
So in any given society at any point in time, 00:43:53.720 |
That distribution, where you lie on that distribution 00:43:58.280 |
So you may be the person who has the thrifty genes, 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, 00:44:12.720 |
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 00:44:30.880 |
and then environment can basically unmask that. 00:44:34.400 |
And so as we've had this change in environment 00:44:38.340 |
and we don't know exactly what the things are 00:44:42.400 |
highly palatable food, just various other things 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 00:45:06.040 |
but it also requires the environmental component. 00:45:09.480 |
You can make anyone lean by just putting them in prison 00:45:15.240 |
I mean, we've done those kinds of experiments. 00:45:19.600 |
They basically, they didn't put people in prison, 00:45:29.400 |
And unsurprisingly, they lose an incredible amount of weight. 00:45:32.320 |
They basically, their body temperature goes down, 00:45:36.440 |
And you could always do that for anyone, right? 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 00:46:05.200 |
Is it fair to say that what's changed in our environment 00:46:11.520 |
You know, I was walking through an airport yesterday 00:46:24.640 |
that tastes great is expensive, I would argue. 00:46:32.720 |
- Yeah, I think that's a plausible hypothesis. 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 00:46:51.120 |
So I think probably the availability of food, 00:46:53.880 |
the free availability, the low cost is one part of it. 00:47:10.320 |
from Kevin Hall at the NIH who's investigated this. 00:47:14.240 |
doing this kind of human obesity research today. 00:47:18.040 |
where he takes people into the NIH, into the hospital, 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, 00:47:37.080 |
so that when they gave the foods to independent raters, 00:47:40.480 |
they would say this is about equally palatable. 00:47:46.800 |
- What's an example of an ultra processed dish? 00:47:53.420 |
- Versus some pasta sitting next to a vegetable 00:48:10.640 |
So they had the selection of ultra processed meals 00:48:13.840 |
and then switch them to the non-ultra processed meals. 00:48:26.320 |
they ate much more of the ultra processed food. 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 00:48:42.240 |
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 00:48:58.000 |
Another idea is that a big thing about whole foods 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, 00:49:12.400 |
on the non-processed food versus the ultra processed food. 00:49:14.680 |
And that's just because whole foods are bigger 00:49:23.640 |
So if you just eat more volume, that could be valuable. 00:49:28.240 |
So I think that's another plausible hypothesis, 00:49:33.800 |
and I don't wanna force you into speculation, 00:49:39.760 |
that the neurons and circuits involved in appetitive 00:49:48.920 |
I think it's fair game to at least ask your thoughts 00:49:52.520 |
So I've been paying a lot of attention to the landscape 00:50:14.280 |
provided people obey the laws of thermodynamics 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 00:50:34.400 |
based on Kevin's work on highly processed foods 00:50:40.360 |
that there's a learning that takes place when we eat. 00:50:44.800 |
- And that this learning takes place over time 00:50:51.720 |
macronutrients, proteins, fats, and carbohydrates, 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. 00:51:05.920 |
- Put a pat of butter on it, has some fat also, right? 00:51:15.000 |
calories, which we already know people with anorexia 00:51:19.280 |
are exquisitely good at counting with their eyes. 00:51:27.500 |
And micronutrient content, maybe even amino acid content, 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 00:52:06.800 |
but eating them separately, if there's some olive oil 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? 00:52:37.940 |
But I could imagine, and here's the hypothesis, 00:52:40.360 |
that that is quote unquote confusing to our neural circuits 00:52:49.740 |
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 00:53:05.120 |
But there seems to be an easier time regulating food intake 00:53:10.840 |
"I'm going to consume minimally processed whole foods." 00:53:21.080 |
but that the brain starts to learn the relationship 00:53:31.340 |
oh, that's enough amino acids because I had a piece of fish. 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 00:53:56.600 |
Okay, now I realize that was long-winded and forgive me, 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 00:54:14.020 |
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 00:54:23.420 |
for whom the following diet has worked exceptionally well. 00:54:27.000 |
I'm not a diet coach, I'm not a nutritionist. 00:54:44.840 |
And without fail, they all lose a ton of weight. 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. 00:55:02.620 |
I think it's that they finally develop an appreciation 00:55:14.460 |
"and it didn't taste good to me after three or four bites." 00:55:23.680 |
But I find it amazing that when people start eating 00:55:32.840 |
and just kind of an unconscious understanding 00:55:48.240 |
or that you need to consume a lot of this food 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 00:56:11.900 |
And so sensory-specific satiety is just the idea 00:56:22.880 |
You get specific loss of appetite for that flavor or taste. 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, 00:56:31.980 |
because you have this sensory-specific satiety. 00:56:38.220 |
make your diet really simple so there's just a few things, 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. 00:56:54.440 |
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. 00:57:05.660 |
It's the reason probably that you want sweets 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, 00:57:27.380 |
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 00:57:43.200 |
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, 00:57:56.420 |
and then change your preference for these foods. 00:58:00.600 |
that you can just imagine from everyday experience. 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 00:58:34.260 |
perhaps this process of learning about the nutrient content 00:58:37.940 |
of different foods and flavors becomes impaired 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 00:59:12.000 |
because those are the primary colors of nutrients 00:59:16.840 |
and nutrients are the way in which we can persist 00:59:22.460 |
I mean, I'm not trying to sound more sophisticated 00:59:25.860 |
What I'm basically saying is that the neurons in our brains 00:59:31.000 |
both eating and cessation of eating an ingredient 00:59:38.740 |
or to chicken or to an egg or to a steak or to lentils 00:59:51.340 |
whatever is going to replace whatever glycogen 00:59:55.020 |
I mean, like if we really break it down into biology, 00:59:59.140 |
And my understanding is that the purpose of eating 01:00:04.340 |
rather than to, you know, taste savory or taste- 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 01:00:42.620 |
- So a little drop of olive oil into the belly 01:00:54.100 |
is equal potent to 120 calories of chicken breast? 01:01:01.900 |
- So they don't care about the macronutrient? 01:01:08.220 |
There are circuitries that are more concerned 01:01:13.180 |
although I don't think we know nearly as much 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 01:01:30.700 |
Basically you can synthesize sugar from other, 01:01:34.220 |
And you don't develop a specific sugar appetite 01:01:46.020 |
There's just this, I forget if it's nine amino acids 01:01:53.720 |
And so, whereas sugar and fat can be interchanged 01:02:18.820 |
that are probably the most strongly regulated 01:02:20.340 |
at the level of the macro and micronutrients. 01:02:24.420 |
and acknowledge one of our sponsors, Element. 01:02:29.620 |
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It's also important that you get adequate electrolytes. 01:02:49.240 |
The electrolytes, sodium, magnesium, and potassium 01:03:11.440 |
and I drink that basically first thing in the morning. 01:03:16.040 |
during any kind of physical exercise I'm doing, 01:03:17.960 |
especially in hot days when I'm sweating a lot, 01:03:26.520 |
although I confess I also like the raspberry and the citrus. 01:03:34.640 |
So these aren't the packets you dissolve in water, 01:03:36.400 |
these are cans of Element that you crack open 01:03:48.320 |
.com/huberman to claim a free Element sample pack 01:03:59.080 |
If we could talk about body weight homeostasis 01:04:05.600 |
So let's say somebody decides they want to lose some weight. 01:04:12.600 |
either by exercising more or eating less or both. 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 01:04:46.120 |
and that chronic activation of those neurons, 01:04:48.800 |
in part because leptin levels are lower in the blood 01:04:57.200 |
- But then how do people ever keep weight off? 01:05:04.640 |
'Cause I would argue like I have these friends 01:05:09.520 |
Most of the excess weight was body fat for a long time. 01:05:18.960 |
I have vegan friends, carnivore friends, et cetera, 01:05:20.520 |
but that pattern of eating I described before 01:05:27.400 |
It's not my job to do that in the realm of nutrition, 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. 01:05:41.440 |
- Well, so I would say that there have been efforts 01:05:48.560 |
that would help people consistently lose weight. 01:05:53.300 |
There are some people who, for various reasons, 01:05:55.480 |
can successfully lose weight and keep it off. 01:05:59.360 |
for what's going on in those individual cases, 01:06:02.920 |
What about them is different that makes sense. 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? 01:06:20.560 |
It was first studied in the context of 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 01:06:46.720 |
Now, so not a ton, but that is significant, right? 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. 01:07:31.180 |
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. 01:07:38.300 |
who looks the same as them, is the same height as them, 01:07:43.340 |
What's unclear is whether that's because those people 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, 01:08:05.500 |
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, 01:08:23.260 |
is he reasoned that you can measure people's body weight, 01:08:26.580 |
and you can measure people's energy expenditure. 01:08:38.900 |
So let's see what happens when you have people lose weight. 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 01:08:52.220 |
they're thinking about the fact that they're doing this. 01:08:55.980 |
so that you increase their energy expenditure, 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. 01:09:08.300 |
They block this protein, SGLT2, in the kidney 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 01:09:33.440 |
So basically you've got a 30 kilocalorie decrease 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, 01:09:59.080 |
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. 01:10:31.980 |
but there's a similar peptide made in mice and in humans 01:10:38.940 |
If you would, could you tell us what is known 01:10:50.180 |
and what's happening there, good, bad, exciting, ugly. 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? 01:11:11.780 |
where basically you have elevated blood glucose, 01:11:13.700 |
either because you don't produce enough insulin 01:11:21.580 |
right around the time insulin was discovered, 01:11:34.020 |
in numerous places in daily life and online, just kidding. 01:11:43.140 |
And the idea was that if you take glucose by mouth, 01:11:47.380 |
versus if you have the same amount of glucose 01:11:50.180 |
injected intravenously, more insulin is produced 01:11:59.660 |
of ingesting the glucose causes more insulin to be released 01:12:03.780 |
and causes you to lower your body sugar more accurately 01:12:15.020 |
The pancreas senses the glucose concentration 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, 01:12:29.420 |
that this incretin effect comes from the intestine, 01:12:31.780 |
that there's some substance being produced by the intestine 01:12:38.660 |
that boosts this insulin response to glucose in the blood. 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? 01:12:50.540 |
you can kill yourself by making yourself hypoglycemic, right? 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. 01:13:11.620 |
And there's lots of failures, they weren't the incretin. 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, 01:13:28.140 |
glucagon is released in order to cause your liver 01:13:32.180 |
So glucagon and insulin are these two opposing hormones. 01:13:39.820 |
that the glucagon gene is expressed in other tissues 01:13:51.060 |
And they discovered there was one in the intestine, 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 01:14:20.900 |
also a hormone that comes from the intestine. 01:14:23.660 |
And so the challenge with making GLP-1 into a drug 01:14:30.740 |
So it has a half-life of about two minutes in the blood. 01:14:39.060 |
you don't affect blood sugar 'cause it's just degraded 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. 01:15:02.780 |
the natural GLP-1 produced from the intestine 01:15:12.500 |
And that's one of the key reasons that we know 01:15:28.080 |
but you'd like to increase it even more, right? 01:15:36.580 |
And that's where this lizard that you mentioned 01:15:40.580 |
It produces a stabilized form of GLP-1 and it's a venom. 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. 01:16:01.500 |
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. 01:16:24.860 |
"Can we basically improve this even further?" 01:16:40.660 |
And liraglutide was approved for diabetes in 2010 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 01:17:00.900 |
And they started to see that some people were losing weight. 01:17:10.520 |
just sort of example of how drug discovery works 01:17:13.060 |
You know, a lot of these people would take liraglutide. 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. 01:17:31.540 |
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, 01:17:44.280 |
And then once you got up to the highest doses, 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. 01:18:01.800 |
So the idea is that the receptor that's affecting, 01:18:14.580 |
you know, it's been on the market for 14 years now, 01:18:21.620 |
which is good, but not like, you know, amazing, impressive. 01:18:37.900 |
And semaglutide now has a half-life of seven days. 01:18:50.880 |
And then they saw people started really losing weight. 01:18:54.860 |
people lost, you know, 16% of their body weight, 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 01:19:17.860 |
somewhere between 25 and 33% of what you lose 01:19:23.300 |
- But as you said, some of that could be offset 01:19:30.180 |
- Yeah, you can almost completely eliminate that 01:19:32.060 |
if you eat enough protein and do serious weightlifting. 01:19:46.220 |
because you're already losing so much muscle mass. 01:19:48.380 |
On the other hand, the counterargument that has been made, 01:19:59.140 |
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? 01:20:05.500 |
- Yeah, the calves on very obese people are often enormous. 01:20:15.140 |
because they're carrying a lot of the body load. 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, 01:20:41.700 |
And if it's the consequence of reduced appetite, 01:20:44.740 |
is that occurring at the level of the brain and gut 01:20:56.260 |
- It's thought that the key targets of these drugs 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. 01:21:09.420 |
in that decerebrate rat story I was telling earlier. 01:21:12.220 |
These are the brain regions that are preserved 01:21:20.580 |
because they get direct input from the vagus nerve. 01:21:23.700 |
So the vagus nerve is the nerve that innervates your stomach 01:21:28.060 |
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, 01:21:42.460 |
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 01:21:56.420 |
with the idea that stimulating, activating receptors 01:22:01.940 |
might explain part of the transient nausea side effect 01:22:09.220 |
a lot of the nausea is coming from activating the neurons 01:22:12.700 |
and that a lot of the sort of physiologic satiety 01:22:18.680 |
Now, the whole brain is connected to each other, 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. 01:22:36.380 |
fluorescently labeled versions of these drugs 01:22:41.620 |
they're enriched in these structures in the brainstem. 01:22:46.300 |
- Is that because there's an abundance of the receptors 01:22:59.620 |
- It's because the blood-brain barrier is weaker. 01:23:06.140 |
meaning it's one of these rare places in the brain 01:23:09.940 |
and so substances can come from the outside into the brain. 01:23:17.180 |
these are big peptides with lipid chains on them 01:23:19.860 |
So they can really only get into areas of the brain 01:23:33.340 |
did not lead to weight loss despite increasing, 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 01:23:56.820 |
but it contains caffeine and other stimulants 01:24:02.260 |
to the point where most people would rely on it 01:24:07.060 |
But anyway, it's my preferred source of caffeine, 01:24:11.020 |
there's some evidence that it can increase GLP-1, 01:24:21.080 |
that would lead to any significant weight loss 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. 01:24:59.360 |
it's very unlikely to increase its GLP-1 to that level. 01:25:02.980 |
Meaning, unless you're getting into the hundredfold 01:25:12.440 |
being the source of any appetite suppressive effect. 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 01:25:28.800 |
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. 01:25:40.080 |
These GLP-1 agonists are really a pharmacologic effect, 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. 01:25:53.560 |
there's no diet that's ever gonna give you 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 01:26:08.640 |
if we were talking about a different peptide hormone, 01:26:16.800 |
they're not really, you know, broadly speaking, 01:26:20.040 |
most people would be concerned about thousandfold dosing 01:26:27.600 |
However, my observation of the ever-expanding literature 01:26:31.480 |
on GLP-1 agonists is that there seems to be improvements 01:26:49.080 |
It seems like there's an ever-expanding list of things 01:26:55.680 |
I would say supra-physiological levels when one takes it. 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. 01:27:14.920 |
And it can only be answered through experiments. 01:27:16.540 |
And I think the nice thing about these GLP-1 drugs 01:27:25.480 |
which maybe only entered the public consciousness 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. 01:27:40.440 |
but they seem to have all these unexpected health benefits 01:27:48.120 |
And so, because of the reasons you mentioned, 01:27:52.600 |
from these pharmaceutical companies for diabetes drugs 01:28:09.500 |
And the data from the semaglutide, the Ozempic trial, 01:28:28.860 |
between the placebo group and the semaglutide group 01:28:37.520 |
and how well they were protected from heart disease. 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. 01:28:51.760 |
So these brain regions, the areoposteum and the NTS, 01:29:00.200 |
that basically acts, starts with the vagus nerve, 01:29:02.920 |
goes to these brain regions of the brainstem, 01:29:26.760 |
drugs can be patented and sold as a commercial version 01:29:30.520 |
and not as generic versions until the patent runs out, 01:29:42.720 |
So a lot of companies, once they do the safety testing 01:29:57.560 |
and not allowing generic versions into the picture. 01:30:03.160 |
based on these what sounds like additional uses 01:30:10.640 |
a long time before there's generic ozempic available. 01:30:15.240 |
I don't know the exact status of the patents, 01:30:28.120 |
- And some of them are really exciting, actually. 01:30:39.120 |
which is already giving you 15% weight loss or so, 01:30:56.040 |
which is even better, really, in almost every respect, 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, 01:31:15.680 |
So whereas ozempic is just a GLP-1 receptor agonist, 01:31:23.280 |
and this other incretin that we talked about, GIP, G-I-P. 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, 01:31:39.440 |
Just sort of, it allows you to crank up the dose 01:31:52.360 |
So Eli Lilly, the company that makes this drug, 01:31:54.800 |
terzepatide/Mujaro, they have a triple agonist 01:32:11.320 |
And so there's these three hormones all combined in one pill. 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 01:32:34.080 |
at the end of the, I think it was 48-week period, 01:32:42.560 |
So there are bigger, longer trials going on now 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? 01:32:52.480 |
you know, like these surgeries people do to-- 01:33:02.560 |
The other one that I think is really exciting, 01:33:06.000 |
it's called, it's just right now, it's just a code, 01:33:13.160 |
in the sense that it targets both GLP-1 and GYP. 01:33:19.000 |
But unlike terzapatide, which activates the GYP receptor, 01:33:24.480 |
And for reasons that people don't understand, 01:33:26.680 |
either activating or inhibiting this receptor 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, 01:33:44.780 |
but this is a much bigger, it's actual protein, 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, 01:34:04.400 |
and people maintained the weight loss for six months. 01:34:07.640 |
- Potentially because of the long-lasting effects 01:34:09.680 |
of this antibody, or potentially because of other things 01:34:13.920 |
there's all sorts of other crazy things happening. 01:34:15.500 |
So really, I think it's just created this explosion 01:34:23.960 |
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, 01:34:34.960 |
'Til now, everybody's sort of all in on this. 01:34:37.640 |
- Yeah, I remember in college, the fen-fen debacle, 01:34:42.440 |
and people had cardiac issues, started dying, 01:34:45.200 |
and then it was essentially a quiet field for a long time. 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, 01:35:13.320 |
And by the way, people were taking GLP-1 analogs 01:35:21.560 |
I'll stick an ear into one of these communities 01:35:24.040 |
And a big thing right now in these communities 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 01:35:57.800 |
but I do think that given that some of these neurons 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 01:36:15.600 |
and that I predict, based on their potential involvement 01:36:21.360 |
are likely to enter the picture with more prominence 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, 01:36:51.240 |
they're in the arcuate nucleus of the hypothalamus, 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. 01:37:15.480 |
which is important for body weight regulation. 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 01:37:44.800 |
It's called, I think, I'm gonna get the name wrong, 01:37:46.720 |
it's like setmelanotide or something like this. 01:37:51.520 |
It's mainly used in relatively small populations of people 01:37:55.320 |
that, for example, have mutations in this pathway. 01:38:00.520 |
And the challenge has been really side effects. 01:38:04.200 |
So there's an increase in blood pressure that happens 01:38:08.520 |
partly because this pathway controls not only appetite, 01:38:27.080 |
that controls energy balance and body weight. 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 01:38:40.240 |
the dogma was you could only affect body weight 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. 01:39:07.080 |
because they would just eat more meals to 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, 01:39:27.360 |
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? 01:39:44.080 |
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, 01:39:54.480 |
now that we've seen the success of the GLP-1s. 01:40:05.480 |
So perhaps, what would make a lot of sense scientifically, 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 01:40:24.460 |
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 01:40:35.260 |
have just a lot of benefits, even beyond weight loss, 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, 01:41:08.860 |
But it certainly is believed that dopamine is involved 01:41:13.420 |
in our either craving for food or pleasure from food. 01:41:22.340 |
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. 01:41:36.100 |
of your discoveries on dopamine as it relates to feeding, 01:41:50.380 |
and a difficult question, I think, to answer. 01:41:56.500 |
probably isn't so much involved in the pleasure of food, 01:42:01.680 |
One reason we think this is because you can make mice, 01:42:09.580 |
and they still show the same sort of effective responses 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. 01:42:32.860 |
if it doesn't have any dopamine, it won't do it. 01:42:37.860 |
So dopamine is important for sort of energizing action 01:42:48.100 |
which cues predict something useful for the body. 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 01:43:07.500 |
is learning about how external cues in the environment 01:43:10.340 |
predict something like food availability, right? 01:43:14.700 |
that that means there's some tasty food in there. 01:43:21.300 |
of sort of learning what that external cue means. 01:43:26.740 |
So in the laboratory, for example, we will play a tone 01:43:37.180 |
And it can learn the association between that tone 01:43:41.540 |
if they're separated by a few seconds, but that's all. 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, 01:43:59.260 |
how that relates to the post-ingestive effects. 01:44:01.380 |
- And I should say that this seems extremely relevant 01:44:15.440 |
but most of the food that I've consumed from McDonald's 01:44:21.700 |
like really delicious hamburgers or French fries 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. 01:44:36.380 |
- But not to the experience of pleasure from that food. 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 01:44:52.460 |
is just something that people in neuroscience talks 01:44:57.660 |
even though I also haven't eaten McDonald's in decades. 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, 01:45:09.520 |
because what we're talking about here is related, 01:45:12.500 |
I think, to this notion of highly processed food, 01:45:17.540 |
just the idea that we are drawn to food for things 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 01:45:40.560 |
- Yeah, so liking is the subjective hedonic pleasure 01:45:48.520 |
You can want things that at the end of the day, 01:45:58.780 |
at making you want something, but not necessarily like it. 01:46:03.200 |
But then there's this other element that is important, 01:46:12.260 |
associated with food, its taste, its flavor, its smell, 01:46:18.380 |
And this is so important because so much of whether we like 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. 01:46:37.480 |
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 01:46:52.580 |
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 01:47:02.980 |
There's been an idea that dopamine might be involved, 01:47:06.360 |
but it hadn't really received a lot of attention. 01:47:23.820 |
or when you deliver water directly to your stomach 01:47:27.940 |
And what we saw was that there are these different 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 01:47:39.220 |
There are others that respond in a thirsty mouse 01:48:01.860 |
So that sort of, that delayed dopamine signal 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. 01:48:20.440 |
You have to learn what all these different flavors mean. 01:48:24.280 |
For thirst, people find it a little less obvious 01:48:34.560 |
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, 01:48:44.840 |
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, 01:48:52.400 |
'cause who cares, but it's kind of interesting. 01:48:54.380 |
And so in New Zealand, there's this huge rabbit problem 01:49:02.120 |
And so there's lots of money to study rabbits, 01:49:06.480 |
And so a group of researchers did this experiment 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 01:49:27.720 |
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. 01:49:41.920 |
from the way we think about ingestive behavior. 01:49:43.560 |
But that fact that animals have to get water from food 01:49:48.120 |
how do they know which foods are rehydrating? 01:49:55.480 |
oh yeah, this is something that's very water rich 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 01:50:11.360 |
And he showed there was this delayed dopamine response 01:50:15.560 |
that correlated with rehydration of the blood. 01:50:20.120 |
get strongly activated when the blood is rehydrated. 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. 01:50:44.000 |
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. 01:50:56.640 |
When I was in college, for reasons that I don't recall, 01:51:08.800 |
like a piece of meat or something with some cheese, 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. 01:51:35.840 |
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 01:52:09.540 |
either by virtue of the foods that they include 01:52:13.120 |
or by virtue of the fact that they're not diluted, 01:52:16.400 |
it's a different taste experience to eat those foods 01:52:27.320 |
I just sort of stopped, but it was a fun experiment. 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. 01:52:40.500 |
to what extent do you think humans overeat or undereat 01:52:57.060 |
And the idea is that perhaps humans can't always, 01:53:04.700 |
our ability to sense what our body needs is not perfect. 01:53:08.500 |
and we could really be thirsty when we're hungry 01:53:11.860 |
And there's some evidence that that could help. 01:53:25.700 |
something that your laboratory has worked on extensively 01:53:27.980 |
and the topic of osmolarity of salt consumption 01:53:43.420 |
and we end up eating a bunch of Parmesan cheese? 01:53:51.500 |
So I'll bring a chunk of really nice Parmesan cheese. 01:53:55.380 |
I'll have half a cucumber and I'll have a can of, 01:53:59.460 |
but there are these wonderful jarred filet of tunas 01:54:13.660 |
than like what's put in front of me on an airplane, 01:54:23.060 |
oh, actually what I really just want is the salt. 01:54:36.060 |
- When in fact, what I'm going for is the salt. 01:54:39.980 |
our understanding of exactly what we need is fairly crude 01:54:53.780 |
How do we accurately or inaccurately pursue those 01:55:22.740 |
In general, hunger and thirst are pretty separable. 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 01:55:40.940 |
because basically you're gonna get dehydrated 01:55:44.660 |
my fluid balance even if I eat less calories. 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. 01:56:08.780 |
so the thirst for water and the desire for salt 01:56:19.820 |
So you want to have the right osmolality of the blood, 01:56:24.420 |
as sort of the total concentration of all the salts. 01:56:37.460 |
And there are really powerful innate mechanisms 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 01:57:05.020 |
these neurons are sensors for the osmolality of the blood, 01:57:07.500 |
and they're activated when the blood osmolality 01:57:11.820 |
So you can perceive an increase in your blood osmolality 01:57:20.020 |
- That's how critical it is to maintain salt balance. 01:57:23.340 |
And so you get to 10% increase in blood osmolality, 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. 01:57:51.220 |
So I should emphasize that there's two components 01:58:01.140 |
And so the reason that drinking the salt water 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. 01:58:11.500 |
The kidney's controlling how much of the salt 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 01:58:21.040 |
And so, yeah, I mean, the experiments led to the discovery 01:58:26.700 |
It was this guy, Bengt Andersen, working in the 1950s, 01:58:31.180 |
that there was an osmosensor in the brain, right? 01:58:36.580 |
but it was not really, really strongly supported 01:58:41.740 |
and he just started infusing small amounts of salt 01:58:54.820 |
I feel for everyone involved in that experiment, 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 01:59:12.860 |
And so he reasoned, okay, this must be the osmosensor. 01:59:15.580 |
And then he went back and stimulated those neurons. 01:59:20.980 |
And so now we know there's this couple small regions 01:59:26.100 |
another one's called, well, it doesn't really matter, 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, 01:59:54.820 |
and then for these osmosensors that Bank to Anderson 01:59:56.980 |
discovered in your brain to be sort of sense that 02:00:05.520 |
you know that you can quench your thirst within minutes, 02:00:08.020 |
right, and so how does that work within seconds even? 02:00:13.360 |
we did early in my lab was to ask that question, 02:00:18.660 |
the activity of these neurons that Bank had discovered 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, 02:00:28.020 |
And what we saw was that the neurons don't wait 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, 02:00:48.060 |
the volume of water that's passed through the mouth. 02:00:55.780 |
And basically, when the mouse has drank enough 02:01:00.840 |
that the blood osmolality is going to return to normal, 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, 02:01:13.700 |
linking it to the pleasure of ingesting good, clean water 02:01:21.340 |
in anticipation of adjusting blood osmolarity in 20 minutes. 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, 02:01:37.020 |
- 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 02:01:56.660 |
because water is usually cooler than your body, 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, 02:02:13.260 |
but he put a cold piece of metal on the mouse's tongue. 02:02:21.000 |
- So a lot of these sort of oddities of everyday experience 02:02:32.140 |
as the sensation of drinking really nice, clean, cold water 02:02:39.900 |
I used to take my dog hiking in Palomar Mountain, 02:02:44.500 |
He was a bulldog mastiff, they overheat easily, 02:02:50.700 |
It was a actually dangerous situation for him. 02:03:02.740 |
and you could just see him fill back up with life. 02:03:12.700 |
that one experiences with food when you're hungry. 02:03:15.660 |
- It's like that basic critical need for water 02:03:19.900 |
- under conditions where you're clearly dehydrated 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 02:03:34.340 |
that make an animal thirsty, the mice hate it. 02:03:40.060 |
So we can artificially stimulate these thirst neurons, 02:03:43.860 |
They'll lever press hundreds of times to make it stop. 02:03:52.940 |
They won't really do much of anything to shut them off. 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 02:04:20.100 |
And so I think that distinction is very real. 02:04:22.900 |
I think there are two different motivational mechanisms 02:04:27.980 |
Thirst is mostly about, this is just really unpleasant. 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." 02:04:50.620 |
Or are we broadly speaking about the forebrain, 02:04:52.340 |
for instance, the hypothalamus being in the forebrain? 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. 02:05:16.780 |
are located in the two circumventricular organs 02:05:25.100 |
But so why it evolved to have the thirst neurons 02:05:29.820 |
and the neurons that sense nutrients more in the hindbrain 02:05:34.460 |
And so there is definitely an element of learning, 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 02:05:49.940 |
A colleague of mine at Stanford in the psychology department, 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 02:06:35.740 |
perhaps even more interesting areas in my opinion, 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, 02:06:50.900 |
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. 02:06:57.820 |
Then just that mere knowledge can drive more satiety, 02:07:05.160 |
Even, I believe, I have to double check on this, 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, 02:07:45.840 |
but if they understand that certain foods are nutritious, 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. 02:08:03.960 |
They're trying to estimate what's happening in the future. 02:08:06.740 |
And I talked about how these AGRP hunger neurons, 02:08:19.660 |
A mouse has, you know, 1,000 times fewer neurons 02:08:23.380 |
So the computational capacity that the human brain has 02:08:29.340 |
And these mice are already doing amazing things, right? 02:08:34.540 |
in terms of anticipating changes in nutritional state 02:08:39.500 |
can change the expected physiologic outcomes? 02:08:44.260 |
I mean, there's just this whole other element 02:08:48.320 |
because it's happening in the brains of humans 02:08:55.320 |
about these flavor nutrient conditioning experiments. 02:08:58.600 |
These are the experiments where, essentially, 02:09:08.640 |
to consume bitter vegetables because they're good for you 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. 02:09:24.440 |
where you show the different numbers of calories, 02:09:26.240 |
then basically they sort of adjust their expectations 02:09:31.360 |
it's very sensitive to what information you give them 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 02:09:48.900 |
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 02:09:55.200 |
But given that you have deep knowledge in this, 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? 02:10:25.880 |
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 02:10:36.920 |
basic recommendations from physiology and neuroscience. 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, 02:10:50.780 |
is limiting consumption of ultra processed food, 02:10:52.900 |
eating more whole foods for lots of different reasons. 02:10:57.780 |
because they don't have this sort of engineered palatability 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, 02:11:15.100 |
just to try to achieve that minimum amount of protein. 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 02:11:37.900 |
I've heard other people say that's a complete-- 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. 02:12:00.180 |
even though water provides a very limited distention signal, 02:12:12.100 |
where you can get distention just from drinking 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. 02:12:38.580 |
If you drink something like a glass of orange juice, 02:12:42.180 |
And if you drink something that's really high in fat, 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 02:13:01.100 |
And the purpose for this is that you don't want nutrients 02:13:09.220 |
your intestine can only metabolize nutrients so fast. 02:13:22.660 |
Hypothalamus, brainstem, gut, the rate of emptying 02:13:27.960 |
based on the difference between water and orange juice. 02:13:34.340 |
- Yeah, and that's part of the reason I think it's so hard 02:13:49.500 |
that what you thought happened the first time 02:13:56.780 |
They're the product of so much natural selection. 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. 02:14:15.060 |
- 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, 02:14:29.980 |
I mean, look, I think that you couldn't have asked for more 02:14:37.500 |
Incredible weight loss, unexpected health benefits, 02:14:51.180 |
and they've been in a lot of people for a long time now 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, 02:15:07.380 |
There'll be five different, 10 different drugs 02:15:11.220 |
that have slightly different side effect profiles, 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. 02:15:27.180 |
with the understanding of the basic biology, you know? 02:15:38.700 |
and clearly in the minds of everyone listening 02:15:55.860 |
in everyone's minds and everyone's hearing about. 02:16:04.400 |
I've tracked your career for a very long time. 02:16:13.140 |
to our understanding of these important processes. 02:16:17.500 |
I know that to be true given that we, you know, 02:16:24.980 |
and I'm familiar with your work at a deep level. 02:16:41.900 |
I learned so much basic and practical knowledge 02:17:03.020 |
- Thank you for joining me for today's discussion 02:17:09.700 |
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