Dr. Zachary Knight: The Science of Hunger & Medications to Combat Obesity
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Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Zachary Knight. Dr. Zachary Knight is a professor of physiology at the University of California, San Francisco, and an investigator with the Howard Hughes Medical Institute.

For those of you that don't know, Howard Hughes Medical Investigators are selected from an extremely competitive pool of applicants and have to renew in order to maintain their investigatorship with the Howard Hughes Medical Institute every five years or so, placing him in the most elite of categories with respect to research scientists. His laboratory focuses on homeostasis, in particular, what drives our sense of hunger,

what drives our sense of thirst, and what controls thermoregulation, which is the ability to maintain body temperature within a specific safe range. Today, we mainly focus on hunger. Dr. Zachary Knight explains the biological mechanisms for craving food, for consuming food, and believe it or not, you have brain circuits that actually determine how much you're likely to eat even before you take your very first bite.

And he explains the biological mechanisms for satiety. That is the sense that one has had enough of a particular food or food group. Dr. Knight also explains the role of dopamine in food craving and consumption, which I think everybody will find very surprising because it runs counter-current to most people's understanding of what dopamine does in the context of eating and other cravings.

Today's discussion also includes a deep dive into GLP-1, glucagon-like peptide, and the novel class of drugs such as Ozempic and Monjaro and other related compounds that are now widespread in use for the reduction in body weight.

Dr. Knight explains how GLP-1 was first discovered and how these drugs were developed, how they work, and importantly, why they work and how that is leading to the next generation of so-called diet drugs or drugs to treat obesity, diabetes, and related syndromes.

We also discussed thirst and the intimate relationship between water consumption and food consumption. And we also talk about the relationship between sodium intake, water intake, and food intake. By the end of today's conversation, you have learned a tremendous amount about the modern understanding of hunger, thirst, and salt intake, as well as this modern class of drugs, such as Ozempic and related compounds, all from a truly world-class investigator in the subjects of researching hunger, thirst,

and thermal regulation. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online.

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in which to meditate. I also really like doing yoga nidra or what is sometimes called non-sleep deep rest for about 10 or 20 minutes, because it is a great way to restore mental and physical vigor without the tiredness that some people experience when they wake up from a conventional nap. If you'd like to try the Waking Up app, please go to wakingup.com/huberman, where you can access a free 30-day trial. Again, that's wakingup.com/huberman to access a free 30-day trial. And now for my discussion with Dr. Zachary Knight.

Dr. Zachary Knight, welcome. Great to be here. Today we're going to talk about hunger, appetite, thirst, other motivated behaviors, the role of dopamine, the vagus nerve. These are terms and topics that a lot of people hear nowadays and for which there's a ton of interest. But just to march us in sequentially, could you describe some of what's happening in the

then decide that we've had enough to eat. I think most people just assume that, okay, that my stomach's full is what we say. I've had enough or we self-regulate it for some other reason, caloric restriction or monitoring in some cases. What's happening in the brain in terms of the circuitries

And what have you discovered about what that process looks like in terms of its kind of universality across people? And then maybe how it sometimes differs between people. Okay. There's a lot in that that I'll try to unpack. And I can remind you of some of the nuances. But just in other words, as a biologist, as a neuroscientist, how do you think about this thing that we call hunger and feeding? Absolutely. So I think at a very high level, a good way to think about the regulation of food intake by the brain is that

There's two systems, a short-term system and a long-term system, that are primarily localized to different parts of the brain, operate on different timescales, one on the timescale of a meal, so 10, 20 minutes, and the other on the timescale of sort of weeks to months to years and tracks levels of body fat. And these two systems sort of interact so that these short-term behaviors we do, eating, are matched to our long-term need for energy. And so I think one of the

One of the initial experiments that really led to this idea is this great experiment by Harvey Grill about 50 years ago. It's called the decerebrate rat. And so essentially what he did was he made a cut in the rat brain. So he took these rats in the lab, made a cut so that he separated the brainstem, so the most posterior part of the brain, from the entire forebrain. Basically got rid of 80% of the rat's brain. So basically creating these zombie rats. All they have is a brainstem. And asked, what can these rats still do?

And as you might imagine, they can't do a lot of things, right? Because they basically have lost most of their brain. But he discovered that one thing they can still do is regulate the size of a meal. And so... Very informative experiment. And so, and you have to be careful how we talk about this because the way this meal works is you have to actually put food into their mouth and then they'll swallow it as you put food into their mouth. But eventually at some point, they'll start spitting it out. And that basically is an indication that in some sense, they're becoming sated.

and they're just using the brainstem that they have left, they're able to sense those signals from the gut and drive the termination of a meal. And he did other experiments showing that many of these signals that come from the gut, gastric stretch, hormones that come from your intestine in response to food intake like CCK, these decerebrate rats that just have a brainstem, if you inject those or manipulate the gut in those ways, it can, in an appropriate way, change how much the rat eats. Now what can't the rat do when it doesn't have a forebrain?

And the thing it can't do is it can't respond to longer-term changes in energy need. Meaning if you fast the rat for a couple days, this decerebrate rat, then start putting food in its mouth, the amount that it eats doesn't change. So basically it doesn't eat a larger meal the way you would if you were fasted for several days and then refed. And...

That experiment, along with other evidence, has led to the idea that in the brainstem and in the most posterior part of your brain, there are neural circuits that control sort of a meal and the timescale of 10 minutes or 20 minutes deciding when a meal should end. And in the forebrain, primarily in the hypothalamus, there are neural circuits that then track what is my overall level of energy reserves, what is my level of body fat, things that would fluctuate on a timescale of, say, days when you're fasting.

And those four brain centers feed back to talk to the brainstem and modulate those brainstem circuits that are controlling the size of a meal to sort of match these two timescales. So that's at the highest level how I think about the neural circuitry that controls feeding. There's obviously a lot more going on underneath that. Fascinating. You mentioned body fat and that somehow the brain is tracking the amount of body fat that

That caught my ear because while it makes total sense, I'd like to know how that happens if we happen to know the mechanism. And the second question is why body fat and not body fat and muscular mass or body fat and overall body weight? What is being signaled between body fat and the brain that allows the brain to track body fat? And why do you think body fat is the critical signal? I realize it represents an energy reserve, but

But certainly there are other things about the bodily state that are important. Yeah, well, there are certainly other things about the bodily state that are important. And there are other things about physiology definitely that are regulated other than body fat.

Um, but body fat is, is unique because it represents this energy reserve. So the neural circuitry that regulates eating behavior is in some ways very unique because it has this reserve of energy. So if you, we also study thirst in my lab and drinking and you don't have a reserve of water in your body. Right. Um, and that's true for basically everything else, but for fat, we have this, this, this reserve of energy. And so it's very important that, uh, the brain know, uh,

how much remains and then adjust behavior in coordinates with that so that you know how urgent it is to get the next meal. And so the thought is that the major signal of the level of body fat that we have is leptin. It's this hormone. It was discovered, it was cloned in 1994 actually by my postdoctoral advisor, a scientist named Jeff Friedman at Rockefeller University, although its history goes back way before 1994. So the story behind leptin is that there's a

a facility called Jackson Labs that you I'm sure are familiar with in Maine that since the 1920s has been raising mice and selling them to academics basically who study physiology and behavior. And so they breed thousands of mice. It's sort of a nonprofit organization that distributes mice to the scientific community.

And at some point in the 1950s, they spontaneously, just because they were breeding so many mice, they came across some spontaneous mutations, mutant mice that were extremely fat, like the fattest mice they had ever seen. These mice just eat constantly. They're just enormous, three times the size of a normal mouse. And it's all body fats. They're just these huge fat mice. And they came across several different mutant strains.

that all had the same phenotype in the sense that they were all extremely fat, all extremely hyperphagic, but they could tell even in the 1950s that these mutations were on different chromosomes. They didn't know anything about how to identify the genes at that point, that was just science fiction, but they knew that there were chromosomes and they were on different chromosomes. And so they labeled one obese, one of these mouse strains obese, and the other one diabetes, but they're basically the same. And so people wondered for a long time, well, what's going on in these mice?

Then there was a scientist at Jackson Labs, Doug Coleman, who had the idea, what if we do an experiment where we connect the circulations of these two different strains of obese mice and test the hypothesis that maybe there's a circulating factor, a hormone, that is produced by one of these strains and that controls appetite? Because at that point, insulin was known, glucagon was known. There were some hormones that were known that were involved in metabolism, so it was logical that there could be a hormone that perhaps regulates body fat levels.

And what they found, which was remarkable, when you attach the OB strain to the DB strain, so you basically connect their circulation, so hormones are transmitted between the two, the OB mouse, that strain dramatically loses weight. In fact, within a couple weeks, it looks like a normal mouse. It just stops eating. It loses almost all of its body fat. And it essentially, in all respects, becomes a normal mouse. The DB mouse, nothing really happens. It still remains obese. It still remains hyperphagic.

And based on just that piece of data, Doug Coleman hypothesized that what was going on is these two mutations were mutations in a hormone and a receptor. The OB mouse had a mutation in the hormone that comes from fat, so it couldn't produce this hormone that comes from fat and signals to the brain how much fat you have. And the DB mouse has a mutation in the receptor, so it can't sense the hormone.

And it was just an idea, it was hypothesis. But in the 1980s, as technology advanced, as molecular biology had been invented, it became possible to clone genes. A number of people tried to identify what are the genetic mutations that are occurring in these mice that make them so obese. And Jeff basically cloned leptin and showed that in fact, Doug was exactly right. The OB mutation is a mutation in this hormone, leptin.

And later, Millennium Pharmaceuticals showed that the DB mutation is in fact a receptor. And it was an important discovery for a couple of reasons. One, because this OB gene is just expressed in fat. It's exclusively expressed in adipose tissue. And how much it's expressed is directly proportional to how much body fat you have. So as you gain weight...

The expression of this hormone increases in a linear manner, and then it's secreted into the blood. So the level of leptin in your blood is a direct readout of your body fat reserves. This receptor for leptin, the leptin receptor, the functional form of it is expressed almost exclusively in the brain. And it's expressed in all of the brain regions that we knew from previous work were important for appetite. So basically the expression of this receptor gives you a map in the brain of the neurons that control hunger. And so what happens is basically when you lose weight,

the levels of leptin in your blood fall because basically you've lost adipose tissue. The absence of that hormone sends a signal to all these neurons that have leptin receptors in the brain. They're not getting that signal that I'm starving. And it basically, that initiates this entire homeostatic response to starvation.

So a big part of that is obviously increased hunger, but it's also decreased energy expenditure, decreased body temperature, even decreased fertility because you don't want to reproduce if you're starving. Less spontaneous movement. Less spontaneous movement, all of this.

And so the thought is, which I think is absolutely correct, is that this hormone leptin is part of this negative feedback loop from the fat to the brain that basically tells you about your level of body fat reserves and how urgent it is to find the next meal. Fascinating. As I recall, Amgen Pharmaceuticals owned the patent for leptin in hopes that it would become the blockbuster diet drug, the logic being that

If you were to take this hormone somehow or activate this pathway that the brain would be tricked into thinking that there was more body fat, more energy reserves than there was. And then people would basically be less hungry, eat less and lose body fat. Yes.

What happened with that? Do we know why it did not work? Yeah. So that's a great question. So there was a lot of excitement when leptin was cloned because it was thought basically we've cured obesity. There was an auction for the patent Amgen won. I think it was something like $20 million upfront payment plus royalties, which at the time was, I mean, it still is a lot of money, but even more money. Nowadays it would be a drop in the ocean compared to what companies will invest into potential diet drugs. Exactly. So, but, but, you know,

at the time, and still a lot of money today. And they did a clinical trial, gave obese people leptin, subcutaneous injections of this hormone, and they didn't lose a lot of weight. And the question was why? And so what was subsequently revealed is that the challenge with leptin is that individuals who are obese do not have low levels of leptin for the most part,

they actually have high levels of leptin. And so what they have is a state of leptin resistance. So it's analogous to someone who has type 2 diabetes. It's not because they lack insulin. It's because they actually have, over time, a high level of insulin. And so target tissue stop responding to insulin. And the thought is that it's the same way in obesity and leptin. Now, subsequently, they went back and did a reanalysis of that clinical trial.

and ask, what if you take all of these people and stratify them according to their starting leptin level? So some people have relatively low levels of leptin, some have higher, some have really high levels of leptin. And then ask, if we reanalyze the data,

how effective is leptin? And as you might expect, the people with the lowest levels of leptin, they lost the most weight when you gave them this drug. And the people with the highest levels of leptin lost the least weight. So there is a rationale there for a scenario in which leptin could work, either among the subset of people who just have, for some reason, lower levels of leptin. These aren't people with mutations like the OB-MALS. They have some leptin. They just don't have unusually high levels. Or alternatively, after weight loss. So after you've lost a lot of weight,

your leptin levels plummet, they become very low. And that part of the reason, it's a big part of the reason it's so difficult to keep weight off is because those leptin levels are so low. And so it's been thought for a long time that that is a scenario where treating people with leptin could be really useful to help them keep the weight off. Why it never made it as a drug for that application, I really don't understand. It has something to do, I think, with the pharmaceutical industry, with the economics, with a bunch of other issues that aren't necessarily scientific.

But I think there's still in the future is a possibility that it could come back for that indication, especially now that we have these GLP-1 drugs. And now there's just millions of people losing so much weight. And perhaps they want to transition to a different kind of drug to keep the weight off. Well, we are definitely going to talk about GLP-1, Ozempic, and some of the related compounds in a few minutes. But before we do that,

I'd love to get to this issue of what's happening in the brain as we get hungry, approach a meal, decide what to eat, and decide when we've had enough. Are there separate circuitries or at least separate neurons for each of those steps? And if you would, could you walk us through what that process looks like since we do it every day? Most people do it every day unless they're fasting multiple times per day. What's going on in our brain and body as we

think about and approach a meal, consume a meal and decide enough. Sure. So there are different neurons that are preferentially involved in different aspects of those processes. So I think people often divide feeding behavior and many other kinds of motivated behaviors into appetitive and consummatory phases. So appetitive is the phase of the behavior where you're

For example, searching for food, it's foraging, it's all the actions that lead up to the actual behavior itself, which then we call the consummatory phase. That's actually putting the food in your mouth and eating it. And the general thought is that these four brain circuits in the hypothalamus are more important, particularly in the hypothalamus, but other parts of the forebrain as well, are more important for the appetitive phase. And the brainstem circuits are more important for the consummatory phase, the actual putting it in your mouth and licking, chewing, swallowing, and all of that.

Within the hypothalamus, there's a population of neurons called AGRP neurons. So it's just an acronym, AGRP, and it stands for agouti-related peptide, but it doesn't really matter. They're absolutely critical for that appetitive phase, for the searching for food, for the desire to find food and consume it when you're hungry. Sorry, just to touch on the AGRP neurons and this appetitive phase.

Are they known to connect to areas of the brain and body that stimulate the desire to move? Because I think about when I get hungry, if I'm at my desk or something, I need to get up and find food. I need to walk to lunch or go to the refrigerator. Are they somehow linked to the circuits that promote locomotion? Well, they have to promote those things.

but they're not directly linked to any of those circuits. They're linked directly to other forebrain circuits involved in motivation. So the way we think about what these kinds of neurons like HRP neurons are doing, they're not directly talking to the motor circuits to tell you to move your legs or arms to pick up the sandwich or whatever. They're rather creating this general problem that the animal has to solve, which is that

I'm hungry. I need to get food. It would be really great if I could have a sandwich. And then the animal uses all of its mental capacities, right, to solve that problem. So they're just there to set the goal, not so much to direct the solution. And so, but these HRP neurons, there are a few thousand neurons at the base of the hypothalamus. So basically the most ventral, the most bottom part of the forebrain.

So tiny population of cells, but outsized importance for the control of feeding behavior. So if you stimulate these cells in a mouse or a rat that's not hungry, the animal will voraciously eat like it's starving. If you silence these cells, animals will starve to death. So you can basically give them food. They just won't eat it voluntarily until basically you have to euthanize them because they've lost so much weight. And the activity of these AGRP neurons

is thought to track the body's need for energy. One reason that's thought is that they express these receptors for leptin, this hormone that I was just talking about that comes from fat and signals the level of body fat reserves. And leptin inhibits AGRP neurons. So as you might expect, if you have lots of body fat, then a neuron that controls hunger should be less active than if you have very little body fat. So that's one mechanism by which leptin controls hunger.

We in my lab have investigated the role of these AGRP neurons from a slightly different perspective, which is, and this relates to your question about what happens when we approach food, when we start a meal. And to ask, what are their activity patterns? What is the natural sort of firing of this population of neurons when an animal eats a meal? It's a very basic question, something I think we've wanted to know for a long time.

was not really addressable until about 10 years ago because the technology didn't exist, because these are such a tiny population of cells so deep in the brain. So one of the very first experiments we did in my lab was to investigate that, to ask for the first time what happens to these AGRP neurons when an animal eats.

One of my first graduate students, Yiming Chen, he used a technology called fiber photometry, which allows us to put a fiber optic into the mouse's brain. So then we could record fluorescence from these AGRP neurons, which we could use as a readout of their activity. It's basically using a calcium sensor. So calcium is a surrogate for neural activity. And one of the very first experiments he did, he said, let's make the animal hungry. These AGRP neurons will be very active because the animal's hungry. And then let's give it some food and see what happens during a meal.

And our expectation was that these AGRP neurons would gradually decline in activity as the animal eats and levels of hormones in the blood start changing, feeding back to inhibit these neurons. What we found was really surprising. I remember when he made this discovery, basically him running into my office and saying, Zach, I gave the mouse a piece of food, but the weirdest thing happened. The neurons shut off almost immediately.

And I said, you made a mistake. It's okay. You're just starting off in graduate school. This happens. Go back and repeat the experiment, and then we'll discuss it. But he did several times. He said, you know, Zach, every single time I do this happens. I give a hungry mouse food, and the AGR pinerons, within just a few seconds, their activity has greatly diminished back to the level it would be in a fed mouse, even before they take the first bite of food.

And so Yiming then went to do a series of experiments to try to understand what was going on. And what he basically showed by changing the kind of food he gave them or the accessibility of the food or how hungry the mouse was and measuring the response of these AGRP neurons was that what the neurons were doing was predicting

The mouse looks at the food, it looks at how palatable it is, imagines how hungry the mouse is, how accessible it is. And then within a few seconds, these neurons predict how much food the mouse is going to eat in the forthcoming meal. And so essentially, these neurons know how much the mouse is going to eat before the mouse even takes the first bite.

And you can show this by a very simple analysis in which you give the mouse different foods and you look at how much these AGR pinerons drop when the mouse sees and smells the food. And then you plot that against this drop happens in three seconds, four seconds, something like that. Then you look at

how much does the mouse go on to eat in the next 30 minutes? You can just draw a straight line. This was one of the first results from my lab, and it was really surprising to all of us, and I think everyone. But it illustrated a theme that we've now seen again and again, which is that these circuits that control internal state, control things like hunger and thirst, what they're constantly doing is predicting the future.

They can sense these signals from the body that tell you about what's happened, but those signals are slow. And you don't want to wait 20 minutes from the food that you ingested to reach your stomach and then slowly start entering your intestine to figure out what was the nutrient content of the meal.

You want to try to figure that out as soon as you can, right? And so the animals learn presumably through just experience that, okay, something that smells like this and looks like this, it has about this many calories and I know I'm this hungry, so I'm going to eat about this much. And then that information is all transmitted to these circuits to start the process of satiation before the meal begins. Is it satiation or it's...

ceasing of foraging so that the animal, or if I translate to a person, decides, okay, now I'm going to consume this sandwich, this package of food. - Yeah, that's a great question. So we don't fully know the answer. So one interpretation of the data I just showed you is exactly what you said, is that what these neurons do is they control foraging alone. They don't control eating. And so this is perfect. You see the food, you know it's got enough calories, the neurons shut off and then you stay there and eat it. You transition from this appetitive to this consummatory phase.

But that doesn't seem to be the whole explanation. Because if you artificially stimulate these neurons, so prevent that drop from ever happening, just stimulate them continually, the muscle just sit there and eat. So you can't fully separate, although we like to make this distinction between repetitive and consummatory, and we know that in different parts of the brain, there's more important for one versus the other. The reality is that the entire behavior is linked and you can't fully separate them. So there's a number of ideas about what this means. So one idea that I just mentioned is that

Starting the process of satiety before the meal begins. Another idea which you mentioned, which could be part of the answer, is that it is reducing this repetitive drive and allowing the transition to consummatory behavior. Another idea is that, and I call these ideas because we don't really fully know the answer yet for exactly what the purpose is. In biology, it's always hard to answer why something happens. You can figure out what happens, but then you can, the reason why it evolved that way is challenging.

Another idea is it's involved in these, what we call cephalic phase responses that are necessary to prepare you for a meal. So the famous example of this is Pavlov basically trains the dog to associate the ringing of the bell with the presentation of food. And then eventually the ring of the bell alone causes the dog to salivate in the absence of any food.

Salivation is one example of a cephalic phase response. The purpose of that is to have enzymes in your mouth that basically are going to digest the food and get them there right before you need them. But there's all sorts of other things, like basically the secretion of insulin occurs in response to food cues, changes in gastric acid, gut motility. All these things are getting ready for the meal to happen. And so another idea is it could be part of that. But probably it's doing all of these things.

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If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs with your order, plus a year supply of vitamin D3 K2. Again, that's drinkag1.com/huberman. It's so interesting. I have a number of questions, but I think the one that I'll put at the top of the list is the other night we were out to dinner in New York and I was very hungry. I hadn't eaten much that day and I was looking forward to a nice steak.

They brought out bread, French bread. It was a French restaurant. I took one bite. I realized it was absolutely delicious French bread. The butter was fantastic. And so I had some bread and butter, which I love. Yes. Then they brought more. And then they started bringing out – I don't know who ordered them because I didn't – appetizers. And I realized that this was going to be a much more –

extensive, calorically dense meal. And suddenly my appetite for the appetizers, it sort of went down because I knew there was more food coming, right? Had I not known that there was more food coming, I think I would have consumed more of the appetizers, which also looked great. So clearly there's something going on with these AGRP neurons at the moment. You're sort of integrating based on new information. Exactly.

On the other end of the spectrum, I did a solo episode about eating disorders and anorexia nervosa in particular. And one of the things that I learned from experts in that field, the psychiatrists who work on this and the scientists who work on this, is that people with anorexia are unbelievably tuned to the caloric content of food.

That their visual system and presumably other systems have become like almost –

hyper-accurate calculators of the amount of calories in food. They've devoted a lot of cognition to it. It sometimes can border on or be placed within the obsessive realm, but that they see food and they can tell you a tremendous amount about the caloric amounts with these foods, even food combinations with a very small margin of error. So

And that drives in that condition obviously a food avoidance. So I have to assume that these AGRP neurons are involved in this kind of thing. One represents a regulation in the case of the example I gave and in the other case, let's just call it what it is because anorexia nervosa is the most deadly of the psychiatric conditions sadly, a pathologic dysregulation, a maladaptive dysregulation. So what is known about these AGRP neurons in humans? Meaning, do they exist in humans?

Presumably they express the leptin receptor. It sounds like they are able to integrate information both cognitive, based on immediate experience, visual, olfactory, but also a lot of prior experience. You know, a hamburger patty, I can't tell you how many calories it has. All I know is that it's mostly protein and some fat.

you know, what are these neurons doing? What do they have access to? They sound like, you know, anytime I hear about hypothalamus, I think very basic drives, but you're talking about a pretty sophisticated analysis of a real-time process.

event. Yeah. That is driving fairly nuanced behavioral decisions and updating that, which is a big deal. You know, we're both neuroscientists, but for everyone listening and watching, this is a big deal. This is as nuances deciding whether or not somebody is friend or foe or deciding whether or not you like a movie or you don't. I mean, this is some pretty sophisticated processing. This isn't eat, don't eat or eat less, eat more. These aren't switches.

Exactly. These are dials. Exactly. Yeah. So there's a lot there. I'll try to unpack that. So the first thing I would say is they are present in humans. And humans have agaropinerons. Human agaropinerons express the leptin receptor. And we think the functions are very similar. So one of the nice things actually about studying these kinds of things, like basic mechanisms of hunger, thirst,

because these things are so important for survival, they've been under really strong selection, right? And so many of the components of these systems are genetically hardwired, meaning these are cell types that have a single purpose, in this case to control hunger. They're labeled by specific genes and those are conserved through evolution.

We also know that this pathway, this AGRP neuron pathway, is important in humans due to human genetics. So just to add a little bit more information here, there's a companion set of neurons called POMC neurons that promote satiety. So they're sort of the yin and yang of hunger. AGRP neurons promote hunger, POMC neurons promote satiety. They're intermingled in the same part of the hypothalamus.

They're axons that project to the exact same downstream brain regions. Then it's thought that these two neurons compete with each other to control appetite. And that competition occurs through neuropeptides that they release, one of which is an agonist for a downstream receptor and the other one of which is an antagonist. We know from human genetics that

that among severely obese people, mutations in this pathway, AGRP, POMC neurons, and their direct downstream targets are quite common. So is it fair to say that some amount of obesity is genetic in nature at the level of neuronal firing or circuitry? I think a lot of body weight regulation is genetic. It's highly heritable.

there's a question of how much of it is due to single genes. And the number people quote, and this is among people who are severely obese, so not just people who you've seen someone who's overweight, but people have sort of syndromes where they're very obese from a very young age. Among those people, something on the order of 10% have mutations in this pathway. And it can either be this hormone POMC or an enzyme within those cells that processes POMC into the right form

or in the down, and this is the most common mutation, in the downstream receptor for POMC. It's called the melanocortin-4 receptor. And so among the severely obese people who have sort of genetically inherited severe obesity from childhood, something under 10% have mutations in this pathway. So it's very clear that this pathway is involved in body weight regulation in humans. Most obesity, although there is a very strong genetic component,

is not associated with single gene mutations like this, it's associated with effects of many mutations. But we know that even in that sort of polygenic obesity that has many different genetic causes, that the brain is important. And one of the reasons we know that is if you look at the genes through genetic association studies that have been associated with body weight, and there's been lots of genetic association studies trying to find mutations that are associated with whether you're lean or obese, something on the order of a thousand genes have been linked to body weight regulation.

And the vast majority of those are expressed in the brain. They're highly enriched for brain processes, which makes sense because body weight is controlled by food intake, right? And the brain controls behavior and also the brain controls energy expenditure. So maybe it's not so surprising, but it's clear that mutations in genes in the brain are important for body weight, which is consistent with the results of twin studies. So if you look at monozygotic versus dizygotic twins,

the estimates for the heritability of body weight is something on the order of 80%. We should explain mono's I got it, die's I got it, which I've talked about before on the podcast, just to brush people up. Just identical versus fraternal twins, basically. And by comparing basically their body weight when they become adults, you can get a sense for how much of this is genetic versus environmental. And something on the order of 80% is thought to be the variation between individuals is thought to have a genetic component.

- Wow. I don't think most people appreciate that. And a lot of the debate we hear nowadays is because there are things that people can do to lose body fat, exercise, eat differently, et cetera, maybe embrace pharmacology if that's appropriate.

There seems to be this, to me, silly debate as to whether or not people should be eating better and exercising or assuming that all of the obesity they might have arises through genetic causes and therefore take a prescription drug. I mean, why wouldn't it be a combination of things? Like to me, it just seems like why wouldn't people embrace all...

some or all of the tools that they could afford and that are safe for them. So I just want to get that out there because the moment this comes up, people start thinking, oh, well, the moment we assign a genetic source to something, we're removing personal responsibility. But of course, there are people, I know people who have struggled with their weight their entire lives for whom some of these new pharmaceuticals like Ozempic have provided them the opportunity to finally be able to lose weight and feel better and exercise safely. Yeah.

For instance. I completely agree with that. I think there is a misconception out there about this, about what it means for something to be genetically heritable. And I think this gets to the root of why so many people find this sort of hard to believe that there's such a strong genetic component to body weight.

And that's the idea that, you know, if you look at people, say, 75 years ago, right, they were much leaner, right? And you look at people today and there's been this, starting sometime around, you know, the 1970s, there was this explosion in body weight and increase in obesity. Is that when, that's when it started, mid-70s? Sort of the 1970s is when a lot of that started. Snack food, snacking. So there's lots of explanations. Seed oil, snack. By the way, I don't think that's the reason, folks. I think there are a lot of reasons. But the theories that abound right now on social media are...

I have a list of theories as to why the obesity is increasing. You get everything from seed oils to snacking to smartphones to conspiracies to it's wild. It's wild. The range of hypotheses is wild. - I mean, the challenge is, I mean, some of them could be true, but it's just very hard to test those things. - Sure. - Mentally, 'cause they're happening in the whole population, right?

But so I think the thing that people find hard to wrap their heads around, because it is a little bit of a confusing idea, is that how can it be that in, say, 50 or 75 years, there's been this explosion in obesity, which is the environment has changed, but human genetics has not changed in that amount of time. It's just not fast enough for people to evolve. So it can't be due to mutations in humans. What about devolve?

My understanding is that within a species evolving new traits is very slow. Yes. But mutations arise like the OB mutation, and then you can get very fat versions of an animal very quickly, right? All you need is a... Sure. You know, if it's a recessive allele, you need two copies. And the next thing you know, you've got a mouse that's four times larger than a typical mouse. Sure. And it's all explained by increased body weight. So that can happen very quickly within a species. Sure.

What's rare to find is an entire new branch of a species that has a very new adaptive function. That seems more rare. So that's true. So definitely there's some things that take longer to evolve than others. But with humans, we're talking about just two generations. There just isn't enough time for any evolution of any significance to happen. Yeah, we went baby boomers, right? Yeah.

- Generates, that's me, right? And then whatever is YZ millennial, I lose track after that. - Exactly. So I think the thing that people find hard to wrap their heads around is how can it be that this is how, that increase in body weight is clearly environmental, right? Because that's all that's changed is the environment. Nothing's changed genetically. Yet it's also true what I said that body weight is extremely heritable. It's one of the most heritable features and something on the order of 80%. One of the only things we know about that's actually more heritable than body weight is height, right? Most diseases are not as heritable as body weight.

How can you explain that? And the idea is this: there's a distribution of body weights among people. So in any given society, at any point in time, some people are going to be leaner, some people are going to be more obese. That distribution, where you lie on that distribution, is determined primarily by genetics. So you may be the person who has the thrifty genes, so that basically cause you to save energy, and so you would be more on the obese side. Or you may be a person who has different genes that cause you to be a little bit less hungry, so you would be on the leaner side.

What environment does is then it shifts that whole distribution so that basically the mean shifts so that everyone becomes, or most people become heavier. And so sort of a phrase that people sometimes use is that genetics loads the gun and environment pulls the trigger. So basically genetics sets your propensity and then environment can basically unmask that. And so

As we've had this change in environment where there's all of this, and we don't know exactly what the things are that have changed that are important, but there's all this ultra-processed food, highly palatable food, just various other things that you mentioned, seed oils, who knows if that's important. Certain people had these latent mutations that made them, say, very sensitive to palatable food. And in an earlier time, they may have been lean, but now because they have that latent capacity to be sensitive to ultra-processed food, they now gain tons of weight in the environment that we're in. It's

It's still because of genetics, but it also requires the environmental component. I mean, just take a step back, right? You can make anyone lean, but just putting them in prison and just only feeding them 1500 calories. I mean, we've done those kinds of experiments. There's this famous experiment, the Minnesota starvation experiment, right? They basically, they put people in prison, but this is in World War II. They

took a bunch of healthy volunteers, fed them 1600 calories a day, and just asked what would happen if you basically semi-starved people. And unsurprisingly, they lose an incredible amount of weight. All they think about is food. They basically, their body temperature goes down, their heart rate goes down. They just become obsessed with food. And you could always do that for anyone, right? But in a given environment where you're not in that kind of situation, then your propensity to gain weight will be determined by genetics. So that's the idea. I very much appreciate that description. And I know a great number of other people will as well, because

The explanation for the increase in obesity has not been described with that level of accuracy and detail with respect to the interactions between genetics and the environment. Is it fair to say that what's changed in our environment is the free availability of food? You know, I was walking through an airport yesterday and every 20 meters or so there's a vending machine or a restaurant. The cost of calories is fairly low. Yeah.

Getting high quality nutritious food that tastes great is expensive, I would argue. But getting calories is fairly inexpensive. I think that's a plausible hypothesis. It's one of several plausible hypotheses, and it would be surprising to me if it didn't contribute. But the reality is these population level questions is just so hard to actually know because you can't do an experiment. We can't create a parallel society where we manipulate one of these variables and see if the people become obese. Right.

So I think probably the availability of food, the free availability, the low cost is one part of it. Another part of it is probably, although again, it's not proven, is that these ultra-processed foods have a number of features that make people prone to gain weight. And there's really beautiful work, I don't know if you know this, from Kevin Hall at the NIH who's investigated this. He's really, in my opinion, the best person doing this kind of human obesity research today. And he does these experiments where he takes

takes people into the NIH, into the hospital, hospitalizes them for several weeks so he can exactly control what they eat. And he did this beautiful experiment where basically he had chefs prepare two kinds of food, one ultra-processed and the other not ultra-processed, sort of more whole foods, more healthier foods. But

had them take a lot of care so that when they gave the foods to independent raters, to people to test, they would say, this is about equally palatable. So I like this ultra-processed dish as much as this non-ultra-processed dish. What's an example of an ultra-processed dish? Like an out-of-package macaroni and cheese? Exactly, that kind of stuff. With bacon kind of thing? Exactly. Versus some pasta sitting next to a vegetable and a nice piece of salmon or something? Exactly, exactly.

and took people into the hospital, basically allowed them to eat just as much as they would like first of the ultra-processed meals. So they had the selection of ultra-processed meals for a couple weeks and then switched them to the non-ultra-processed meals and then also did it in the reverse order. So the other half of the people, they got the regular food first, then they got the ultra-processed food.

What he found is that even though people rated the foods as equally palatable, they ate much more of the ultra-processed food. And they actually gained weight during that two-week period when they were being given the ultra-processed foods. And then when you switched them, they lost weight. So...

The idea being that you can have two sets of food that you have equal preferences for, but something about the ultra-processed food is making you eat more of it when you actually consume it. And there's a number of ideas about why that could be. So one idea is that these ultra-processed foods have been optimized to have the right percentage of fat and sugar and protein to sort of promote more consumption once you start eating it, so that could be part of it.

Another idea is that, you know, a big thing about whole foods is that they take more energy to digest and they have more volume. So one of the striking things from that study is if you just look at the pictures of the meals, they're the same number of calories, but there's so much more food seemingly on the non-processed food versus the ultra-processed food. And that's just because whole foods are bigger because they're not so energy dense. So, and we know that, for example, volume is a major signal in the short term for regulating food intake. So if you just eat more volume, that could be valuable.

And there's lots of things like that. So I think that's another plausible hypothesis, but the truth is we don't really know. I have a hypothesis, and I don't want to force you into speculation, but given that you've studied and discovered that the neurons and circuits involved in appetitive and consummatory behaviors can learn based on experience and expectation, right?

I think it's fair game to at least ask your thoughts on this. So I've been paying a lot of attention to the landscape of what the general public think about, let's call them elimination diets, where people will just eat meat or will go onto a vegan diet or do some time-restricted feeding or do any number of different things that have been shown to promote weight loss, provided people obey the laws of thermodynamics and consume fewer calories than they

then they burn. I do believe in calories in, calories out. And there are a number of different routes to get there and some are more painful, some are less painful, and it depends on the individual lifestyle exercise and on and on. But let's just suppose for a moment, based on Kevin's work on highly processed foods versus whole foods, that there's a learning that takes place when we eat

And that this learning takes place over time such that our brain and appetite start to link the variables of taste, macronutrients, proteins, fats, and carbohydrates, sort of knowledge about macronutrients. A piece of fish is mostly protein, has some fat. A bowl of rice is mostly carbohydrate, has some protein. Put a pat of butter on it, has some fat also, right? It's sort of obvious. But taste, macronutrient content...

Calories, which we already know people with anorexia are exquisitely good at counting with their eyes. So it's possible they represent, again, a pathologic extreme of this.

and micronutrient content, maybe even amino acid content, like how much leucine is there. Now, most people aren't thinking about how much leucine is in a meal, but we know that leucine is important for certain aspects of muscle metabolism. It's present in certain proteins and not others. You're going to find less of it in a vegetable typically than you would in a piece of chicken and so on. And that when people eat

mostly non-processed or minimally processed foods and not in combination. So we're not talking about stewing all this together or blending all of it together, which sounds disgusting, right? Broccoli rice and a chicken breast blend together just sounds horrible. But eating them separately, if there's some olive oil and a little pat of butter involved, like that sounds pretty good. But a highly processed food in some ways is a blending together of macronutrients, micronutrients, if there are any,

and other features of the food that neurons in the brain seem to pay attention to, and then giving it a unified taste, a Dorito, right? A candy bar that we attach to the product, we attach to the name of the processed food, to the packaging. But I could imagine, and here's the hypothesis, that that is...

quote unquote, confusing to our neural circuits in a way that doesn't match up well with our thermodynamic requirements of how much we're burning versus how much we need to eat. Whereas when I eat a piece of steak and a vegetable,

I actually want less carbohydrate afterwards. If I eat the carbohydrate first, for me, it's difficult because I love the taste of carbohydrates, especially when they're combined with fat. But there seems to be an easier time regulating food intake when people step back and say, I'm going to consume minimally processed whole foods. And I'm guessing it's not just because they're trying to be healthier. That might be what stimulates the shift, but that the brain starts to learn the relationship between food volume and

smell, taste, what these things look like and satiation at the level of, "Oh, that's enough amino acids because I had a piece of fish. So maybe I don't need to consume as much of some other things." Or the vegetables provide volume and fiber and often vegetables can taste really delicious too. So that there's a linking of nutrients, calories, and taste in a way that's more appropriately matched to the energetic demands of the organism, in this case us humans.

that highly processed foods bypass. Okay. Now I realize that was long-winded and forgive me, but my audience is used to that. Whenever I'm trying to table something for, no pun intended, for discussion that I would like to think can at least stimulate some additional thinking about

a landscape, in this case, nutrition and feeding behavior that for a lot of people is just really confusing. And here's why, and this is the last thing I'll say. I have several friends who have been very overweight their entire lives for whom the following diet has worked exceptionally well. I'm not a diet coach. I'm not a nutritionist. I don't pretend to be one. I say eat proteins like meat, fish, eggs, vegetables, and fruit, and do that for a couple of months and then add back in starches as you

see fit based on your food intake. And without fail, they all lose a ton of weight. They're very happy with that. They add back in a minimum of starches. They keep the weight off and they're also exercising, but not more than they were before in most cases. And I don't think that it's meat or fish or vegetables per se. I think it's that they finally

develop an appreciation for what different foods have in terms of what they actually need. And without fail, they all say, oh, you know, I went to this party and I had a piece of cake and it didn't taste good to me after three or four bites. So that's interesting too. So I just would like your thoughts on this. We're not defining any new diets. I don't sell any diets. I don't do any of that. But I find it amazing that when people start eating minimally processed whole foods, I have to assume that their brain changes as it relates to appetite, craving, and just kind of a

an unconscious understanding about what food is providing them or not. And that highly processed foods basically bypass all of this and just get you to consume more, perhaps in hopes of getting something that you probably aren't getting at all, or that you need to consume a lot of this food in order to get. Yeah. There's several interesting ideas there. So there's two that come to mind, just thinking about what you just said. So the one is the idea of what's going on when these people consume simpler diets, more of a whole foods. And, and

One thing I think that's very likely going on is this phenomenon of sensory-specific satiety as being engaged. And so sensory-specific satiety is just the idea that as you expose yourself repeatedly to a certain flavor or taste, you basically lose appetite for that. You get specific loss of appetite for that flavor or taste. This is why, as you said, basically if you start off eating the protein, after a while you're like, I don't want any more salmon, but I would like some carbohydrates now because you have this sensory-specific satiety.

And so it's well known, actually, that if you simplify your diet, make your diet really simple so there's just a few things, that sensory-specific satiety alone can cause you to eat less, basically because there's just less variety in your diet and you don't want to eat more of that same thing. And so I think a lot of diets actually, it's not about the specific macronutrient or the specific food. It's just that they're reducing the variety in the diet. Eventually, you just get sick of eating the same thing.

And the thought behind that idea is that it's important evolutionarily so that you eat a diverse diet. It's the reason probably that you want sweets after you've eaten a savory meal and so on. A second idea, though, that comes to mind is just, as you mentioned, this idea of learning. And so much about our preferences for food

They're not innate, they're driven by learning. And so there are some things that are innate. So if you put sugar on a baby's tongue, it'll smile, indicating that it likes it. And if you put something bitter, it'll frown. And a rat will do the same thing, a neonate rat. But most of flavor and the perception of food is not just sweet or bitter. It's this much more complex sensation that involves smells,

It involves taste. And then it involves how those tastes and smells interact with the post-ingestive effects of the nutrients. So the sensing of those nutrients in your stomach and in your intestine, primarily in your intestine, are thought to then feed back and then change your preference for these foods. And so there's lots of examples of this that you can just imagine from everyday experience. Most people, the first time they had a beer or the first time they had a glass of coffee, found it repulsive because it's extremely bitter.

But then we come to crave these things because we know what they do to our body. We like what they do to our body. And that doesn't just make us take them like their medicine. We actually somehow change our very perception of how that flavor is. We actually come to savor that flavor we previously found disgusting. And it's because our sensation of what is...

whether something's good or bad depends on our internal state. And so it's an interesting idea, you know, perhaps if these ultra processed foods that have so many different ingredients and such an unnatural combination, perhaps this process of learning about the nutrient content of different foods and flavors

becomes impaired because it's just the brain is not used to, the brain's used to saying, you know, this is a piece of chicken and this is primarily protein. And so I can gauge, you know, from this flavor, I can connect this flavor to an amino acid content, but something that's so diverse, it might be harder to do. And isn't it the case that the neurons in the gut and the hormones that are produced by the gut as we digest food and that the neurons in the brain that control appetite and feeding are

have to be tuned to macronutrient content, because those are the primary colors of nutrients, and nutrients are the way in which we can persist on a day-to-day basis, right? I mean, I'm not trying to sound more sophisticated where simpler terms would suffice. What I'm basically saying is that the neurons in our brains that control these behaviors are

both eating and cessation of eating an ingredient or an entire meal can't be tuned to a particular food product

or to chicken, or to an egg, or to a steak, or to lentils, but rather to amino acid content, essential amino acid content in particular, essential fatty acids. And in the case of carbohydrate, whatever is going to replace whatever glycogen we might have depleted, right? I mean, like if we really break it down into biology, eating is for a purpose. And my understanding is that the purpose of eating is to replace those things as needed rather than to...

you know, taste savory or taste, you know. Absolutely. Absolutely. Absolutely. Those are just those things, those sensory cues are just markers that tell the brain what might be in that substance. I think if you look at broadly at this difference between calories and macronutrients and micronutrients, I would say what you see is that most of the circuits that are controlling hunger are primarily calorie specific. So they can, like, for example, an AGRP neuron,

I can put sugar, fat, or protein into the stomach of a mouse and to an equal extent inhibit an AGRP neuron as long as they have equal calories. Really? Yeah. So a little drop of olive oil into the belly of an animal that has, let's say a little bit more, let's say 120 calories of olive oil.

is equal potent to 120 calories of chicken breast? - At the level of these AGRP neurons, it is. - So they don't care about the macular tree? - No, they're really concerned about energy.

There are circuitries that are more concerned with macronutrients individually, although I don't think we know nearly as much about how that works. And I think the evidence is clear that the strongest defended macronutrient by far is protein. So protein, I don't think really sugar and fat intake are strongly defended in the sense that you're fine if you go without eating sugar, right? Basically, you can synthesize sugar from amino acids, for example, and you don't develop

a specific sugar appetite in the same way you do, for example, if you deprive yourself of hunger and you develop a protein hunger or essential. I think the difference is that proteins consist of essential amino acids. There's this, I forget if it's nine, I think amino acids that your body cannot synthesize. You absolutely need them or you will die. And so, whereas sugar and fat can be interchanged with other macronutrients. So, and there's other things also that you absolutely need to ingest like sodium chloride, right? So sodium, so

If you deprive an animal of sodium, they will develop this salt appetite that's incredible, basically, and that's completely innate. But I think salt appetite and protein appetite are the things that are probably the most strongly regulated at the level of the macro and micronutrients.

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If we could talk about body weight homeostasis for a moment, I think that would be useful. So let's say somebody decides they want to lose some weight. They caloric restrict slightly either by exercising more or eating less or both. Their body weight drops by a bit. Let's say they lose 10 pounds, eight of which are body fat. They lose a little bit of lean mass also. They're now at a new lower body weight.

Are the AGRP neurons motivated to have them seek out more food? In other words, are they hungrier and more motivated to find and eat food? Or do these AGRP neurons learn, hey, body weight is lower and I don't need to push to find so much food so often.

No, I mean, the idea is that the HRP neurons are more active when you lose weight. And that chronic activation of those neurons, in part because leptin levels are lower in the blood because you've lost weight, is that drive, that counter-regulatory drive that drives you to then consume more food. But then how do people ever keep weight off? Well, so part of the answer is they don't. I mean, so there's so... Really? Because I would argue, like, I have these friends who were very heavy, right?

And most of the excess weight was body fat for a long time. They seem to be doing great eating the way that I described before. And by the way, I'm not a proponent of any one particular diet. I have vegan friends, carnivore friends, et cetera. But that pattern of eating I described before has been enormously successful for them. I haven't run a randomized control trial. It's not my job to do that in the realm of nutrition. But

They're doing great. They claim to be sated. They are so happy with the way things are going. And I don't hear that they're constantly hungry. I hear that they're constantly sated. Well, so I would say that, you know,

there have been efforts for a long time to develop diets that would help people consistently lose weight. And it has been very unsuccessful. There are some people who, for various reasons, can successfully lose weight and keep it off. And I don't know that I have a good answer for what's going on in those individual cases, how they are the exceptions to the rule. What about them is different? Some also quit drinking alcohol. Yeah, so there's other things. So behavioral regulation is better when you're sober as opposed to... You can change your environment. But you know, so...

What this is sort of getting at is what is the counter-regulatory response to weight loss? And so this has been studied. It was first studied in the context of energy expenditure. And because energy expenditure is actually surprisingly easier to measure in humans than food intake, because people don't tell you accurately what food they eat. If they're free-living humans, they have to fill out a questionnaire. And the idea is that for every kilogram of weight you lose, so it's about 2.2 pounds, I think,

your energy expenditure decreases by about 30 kilocalories a day. Now, so not a ton, but that is significant, right? 30 calories. And then if you lose, as you said, 10 pounds, then that's 150 calories and that adds up over time. One interesting thing about that is that if you take people who were obese and then they've lost a ton of weight. So there's a study by Rudy Lybell about 25 years ago that did this. Take people who lost like 100 pounds and then take a control group that has the same

height, weight, basically the same body composition as those people who've now lost 100 pounds. Compare their energy expenditure. The energy expenditure in the people that lost all the weight is about 25% lower than the people who never were obese. And so those people who lost the weight, we call them the reduced obese, so that's what they were called in those studies. And the idea is that there's now this chronic deficit. They have to eat 25% less than someone who looks the same as them, has the same height as them, same weight as them, in order to maintain that body weight.

What's unclear is whether that's because those people simply always had a slower metabolism, they were always destined to be obese, and then you're just basically comparing two different groups, or whether something about the process of gaining weight and being in a higher weight for a longer period of time changes the brain so that then once you lose the weight it's irreversible. But there have been studies looking at at least a year and it doesn't seem to come back within a year, that difference in energy expenditure. Now the question is, is that really the big effect? Is that why it's so hard to lose weight, energy expenditure, or is it because you're hungrier? And that's actually much harder to measure.

But there was another really nice study, again, by Kevin Hall, investigating this. He used a really clever approach, this drug. So basically what he wanted to do was, is he reasoned that you can measure people's body weight and you can measure people's energy expenditure. And because calories in, calories out, if we can measure body weight and energy expenditure accurately, we can then back calculate how much that person was actually eating.

So let's see what happens when you have people lose weight. How does their food intake change? But the trick to this is you need to do it in such a way that you don't just tell them to go run on a treadmill. Because if you tell someone to go run on a treadmill and lose weight, then basically they're thinking about the fact that they're doing this. So you need to do it in some way covertly so that you increase their energy expenditure, cause them to lose weight, but without them realizing that's what's happening.

So they gave them these drugs, these SGLT2 inhibitors. And it's a pill you can take. They're used for diabetes. They block this protein, SGLT2, in the kidney that is necessary for glucose to be reabsorbed into the blood. And so basically what happens is you pee out about like 90 grams of glucose a day. But you don't know that you're doing that. And that causes you to lose energy. And so these people would lose some weight. And then measure how their food intake changes.

And what that showed is that for every two pounds or so of weight you lose, your hunger goes up by 100 calories per day. So basically, you've got a 30 kilocalorie decrease in energy expenditure, 100 kilocalorie decrease in appetite for every two pounds you lose on average. Some people will be exceptions, right? And they won't experience that at all for aspects of their physiology we don't understand. And so the increased hunger seems to be the main reason people find it so difficult to keep weight off.

That seems the perfect segue to talk about GLP-1, glucagon-like peptide 1, ozempic, monjaro, and similar drugs. My understanding of the back history on these is that a biologist obsessed with Gila monsters.

A reptile that doesn't need to eat very often discovered a peptide within their bloodstream called extended that, um, allowed them to eat very seldom. It curbed appetite in the Gila monster of all things. And it has a analog homolog, you know,

We don't know. I don't know the sequence homology exactly, but there's a similar peptide made in mice and in humans that suppresses appetite. If you would, could you tell us what is known about how GLP-1 works to suppress appetite, where in the body and or brain? Sure. And your sort of read of these drugs and what's happening there, what's

good, bad, exciting, ugly, anything else. - Sure, I'd be happy to. So the story of GLP-1, so the Gila monster is an important turn and I'll talk about that. It actually goes back before that quite a ways. So I should take a step back and say, these were developed as drugs for diabetes, right? And so, and diabetes is a condition where basically you have elevated blood glucose, either because you don't produce enough insulin or because your insulin is not effective.

And so back in sort of the 1920s, right around the time insulin was discovered, there was this phenomenon discovery known as the incretin effect. And what it was- Incretin? Incretin, yeah. Not the cretin effect. Not the cretin effect. You can observe the cretin effect in numerous places in daily life and online. Just kidding. So it's called the incretin effect. You can think of it as increase insulin because that's what the effect is. And the idea was that if you take glucose by mouth, if you consume glucose orally,

versus if you have the same amount of glucose injected intravenously. More insulin is produced when you take the glucose orally versus if it's delivered intravenously. Suggesting something about the process of ingesting the glucose causes more insulin to be released and causes you to lower your body sugar more accurately and more strongly. Interesting. Which is a little bit counterintuitive because in the pancreas, right? So insulin is released from the pancreas, from the beta cell.

the pancreas senses the glucose concentration in the blood directly. And so it suggests that insulin is being released not just in response to changes in blood glucose, but in response to a second factor. And so they call that an "incretin." And through various experiments, it was shown that this incretin effect comes from the intestine, that there's some substance being produced by the intestine that when you eat a meal, sugar goes through your intestine that boosts this insulin response to glucose in the blood.

And people immediately realized this could potentially be very valuable. And the reason is that you can treat diabetes with insulin injections, but insulin is dangerous, right? Because if you inject too much insulin, you can kill yourself by making yourself hypoglycemic, right? So you have to be very careful. But the thing about the incretin effect is it's not causing insulin release directly, but it's rather boosting the natural insulin release that comes when your glucose is higher in your blood. So it's sort of an amplifier on the natural insulin release.

So basically in the years that followed, whenever someone would find a new hormone, they would test it. Is it this incretin? And there was lots of failures. They weren't the incretin. But then, so there's this other hormone that comes from the pancreas called glucagon. And so glucagon, which was also discovered in the 1920s, glucagon is kind of the anti-insulin.

So when blood sugar goes low, glucagon is released in order to cause your liver to release glucose into the blood. So glucose, glucagon and insulin are these two opposing hormones. Glucagon was known for a long time, but people discovered in the 1980s that the glucagon gene is expressed in other tissues other than the pancreas, and it's differentially processed. The protein is differentially processed to produce different hormones, hormones other than glucagon.

And they discovered there was one in the intestine, and so they called it glucagon-like peptide because it comes from the same gene, but it's just slightly different. It's cut up slightly differently. And this hormone wasn't in creatine. So basically, if you put it on beta cells, you get this increased response of insulin in response to glucose. And so there was the idea, okay, this could be a great diabetes drug, right? And I should say there was one other in creatine that's been found. It's called GIP, G-I-P, and that will be important to talking about some of these other drugs.

also a hormone that comes from the intestine. And so the challenge with making GLP-1 into a drug is that it has an extremely short half-life. So it has a half-life of about two minutes in the blood. And so even if you inject people with GLP-1, it won't really be useful for anything. You don't decrease appetite. You don't affect blood sugar because it's just degraded too fast. And the reason it's degraded is because there's an enzyme, DPP-4 is what it's called, that degrades GLP-1.

So the first thing people tried was let's make inhibitors of that enzyme so we can boost this natural GLP-1 signal. And those are approved diabetes drugs. They're called gliptins. You've probably heard about them. Genuvia is the most common one. And those boost the level of GLP-1, the natural GLP-1 produced from the intestine by about threefold.

And they're effective in treating diabetes. People lose weight? People do not lose weight. Interesting. And that's one of the key reasons that we know that the natural function of GLP-1 is not really to control body weight, because you can boost the level threefold with these DPP-4 drugs. Millions of people have taken them. They do not lose weight. That's a great question.

So, but, you know, a threefold is great, but like you'd like to increase it even more, right? And to do that, you can't block this enzyme. You have to actually produce a GLP-1 that is more stable in the blood. And that's where this lizard that you mentioned comes into play.

It produces a stabilized form of GLP-1 and it's a venom. No one knows why. One hypothesis is that it's something to do with the lizard, as you said, basically having this long time period between meals and it needs to regulate its blood glucose. Who knows if that is true? But it turned out to be fortuitous because then this GLP-1 from this lizard, it has a half-life of like two hours. And so the first GLP-1 drug that was approved was just this molecule from this lizard, basically. And it's called Xenotide.

And it was approved in 2005. Works well for diabetes. Has a half-life of two hours. You inject it. And it doesn't cause a ton of weight loss. But two hours is good, but it's not so great. So then the pharmaceutical industry tried to say, can we basically improve this even further? And so they started engineering this hormone, making mutations, attaching lipid tails to make it bind to proteins in the blood that would stabilize it. Chemistry jockey stuff. Yeah, exactly. And I think the next big advance was this compound liraglutide.

And liraglutide was approved for diabetes in 2010 and then for weight loss in 2014. And so liraglutide has a half-life of about 13 hours in the blood. Now you're getting up to something serious. We've gone from two minutes, two hours, 13 hours. And you get better effects on aspects of blood glucose and diabetes control. And they started to see that some people were losing weight. Very variable responses. Not everyone loses weight on liraglutide.

And one of the things they noticed that I think is just as fascinating as sort of example of how drug discovery works in the real world, you know, a lot of these people would take liraglutide. Now it has this longer half-life. They start to get nauseous. And that would limit how much of the liraglutide they could take. And it's a known side effect of these GLP-1 drugs. It causes nausea and sort of this gastrointestinal distress. But they noticed that over time, the nausea would just sort of go away.

And so they would start dose escalating, sort of raising the dose that the person would take. So you would go a month at this dose, and then a month at a slightly higher dose, and then a month at a slightly higher dose. And you could work your way up. And these side effects would reappear, but then they'd go away. And then once you got up to the highest doses, then people really started losing weight. And so there's a couple of things that our pharmaceutical industry realized, wow, these are potentially really effective weight loss drugs. And also this nausea, which we thought was a killer,

people are able to just get used to it and then it just goes away. It undergoes, the word is tachyphylaxis. So the idea is that the receptor that's affecting in the gut that's causing these effects, it undergoes some sort of down regulation with chronic exposure. So liraglutide, you know, it's been around, you know, it's been on the market for 14 years now, was used, but still you're only getting sort of like 7% to 10% weight loss, which is good, but not like, you know, amazing.

Impressive. But then semaglutide came along, and that was approved for diabetes in 2017. And semaglutide is Ozempic, or also marketed as Wig-Ovi for weight loss. And semaglutide now has a half-life of seven days. So now we've gone from two minutes, two hours, 13 hours, seven days. And you can really jack up the concentration with a seven-day half-life.

And then they saw people started really losing weight. And so in some of those trials, people lost 16% of their body weight, which previously had been unattainable. In what timeframe? Typically takes about a year. Okay. And most of the loss in body weight is from body fat or from other compartments? The typical number is that if you lose weight either through dieting or through taking one of these drugs, and you don't do anything like eat a high protein diet or do resistance training,

Somewhere between 25% and 33% of what you lose is going to be muscle. The rest is going to be fat. But as you said, some of that could be offset by resistance training and or consuming a higher protein diet. Yeah, you can almost completely eliminate that if you eat enough protein and do serious weightlifting.

Obviously not the whole population is interested in doing that. And there's been a lot of discussion of how serious a side effect this is. Among elderly people, you don't want to be losing muscle mass because you're already losing so much muscle mass. On the other hand, the counter argument that has been made, which I think is also kind of convincing, is that

True, you're losing some muscle, but you're also losing all this fat and you no longer need as much muscle when you're not carrying around as much body fat. So people who are heavier naturally have more muscle because they need to, to move their body, right? And so- Yeah, the calves on very obese people are often enormous. Exactly. And then they lose weight and- Exactly. And I mentioned the calves in particular because-

they're carrying a lot of the body load. - Exactly, exactly. So it's still an open question as to whether, as to how serious a problem this lean muscle mass loss is, although the pharmaceutical industry is all in now on making drugs that basically are gonna prevent that. So that's something that will be happening probably in the future. - Is it a, sorry to interrupt, but is the weight loss on these drugs the consequence of reduced appetite or some other aspect of metabolism? And if it's the consequence of reduced appetite,

is that occurring at the level of the brain and gut or a combination? So it's almost entirely reduced appetite, and it's almost entirely occurring at the level of the brain. Which neurons? It's thought that the key targets of these drugs are neurons in these two regions. One's called the nucleus of the solitary tract.

and the other one's called the area posteroma. - So we're back in the brainstem. - Back in the brainstem. So these are actually the neurons in that decerebrate rat story I was telling earlier. These are the brain regions that are preserved in the decerebrate rat. The decerebrate rat still has these very caudal brainstem structures.

They're two very special brain regions because they get direct input from the vagus nerve. So the vagus nerve is the nerve that innervates your stomach and intestines and heart and lungs. It's sort of the major pathway from gut to brain and provides most of the sensor of the neural input from gut to brain telling you about things like this, your stomach distension, how many nutrients are in your intestine, breathing, all that stuff.

And almost all of those vagal nerves terminate on these two structures in the brainstem. When I hear post-trauma, I think about nausea because I was taught that post-trauma contains neurons that can stimulate vomiting. And this seems to link up well, at least in the logical sense, with the idea that

stimulating, activating receptors in these neurons within post-tremor might explain part of the transient nausea side effect of Ozempic and related drugs. Yeah. So the current thought is that a lot of the nausea is coming from activating the neurons of the area post-tremor, and that a lot of the sort of physiologic satiety is coming from activating the neurons in the nucleus of the solitary tract.

Now, the whole brain is connected to each other, and so if you really turn on these neurons in the NTS and the AP, they're going to talk to the hypothalamus and all these other brain regions. It's going to change the whole brain. So it's not just those regions, but

these drugs don't have great access to the brain. They can penetrate a little bit into the brain, but they don't penetrate into the whole brain. And it's thought that if you take fluorescently labeled versions of these drugs and see where they, so you can visualize where do they actually go, they're enriched in these structures in the brainstem. So that's why people think that this is probably where they're acting. And is that because they're

There's an abundance of the receptors for these compounds in post-trauma and NTS, or is it because the blood-brain barrier is somehow weaker at that location? It's because the blood-brain barrier is weaker. So basically, it's a region, what's known as a circumventricular organ, meaning it's one of these rare places in the brain where the blood-brain barrier is weakened, and so substances can come from the outside into the brain.

And that's important for these big peptides, because these are not small molecules. These are big peptides with lipid chains on them and other things. And so they can really only get into areas of the brain where the blood-brain barrier is weakened.

- I really appreciate that you mentioned the half-life issue with GLP-1 and the fact that these DPP-4 antagonists did not lead to weight loss despite increasing circulating GLP by threefold. This is relevant to a number of different claims that people make that a given food or a given drink increases GLP-1. I've actually said before, I'm a big consumer of yerba mate,

Uh, father's side is Argentine and it's a known appetite suppressant, but it contains caffeine and other stimulants that might explain some of that. And it's not a robust appetite suppressant to the point where most people would rely on it as a weight loss compound is. But anyway, it's my preferred source of caffeine, but I've said before, um, you know, there's some evidence that it can increase GLP one, but based on what you've said, the increases in GLP one that it creates are very unlikely to produce the kind of

that would lead to any significant weight loss in somebody that's obese, presumably, that are separate from any caffeine stimulatory effects. - Exactly. - So you can't separate 'cause it's a complex compound, this yerba mate thing. It's got lots of things in it. But also, I've observed you being vocal on social media when people have said, "Hey, this thing increases GLP-1." You quite appropriately, I think,

said, wait, Ozempic and drugs like that increase GLP-1 thousandfold. When you talk about a food or drink or maybe a supplement increasing GLP-1, it's very unlikely that it increases GLP-1 to that level, meaning-

Unless you're getting into the hundredfold or thousandfold increases, probably not right to talk about GLP-1 being the source of any appetite suppressive effect. Yeah, that's all correct. So I mean, I think it's important sometimes to distinguish between pharmacologic and physiologic effects. So physiologic is what the hormone naturally does in your body and what can be modulated by natural things like eating a different food.

And you might get a two-fold change in your GLP-1 by eating a different food, one food versus the other. But as we know from those DPP-4 inhibitors, it's not going to really change your appetite because the drugs increase it three-fold. These GLP-1 agonists are really a pharmacologic effect. In fact, it only happens with drugs. So you get 1,000 to 10,000-fold higher concentrations of these drugs in your blood than the natural hormone. And so...

It's just there's no diet that's ever going to give you that. And there's no precedent for it either. So should we be at all concerned about that? I mean, they run clinical trials and address safety. But when you're talking about a thousandfold increase in essentially a peptide hormone, if we were talking about...

different peptide hormone, pick one, oxytocin or estrogen, testosterone, they're not really, broadly speaking, most people would be concerned about thousand-fold dosing of something like that. And obviously there are clinical indications where that's important. However, my observation of the ever-expanding literature on GLP-1 agonists is that there seems to be improvements in like

reduction in alcohol consumption? And by the way, why would increasing GLP-1 reduce craving for alcohol? It seems like there's an ever-expanding list of things that GLP-1 agonism is good for. But we are talking about, I would say, supraphysiological levels when one takes it. And again, I'm not against it nor for it. I'm just paying attention to the literature. So I would say that

That's absolutely right. When you're increasing the level of hormone a thousandfold, you need to be careful and see what's happening.

But at the end it's an empirical question. What does it actually do to a person? And it can only be answered through experiments. And I think the nice thing about these GLP-1 drugs that a lot of people don't realize is they've been around, proved since 2005, the earliest ones. And even something like Ozempic, which maybe only entered the public consciousness in the last year or two, right? It's been around for seven-ish years, I think. And big clinical trials with these drugs. And so...

And the evidence so far is that they seem to be incredibly safe. And as you said, not just incredibly safe, but they seem to have all these unexpected health benefits that seem to be, in some cases, even unrelated to weight loss. And so...

So, you know, because of the reasons you mentioned, one of the things the FDA requires from these pharmaceutical companies for diabetes drugs is these large cardiac outcome trials. So basically where you measure stroke and where you measure heart attacks and death from any cardiac cause. Big trials, like 20,000 people, four years, costs like a billion dollars to run. And the data from the semaglutide, the Ozempic trial, came out last year and showed

as expected, reduced the rate of heart attacks, strokes, all-cause mortality for cardiac reasons. But what was really surprising was a lot of that seemed to happen before the people even lost weight. So there was already a difference between the placebo group and the semaglutide group before the people on the drug had lost a significant amount of weight. And there was no correlation between the amount of weight they lost and how well they were protected from heart disease.

And that's led many people to think that some of these effects actually could be due to other things the GLP-1s are doing that we didn't expect. And so one thing is there's an idea emerging that they are anti-inflammatory. So these brain regions, the area post-stream and the NTS...

are also really important for this reflex known as the inflammatory reflex that basically acts, starts with the vagus nerve, goes to these brain regions in the brainstem, and then goes back down to the body to basically suppress, to prevent out-of-control inflammation. And so it's thought that these drugs perhaps have an anti-inflammatory effect that explains some of that.

Sounds like the patent on these drugs just got extended by another hundred years. That's a biopharma joke. I mean, just to put context on it, drugs can be patented and sold as a commercial version and not as generic versions until the patent runs out, unless companies are able to find another approved clinical use, in which case it can be remarketed only as a

brand name, not generic version. So a lot of companies, once they do the safety testing and given everything they put into the R&D, into the research and development, there's a very big incentive to not necessarily finding new drugs, but finding new uses for the same drugs and not allowing generic versions into the picture. And that's why it's likely to be based on these

what sounds like additional uses of Ozempic-related compounds a long time before there's generic Ozempic available. - I think it will be a while. I don't know the exact status of the patents, but I'm guessing it's gonna be a while before there are generic versions, but there's a lot of competition coming.

So every major pharmaceutical company or almost every major pharmaceutical company now has a GLP-1 program. And some of them are really exciting, actually. So, I mean, the general trend in this area is what people call GLP-1+, which means you take the GLP-1 agonist, which is already giving you 15% weight loss or so, and then you add additional things to that to give it additional properties. Right.

So one compound is from Eli Lilly, which makes this other, so there's this other drug on the market that we haven't talked about, but Terzepatide, which is known as Moonjaro for diabetes and Zepabound for obesity, which is even better, really in almost every respect, a better drug than Ozempic. So people lose more weight. So it's about 21% weight loss at a year. Fewer side effects, at least at comparable doses.

That seems to be because this other drug, terzepatide, it has two targets, not one. So whereas Ozempic is just GLP-1 receptor agonist, terzepatide is a dual agonist of GLP-1 and this other incretin that we talked about, GIP, G-I-P.

And it seems like having that GIP agonism actually acts as an anti-nausea effect, that sort of counteracts some of the nausea caused by the GLP-1 in the area post-tremor. There are GIP receptor neurons in the area post-tremor, this nausea center. It allows you to crank up the dose of the GLP-1 agonism even further while you're suppressing the nausea and just get even more weight loss. So now, talking about the future, things that aren't available yet but will be in the next couple of years. So Eli Lilly, the company that makes this drug, Tiers Appetide slash Mujaro,

They have a triple agonist that's in phase three clinical trials now. So this is now three hormones in one. It's the GLP-1, which all these drugs have, the GIP, which is the anti-nausea component, and then glucagon itself. And so these three hormones all combine in one pill. And what the glucagon does is it increases energy expenditure. This is a well-known effect of glucagon. And so you're basically eating less, your nausea isn't as bad, and now you're just burning more calories at baseline.

And the results from this drug are incredible. So basically, there's been one phase two trial published and people lost 25% of their body weight at the end of the, I think it was 48 week period. And they were still losing weight. So we don't know where the end point, we don't know what the maximum is. So there are bigger, longer trials going on now to figure that out. But

But at that point, when you get beyond 25% body weight, you're talking about basically bariatric surgery, right? Which is currently the best thing we have. You know, like these surgeries people do to- Stomach staple. Yeah. Removing a portion of the stomach. Removing a portion of the gut. So really, it's a pharmacologic version of bariatric surgery. The other one that I think is really exciting, there's this compound from Amgen. It's called, it's just announced the code. It's like AMG-133. But it's like-

teresapetide in the sense that it targets both GLP-1 and GIP. So it's a dual targeted. But unlike teresapetide, which activates the GIP receptor, this Amgen compound inhibits it. And for reasons that people don't understand, either activating or inhibiting this receptor causes you to lose weight. So still a mystery, but a lot of debate about what's going on there. But the way this Amgen compound activates the GIP receptor, or inhibits the GIP receptor rather,

is that it's an antibody. So all these other things were peptides, but this is a much bigger sexual protein. This is an antibody. And because it's an antibody, it has a much longer lifetime, even than something like semaglutide, which is seven days. So it lasts like a month in the blood or something. And so you give people monthly injections of this and they lose dramatic amounts of weight.

And then at least in this initial trial, at the end of this, they stopped and people maintained the weight loss for six months. That's impressive. Potentially because of the long lasting effects of this antibody or potentially because of other things that we don't understand. So, and those are just two, there's all sorts of other crazy things happening. So really, I think it's just, it's just created this explosion of interest in pharma. Once, basically it's one of these things, you know, it's, it's, you know, once you see that something can be done, all of a sudden that changes everyone's perspective. And so now,

Obesity drug discovery has gone from something that 10 years ago everyone wanted to stay away from because there were so many nightmare stories about drugs that turned out to be not safe, till now everybody's sort of all in on this. - Yeah, I remember in college the Fen-Phen debacle where a diet drug was released and people had cardiac issues, started dying, so it was pulled from market, and then it was essentially a quiet field for a long time. In part to bring us back into the brain, and in part because it's directly relevant to what we've been discussing,

about Ozempic and GLP-1. There are other neurons in the brain that regulate feeding. And there are other peptides involved in appetite control for which I would say niche communities have started to indulge in. And by the way, people were taking GLP-1 analogs long before they were FDA approved in kind of niche communities. These aren't communities I'm a part of, but every once in a while, I'll stick an ear into one of these communities and hear what people are taking. And a big thing right now

in these communities is the use of other peptides that are in the melanocyte simulating hormone pathway. And you mentioned melanocortican

receptor containing neurons. Could you tell us a little bit about what these neurons do in the absence of any pharmacologic stimulation? And then why it would be that people would perhaps stimulate these pathways with these drugs? Not that we're recommending that, but I do think that given that some of these neurons are also involved in sexual behavior and FDA approved for the treatment of

hyposexual function in women, things like that. You know, there is FDA approval for some of these compounds that they're interesting hypothalamic neurons that are starting to gain more attention and that I predict will

based on their potential involvement in feeding appetite and weight control, are likely to enter the picture with more prominence in the not-too-distant future. So alpha-MSH, as scientists call it, the hormone you were just referring to, is a product of the POMC gene. So in the same way that we just talked about, glucagon can be processed into different things. In some cells, it's made into the glucagon hormone. In other cells, it's made into GLP-1.

POMC, that gene can be processed to produce different hormones. And one is alpha-MSH, which is very important for feeding control. And so these POMC neurons, they're in the arcuate nucleus of the hypothalamus, the same region where these AGRP neurons I talked about earlier are located. And there's sort of these two sets of neurons have opposing effects on body weight regulation. And so alpha-MSH inhibits food intake and AGRP neurons promote food intake.

And where they converge is at this receptor, the melanocortin-4 receptor, which is important for body weight regulation. And so alpha-MSH is an agonist. It turns on that receptor. And the AGRP peptide is an antagonist. It turns it off.

And so there's a lot of human genetics, as I mentioned earlier, implicating this pathway in body weight regulation. There have been a lot of efforts over many years to turn alpha-MSH into a drug, and it's been very difficult. There is one drug that's now approved. It's called, I think, I'm going to get the name wrong, it's like setmelenatide or something like this. It's an MC4 receptor agonist.

It's mainly used in relatively small populations of people that, for example, have mutations in this pathway. It's not used as a widespread as a drug. And the challenge has been really side effects. So there's an increase in blood pressure that happens sometimes with these medicines, partly because this pathway controls not only appetite, but also autonomic tone and sympathetic nervous system activation.

It's just taking a step back from everything we've talked about today. I talked about this short-term system and the long-term system that controls energy balance and body weight. The short-term system in the brainstem, the long-term system in the hypothalamus, the long-term system being leptin and alpha-MSH and AGRP. When I was coming up, learning about this stuff 15 years ago or 20 years ago, the dogma was you could only affect body weight

through the long-term system, by manipulating the long-term system. Because any manipulation you did of the short-term system in the brainstem, the animal would just compensate. And there were these famous experiments where they would take CCK, which is a hormone just like GLP-1,

inject it into rats, inject it several times a day. And CCK is known to decrease the size of meals and it would decrease the size of meals, but the rats would never lose any weight because they've just eat more meals to compensate. And they're just perfectly compensated by eating more meals. And so the lore was, it's just impossible. The animal will always compensate unless you hit this body weight set point regulating area, which is the hypothalamus, the long-term system.

But then what the pharmaceutical industry discovered, which I guess maybe shouldn't be so surprising, but I guess it was to some people, is that if you just hit that receptor, that short-term system, 24 hours a day, seven days a week, and never let it stop, then you will lose weight. And so the short-term system alone is enough to cause body weight regulation. On the other hand, the long-term system with alpha-MSH and AGRP neurons and POMC and all this stuff has been a challenge to pharmaceutically target. As you know, leptin, we discussed, didn't really work.

And so I think there's going to be, as you mentioned, a re-emergence of interest in considering this other pathway now that we've seen the success of the GLP-1s. And I think one area where it may emerge is in considering their combination, perhaps at different stages of weight loss. So perhaps what would make a lot of sense scientifically, I don't know if it'll work in practice, is that you would take a GLP-1 drug to lose the weight. And then at some point you might stop that drug.

and switch to a more hypothalamus-centered leptin-based drug to keep the weight off. So basically, use the GLP-1 drug to force yourself to lose the weight, and then use the leptin hypothalamus-based drug to sort of say, okay, this is our new body weight set point. Let's not resist this weight loss that's happened. Whether that will actually make sense practically is hard to say because the GLP-1 drugs have just a lot of benefits even beyond weight loss. People might not want to stop taking them, but that's one idea. Very interesting. I'd love to talk about dopamine. Sure.

We hear so much about dopamine being involved in pleasure. I like to think I've had at least a small level of impact in convincing people that it's also involved in perhaps mostly involved in things like motivation, different forms of learning and lots of other things too, folks. Dopamine does lots of things. It's even expressed in the eye and controls adaptation to light. So it does lots of things, but it certainly is believed that dopamine is involved in our either craving for food or pleasure from food and

What's the real story on dopamine as it relates to food and eating behavior? You had a beautiful paper published in Nature entitled – and we'll put a link to this in the show note captions – Dopamine Subsystems That Track Internal States. And I love this paper for a variety of reasons. But if you could give us the high points of your discoveries on dopamine as it relates to feeding, I think –

I know, in fact, that people would find it very illuminating. Sure, fantastic. So, yeah, the question of what dopamine does with respect to feeding is a great question and a difficult question, I think, to answer. There's a lot of misconceptions. I think the evidence is dopamine probably isn't so much involved in the pleasure of food, that taste, the hedonic experience,

One reason we think this is because you can make mice, Richard Palmer did this decades ago, that don't have any dopamine and they still show the same sort of effective responses to food. So you put something sweet in their mouth, they like it, right? What dopamine seems to be important for with respect to food is two things. One is the motivation to engage in work to get food, particularly when it's high levels of effort. So if you ask a mouse to press a lever to get a pellet of food,

If it doesn't have any dopamine, it won't do it. And if it has low levels of dopamine, it'll just work a little bit. So dopamine is important for sort of energizing action and motivating you to engage in hard tasks. The other thing that dopamine is really important for is learning. And it's important for learning about which cues predict something useful for the body. And feeding is a central example of that. And what that paper of ours is about is the idea that this learning actually happens on two different timescales for two different kinds of cues.

So what we almost always talk about with dopamine and learning, which is important, is learning about how external cues in the environment predict something like food availability, right? So you see a McDonald's sign and you know that that means there's some tasty food in there. And so dopamine is involved in that process of sort of learning what that external cue means. And that's a very fast timescale process. So

In the laboratory, for example, we will play a tone and then give an animal a sip of a solution that has calories in it, for example. And it can learn the association between that tone and that the food is going to be available if they're separated by a few seconds, but that's all. And that's a dopamine-dependent process.

But there's a second sort of much slower timescale learning about food, which isn't about where I go to get a hamburger, but rather about what the experience of eating the food, the oral sensory experience, its taste, its flavor, its texture, how that relates to the post-ingestive effects. And I should say that this seems extremely relevant to the McDonald's example because in your experimental situation, the tone is analogous to the golden arches of the McDonald's sign. But in my experience...

And forgive me, but most of the food that I've consumed from McDonald's does not taste good relative to other like really delicious hamburgers or French fries or something like that. I mean, it's so...

You're saying dopamine is required to link the signal, the golden arches or the tone, to the presence of food at a particular location. Exactly. But not to the experience of pleasure from that food. Exactly. Which squares very well with my experience of McDonald's. And I probably haven't had a bite of McDonald's in years.

20 plus years, I would have to be pretty hungry. I haven't either. And it's funny, the golden arches thing is just something that people in neuroscience talks about dopamine use. And so now I've started subconsciously just talking about golden arches, even though I also haven't eaten at McDonald's in decades. In-N-Out burgers, better tasting, from what I understand, probably better sourcing. We're not going to get into all of this in detail, but everyone has their preferences. But I do think it's interesting because what we're talking about here is...

I think, to this notion of highly processed food packaging, the commoditization of food, which is the idea that we are drawn to food for things other than the taste that we expect for it. There's all this context. That's right. So,

So I think an important distinction that people make is the distinction between wanting and liking. I don't know if you've talked about this previously on the podcast. Yeah, Anna Lemke, my colleague at Stanford, came on the podcast, talked about dopamine is about wanting as opposed to enjoying. Exactly. In most cases. Yeah. So liking is the subjective hedonic pleasure in the moment of eating it. But wanting is just what's what you want.

And these can be uncoupled all the time. You could want things that at the end of the day, you don't actually enjoy it when you get it. I feel like a lot of life is like that. - Indeed. - And so, dopamine is very powerful at making you want something, but not necessarily like it.

So that's one element. But then there's this other element that is important but very much less studied, but I find much more interesting, which is how you connect the sensory cues associated with food, its taste, its flavor, its smell, with...

the consequences for the body. And this is so important because so much of whether we like or dislike a particular food or drink is related to its post-ingestive effects. You come to like things, for example, that have calories. So this is one of the reasons that adults will eat vegetables and other savory foods that children find disgusting. Even though they're a little bit bitter, you learn through experience, this makes me feel good to eat this. And even maybe at a completely subconscious level, there's also a level of learning that occurs.

And this of course happens with other things like coffee and beer and other things like that. And so there's been an idea that this other much slower learning occurs. And the reason I say it's slower is because the time between when you taste the food and when it actually gets into your intestine and releases the hormones that might drive this is quite slow, separated by tens of minutes. But how that works hasn't been clear. There's been an idea that dopamine might be involved, but it hadn't really received a lot of attention.

And so we set out to investigate what is the role of dopamine in these post-ingestive responses and sort of map out for the dopamine system, how does the dopamine system respond? Not when you see the golden arches, which is usually the kinds of experiments that have been performed, but rather when you deliver nutrients directly to your stomach or when you deliver water directly to your stomach if you're thirsty and so on.

And what we saw was that there are these different populations of dopamine neurons that are tuned to respond to signals from inside the body. And so there are some that respond when nutrients are in the stomach and intestine. There are others that respond in a thirsty mouse when the blood is rehydrated, when you basically satiate your thirst. And we showed that the purpose, or at least a purpose, of that activation is to cause you to learn about

the effects of what you just ate, basically to create this connection between the flavor of something and its post-ingestive effects. That delayed dopamine signal after ingested food and fluids is reinforcing this connection between the flavor of what I just ate and that it was something good for me. One of the interesting things about that paper that was not the direction we initially expected to go in is that for food, I think it's kind of intuitive. There are lots of flavors to food. You have to learn what all these different flavors mean.

For thirst, people find it a little less obvious because thirst is just water. Aren't you just born knowing what water is? How do you have to learn anything to do with drinking a glass of water? But it actually is a learning question in part because for many animals, probably most animals, thirst is something that's associated with eating, not drinking. There's this study I love.

of rabbits in New Zealand. So there's not a lot of people studying what animals, how they get their fluids in the wild, because who cares, but it's kind of interesting. And so in New Zealand, there's this huge rabbit problem because they're an invasive pest species that was introduced in the 1800s and they're just eating all the land. And so there's lots of money to study rabbits, to understand their ecology. And so a group of researchers did this experiment where they made this big pen outside where they put a bunch of rabbits in this. The rabbits couldn't escape, but they had all their natural food. It was like an outdoor area.

And they also put a trough of water, so the rats always had access to water, which is a clean water, and they could measure how much water the rabbits drank. And what they basically found is that nine months out of a year, rabbits drink zero water. They drink absolutely zero because they get all of their water from food. The only time they drink is during the winter when all of the greenery has sort of become shriveled, and then they can't get water from that anymore.

And so it's just kind of interesting aspect of how many animals are very different from the way we think about ingestive behavior. But that fact that animals have to get water from food raises this question, how do they know which foods are rehydrating? Presumably they have to learn that because you can't just look at a food and say, if you've never had any experience, oh yeah, this is something that's very water rich and this will rehydrate me when I'm thirsty and this one is not. And so James, the graduate student who led this project, uh,

basically investigated this by giving mice different fluids and then measuring the dopamine response. And he showed there was this delayed dopamine response after the mice had drank the fluids that correlated with rehydration of the blood. So a whole bunch of dopamine neurons get strongly activated when the blood is rehydrated.

And he hypothesized this might be a signal, this delayed activation of dopamine neurons that allows animals in the wild to learn that food I just ate is rehydrating. And so he did an experiment where he basically gave them two different flavors, mimicking sort of the flavors of two different foods, one of which was hydrating and one of which was not. And the animals couldn't tell because he infused the water directly into their stomach. And he showed that basically these dopamine neurons are critical for them learning that association.

So that's the story of that. I love it. And I'll tell you why. When I was in college, for reasons that I don't recall, I decided to run an experiment on myself where I would eat one meal that was fairly low water content, like a piece of meat or something with some cheese, you know, what some people call a keto meal, but I wasn't ketogenic. I don't even think I knew what a ketogenic diet was at that point. And then the next meal I would have like a salad and some fruits. And then I would switch back and forth.

And I generally would only eat two or three times a day, you know, anyway, there's only so many hours in the day. And I found it to be incredibly satiating. And I found that I felt great and I,

can imagine any number of different reasons for that. And there are these theories that you probably recall that the, the diet that was being promoted in the nineties where people would either eat carbohydrates or protein separately, like there was some wackiness out there. And as I say that, I'm sure I'll get assaulted in the comments. It's probably not wacky. I'm sure there's some enzymatic basis for why that would be useful. If you enjoy it, go for it. You know, I, I don't have a feeling about it one way or the other, but one thing I noticed was that, um,

low water content containing meals, um, either by virtue of the foods that they include or by virtue of the fact that they're not diluted, so to speak. Um,

it's a different taste experience to eat those foods than it is to eat like a big salad or something of that sort. In any event, I don't do that any longer. I just sort of stopped, but it was a fun experiment. And I think it was efficient because at the time I had very low money as a student. So, you know, generally fruits and vegetables were less costly than meats and things of that sort. But in all seriousness, to what extent do you think humans overeat

or undereat depending on the water content of the food? It's an interesting question. So there is this advice that you should, if you're hungry first, drink something, drink some water and see if you're still hungry. And the idea is that perhaps humans can't always, I mean, our interoceptive sense, our ability to sense what our body needs is not perfect. And sometimes we could be confused and we could really be thirsty when we're hungry and hungry when we're thirsty. And there's some evidence that that could help.

I would say it's probably not a huge effect in most of modern day life, but it's an interesting idea. This brings us to the topic of thirst, something that your laboratory has worked on extensively, and the topic of osmolarity, of salt consumption and things of that sort. In broad terms, how do these things link up? Meaning...

Are there instances in which what we really need is salt and we end up eating a bunch of Parmesan cheese? I got teased yesterday by my team because occasionally when I'm on the road, I don't like most of the foods available in most airports and stuff. So I'll bring a chunk of really nice Parmesan cheese. I'll just break off a piece and eat it. I'll have half a cucumber and I'll have a can of, not a can of tuna, but there are these wonderful jarred filet of tunas that are available that are in olive oil. They taste really good. This is not canned tuna. It's really good.

And I'd rather eat that in most cases until I can get to a decent meal than like what's put in front of me on an airplane most of the time.

So I get teased about this, but I noticed that for instance, sometimes I'll eat the cheese and I think, oh, actually what I really just want is the salt. Yeah. I really want the salt. I've been drinking a lot of coffee today. I've had a couple extra glasses of water. Maybe I'm just craving salt and I'm confused and I'm over consuming this cheese. Yes. When in fact, what I'm going for is the salt as everything.

You point out our understanding of exactly what we need is fairly crude, and oftentimes we overshoot the margin, especially when foods are in combination. So salt, water, and let's just say calories. How do we accurately or inaccurately pursue those at the level of biology? Okay.

I'm throwing tough questions at you. I know. But you're... It feels like my qualifying example. So, well, there are separate systems. There's thought to be separate systems that control salt appetite, thirst for water, and hunger for calories. And so they involve different brain regions for the most part, different neurons, different signals from the body. In general, hunger and thirst are pretty separable.

I would say the instance where they interact is in phenomena such as dehydration anorexia. This is the idea that if I give you some dry food but I don't give you any water, you're going to eat less food because basically you're going to get dehydrated and you're going to decide I need to preserve my fluid balance even if I eat less calories.

So we prioritize hydration. Yes, you will at some point. At the level of survival. At some point you will prioritize hydration. That's related also to the concept of prandial drinking. So many animals, including humans, drink most of their water during meals because you basically want to counteract the osmolites that are in your food. Salt balance, though, and thirst, so the thirst for water and the desire for salt are much more tightly linked because...

The purpose of both systems is to maintain the composition of the blood at its right concentration. So you want to have the right osmolality of the blood, which you can just think of in simple terms as sort of the total concentration of all the salts. It's a little more complicated than that, but it doesn't really matter. And you also specifically need to maintain the sodium concentration at the right level.

And there are really powerful innate mechanisms that drive both. I think thirst is very intuitive to people. You get dehydrated, you lose water, you become thirsty. We know now that there are a very small set of neurons in a few brain regions that control that.

And the way they're thought to work is they contain osmosensors. So they contain basically these neurons are sensors for the osmolality of the blood, and they're activated when the blood osmolality gets too high. And it's an incredibly sensitive system. So you can perceive an increase in your blood osmolality of 1% as the sensation of thirst. So remarkable.

Yeah. That's how critical it is to maintain salt balance. Exactly. Exactly. And so, you know, you get to 10% increase in blood osmolality and you're in extreme discomfort and 20% you're like in the hospital. So if I took, let's just say a half an ounce sip of seawater inadvertently. Yes. It's extremely aversive. It is. It's like, like you just, you want to drink some non-salty water, some nice clean water. Yes, exactly. Immediately. Yeah.

So I should emphasize that there's two components to the fluid homeostasis system, to the water homeostasis system. One is this desire to drink. But the other is, of course, the kidney. And so the reason that drinking the salt water won't put you in a really bad situation is your kidney would then filter out a lot of that salt and cause you just to pee it out, and then you'd be fine. And so those two work in balance. The kidney's controlling how much of the salt gets reabsorbed into the blood. And then this desire for thirst, this desire to drink, allow you to replenish the blood with water at various intervals.

And so, yeah, I mean, the experiments led to the discovery of this third circuitry are amazing. It was this guy, Bengt Andersen, working in the 1950s. And he just had this hypothesis that there was an osmosis sensor in the brain, right? Which is a very, I think, you know,

There was some evidence that suggested, but it was not really strongly supported at the time by the data. And so he took these goats and he just started infusing small amounts of salt into various places in their brain, reasoning that if there was an osmosis sensor... Sorry to tell you, I was wild. I mean, I wasn't chuckling at ingest like I feel for the goats. I feel for everyone involved in that experiment. But what a wild experiment, just to put salt directly into the brain. Concentrated saline solution, yeah. My goodness.

And he found this tiny region in and around the hypothalamus that if you infuse salt in this region, the goats will drink like eight liters of water in five minutes. It's just crazy, right? And so he reached, okay, this must be the osmosensor. And then he went back and stimulated those neurons. It's just the same thing. The goat just drinks like crazy. And so now we know there's this couple small regions around the hypothalamus. One's called the subfornical organ. Another one's called, well, it doesn't really matter what the goat, but basically they have these osmosensors.

One of the interesting things about the regulation of fluid balance is you face some of the same challenges we just talked about with the regulation of food consumption, which is that you have this behavior, this ingestive behavior that leads to replenishment of the body, but there are these delays, right? So if you're thirsty and you drink a glass of water, it can take on the order of sort of 20 to 30 minutes for the water to be absorbed into your blood, for the blood to be rehydrated, and then for these osmosis sensors that Bank to Anderson discovered in your brain to be rehydrated.

to be sort of sense that and return to normal activity. But of course, if you had the experience of drinking a glass of water, you know that you can quench your thirst within minutes, right? And so how does that work within seconds even? So one of the other sort of experiments we did early in my lab was to ask that question by basically recording for the first time the activity of these neurons that Bengt had discovered by putting the salt at the go. So we went back into them now in mice. Mice have the same neurons. You have the same neurons. And recording their activity when a thirsty mice drinks, it asks what happens.

And what we saw was that the neurons don't wait until the blood is rehydrated. They also don't do what the AGRP neurons do, meaning they don't look at the water and predict how much water they're going to drink. But instead, they get a signal from the mouth, which every time the mouse takes a lick of water, their activity goes down a little bit. And basically, they track in that way the volume of water that's passed through the mouth.

They also get the signal from the blood, really relaying the osmolarity of the blood, and they compare these two. And basically, when the mouse has drank enough in order for the animal to predict that the blood osmolarity is going to return to normal, then the animal stops drinking. Beautiful.

It's just beautiful. The brain is essentially predicting with, it sounds like a high degree of accuracy, how much water one needs to drink, linking it to the pleasure of ingesting good clean water under conditions where we're thirsty.

in anticipation of adjusting blood osmolarity in 20 minutes. Exactly. I mean, it's, yeah, I mean, this is the kind of thing that just, it delights me because it just means that the brain as a predictive organ is just, is so accurate. It also explains some sort of funny aspects of thirst that you may have noticed from everyday experience. So

So, you know, one idea is that just cooling your mouth can sort of quench your thirst, right? So if you're in the hospital and you're not allowed to drink any fluids, they'll give you ice chips to suck on to sort of quench your thirst. So why is that? And so one idea is that perhaps because water is usually cooler than your body, that sensation of water passing, it always cools your mouth. And so you learn, or maybe it's innate, that just cooling of my mouth means that basically I'm going to be rehydrated.

So Chris, this was an experiment done by a graduate student, Chris Zimmerman. Chris did the same thing where he was recording these thirst neurons, but he put a cold piece of metal on the mouse's tongue. And you can see when you do that, these thirst neurons go down in activity, and then you remove the cold piece of metal and they go back up. Amazing. So a lot of these sort of oddities of everyday experience have to do with how the system has evolved to make the prediction about what's going to happen to the body.

I mean, few things are as rewarding as the sensation of drinking really nice, clean, cold water when one is very thirsty. When my lab was in San Diego, I used to take my dog hiking in Palomar Mountain. And one day, you know, I really screwed up. He was a bulldog mastiff. They overheat easily. And it was a lot warmer than we thought. We ran out of water. It was actually a dangerous situation for him. We got down to the bottom of the hill, thankfully, with him still alive. And there's this pump that pumps water.

I was told it was spring water and it came out really cold and you could just see him fill back up with life. I filled back up with life knowing he was filling back up with life. And it was unlike the kind of reward that one experiences with food when you're hungry. Absolutely. It's like that basic critical need for water. Absolutely.

under conditions where you're clearly dehydrated is like nothing else. It's delicious in a way that no food is delicious. I would like to actually say something about that. So that distinction you made is really interesting between hunger and thirst. So when you stimulate these neurons that make an animal thirsty, the mice hate it. They will do anything to avoid something that artificially makes them thirsty. So we can artificially stimulate these thirst neurons, create a state of virtual thirst. They'll lever press hundreds of times to make it stop.

The same neurons, the neurons I talked about that control hunger, the AGRP neurons, they actually don't care so much. They won't really do much of anything to shut them off. That raises the question, well, why do animals eat then when you stimulate the hunger neurons? And we think the primary thing that the hunger neuron stimulation does is it makes food itself more attractive. It makes the food more delicious, more of an attractive motivational magnet.

It makes the experience of eating more pleasurable. But it is not itself the most unpleasant state. At least the mice aren't willing to do that much. Whereas for thirst, I think dehydration and thirst is really just unpleasant. And animals just want to avoid that. And so I think the distinction is very real. I think there are two different motivational mechanisms for hunger and thirst. Hunger is mostly about the reward of food.

thirst is mostly about this is just really unpleasant. And removing that unpleasant. Exactly. And you had a paper, which I was going to ask you about, so I will, entitled The Forebrain Thirst Circuit Drives Drinking Through Negative Reinforcement. Yes. And I'm guessing that paper illustrates exactly the point you just made. So it's a forebrain circuit. Yes. So does that mean that there's some elements of learning and cognition around this? Or are we broadly speaking about the forebrain, for instance, the hypothalamus being in the forebrain? So yeah, it's interesting. So

So the thirst circuit, for whatever reason, is mostly in the forebrain. So we talked about the NTS and the areopostrema being important for hunger and signals from the gut. The areopostrema is a circumventricular organ, meaning it's outside the blood-brain barrier. There's only a couple of these in the brain.

The neurons that control thirst are located in the two circumventricular organs in the forebrain. One is called the subfornical organ, the other one is called the OVLT, but they're just acronyms. So why it evolved to have the thirst neurons more in the forebrain and the neurons that sense nutrients more in the hindbrain is a little bit unclear.

And so there is definitely an element of learning, but a lot of this is those neurons are also just directly sensing the blood and sensing changes in both the concentration of salt in the blood and then also hormones like angiotensin that drive thirst. I was going to ask you this earlier, but it seems appropriate to ask now. A colleague of mine at Stanford in the psychology department, Dr. Ali Crum, who studies mindsets, has done some interesting experiments where people are told that a given milkshake is healthy.

calorically dense. Other people are told that a milkshake is calorically sparse. Both groups independently consume the milkshake. Um, and then they measure things like hormone responses in the bloodstream that are associated with satiety. And what she finds is that, um, even hormone responses, um, to the same shake, meaning the same amount of calories, fat, sugar, et cetera, can be significantly modulated based on what we're told. Um,

And it extends into some other, perhaps even more interesting areas, in my opinion, whereby if people are told that, let's say a given meal that has a small piece of fish, serving of vegetables and a carbohydrate is, yes, perhaps a little bit calorically sparse compared to what one would normally eat at a given meal. But they're told this is a highly nutritious meal. This is good for you. Then just that mere knowledge of

can drive more satiety, better feelings about the meal. Even, I believe, I have to double check on this, but as I recall, a heightened sense of it tasting really good. So humans...

are very susceptible to the, in this case, the either inaccurate, in the case of the milkshake experiment, or accurate descriptions of food, meaning they shape our perception of whether or not something is good for us, tastes good or not, and whether or not it leads to more or less satiety. And I think this is important given the obesity crisis, you know, to say nothing of these drugs that are coming out.

whereby people often associate dieting with deprivation and pain, but if they understand that certain foods are nutritious, that can at least partially offset some of the pain of caloric restriction. What are your thoughts on that? Yeah. Well, one thing I've been talking about is how a lot of these circuits are anticipatory. They're making predictions. They're trying to estimate what's happening in the future.

And I talked about how these AGRP hunger neurons, how they can sort of see the food or get input about the sight, smell of food, and that way predict how many calories the mouse is going to eat. I mean, this is a mouse, right? This is all based on a mouse. And a mouse has, you know, a thousand times fewer neurons than you do as a person, right? So the computational capacity that the human brain has to make these predictions is just vast compared to these mice. And these mice are already doing amazing things, right? So when you think about then

what is the human brain able to do in terms of anticipating changes in nutritional state and how information that you're given can change, uh, uh, the expected physiologic outcomes. I mean, you're right. I mean, there's, there's, there's just this whole other element that it's very hard to study because it's happening in the brains of humans and we can't do these kinds of experiments. Um, but I'm sure that's very important. I mean, so I talked a little bit about, about these flavor nutrient conditioning experiments. These are the experiments where essentially an animal learns to, uh,

consume a certain flavor because it learns it's going to be associated with nutrients later. Sort of the paradigm for how you learn to consume bitter vegetables because they're good for you and you get nutrients.

So people have also done those experiments in humans, and that does work. But what they've discovered is it's very sensitive to what you tell the humans about the thing that they're going to consume. So if you put nutritional labels where you show the different numbers of calories, then basically they sort of adjust their expectations and nothing happens. So it really has to be that sort of it's very sensitive to what information you give them before the experiment happens. So I think that's an example of that kind of thing. Without any pressure from

for it to be prescriptive. How do you approach eating given the knowledge that you have about food? I like to assume that you can sit down to a meal and not think about your AGRP neurons too much or any of that. But given that you have deep knowledge in this, has it shaped kind of how you think about food cravings, your own, you don't have to reveal what those are even if they exist, how you observe the eating behavior of others?

And yeah, how has knowledge shaped your feeding behavior? Well, I try not to think too much about my AGRP neurons when I'm eating. I would hope. I think the circuitry is so complex and we're just beginning to see what's happening. So I wouldn't use that kind of information at this stage. We're just beginning to prescriptively. But I think

I think there is a set of basic recommendations from physiology and neuroscience, very simple things you've probably talked about with people on your podcast before, for sort of shaping your diet to be healthier, to limit food intake. So one we've already talked about is limiting consumption of ultra-processed food, eating more whole foods for lots of different reasons because they're more satiating, because they don't have this sort of engineered palatability that causes you to overeat.

Another big one, which I'm sure you've talked about with some of your guests, is protein consumption, making sure you get adequate protein consumption, both because there's this concept of protein leveraging. So if you don't eat a minimum amount of protein, that's going to cause you to eat more calories just to try to achieve that minimum amount of protein. Also just because protein is more satiating and also because there's this idea of thermic effect of food. And so you basically burn more calories metabolizing protein than sugar or fat.

How about consumption of fluids during meals? I've heard it said before that we're not supposed to consume too many fluids because it's going to dilute the enzymes that allow us to digest our food. I've heard other people say that's a complete myth. I've never heard that's a myth, I think. I mean, I think drinking water, I mean, so humans don't have a perfect capacity to determine whether they're hungry or thirsty, and so drinking water will ensure you're not eating because you're thirsty. Right.

And there's no idea of diluting it. I don't think that meant... Distention itself, even though water provides a very limited distention signal, the expansion of your stomach and intestines is one important way that you terminate feeding. And so there is some component of that where you can get distention just from drinking water. I'm sorry, I blurted it out. Interesting, because I didn't realize that fluid consumption...

only provides a limited signal for distension. - Well, it's not fluids, it's water. And so the idea is that you can fill your stomach up with fluids, but the rate at which fluids empty out of your stomach depends on their calorie content. So basically, if you drink water, it empties very rapidly into your intestine and then goes through your intestine and is gradually absorbed. If you drink something like a glass of orange juice, it will empty much more slowly. And if you're drinking something that's really high in fat, really high in calories, it'll empty extremely slowly over hours.

And that's because there's a negative feedback loop from the intestine that controls gastric emptying. So as those first nutrients leave your stomach and enter your intestine, that produces hormones that go back and then slow down the rate of gastric emptying. And the purpose for this is that you don't want nutrients entering the intestine too fast. That's really unsafe. It feels very unpleasant. And it's just that your intestine can only metabolize nutrients so fast.

If there's calories, then it slows down gastric emptying a lot, but water just kind of goes through. What a beautiful system. There's regulation at every point. Hypothalamus, brainstem, gut, the rate of emptying based on the difference between water and orange juice. It's just awesome.

And that's part of the reason I think it's so hard to outsmart the system, right? Because these neurons are making predictions based on the sight and smell of food, but then the gut is doing its own thing. It's calculating it separately and relaying that information. So at every step, there are these checks. Basically, they're just confirming that what you thought happened the first time actually was really going on. And so...

Which makes sense because it's so important for survival, these homeostatic systems are the product of so much natural selection. Which I think at least partially explains why thousand-fold increases in peptide hormones like GLP-1 are required to see significant long-lasting changes in weight. Exactly. Because the system is so strongly regulated. Exactly, exactly. It's hard to beat homeostasis and hard to beat it safely. But it sounds like...

you're more or less optimistic about where that whole field of let's call it anti-obesity drugs is headed? I'm very optimistic. I mean, I think, look, I mean, I think that it's, you couldn't have asked for more so far at this stage with these GLP-1 drugs. Incredible weight loss, unexpected health benefits, really safe as far as we can tell. I mean, it's always possible that some new

some new side effect will emerge. But these drugs are in millions of people, and they've been in a lot of people for a long time now, and nothing seems to have shown up.

So I'm very optimistic. And I think even beyond that, just now that the pharmaceutical industry is reinvigorated to investigate this question, there's so many different people looking at it. In five years, people have so many different options. It won't just be Ozempic or Monjaro. There will be five different, 10 different drugs that they can choose from that have slightly different side effect profiles, slightly different efficacy, perhaps used for people with slightly different metabolic conditions. And so it'll really be a whole palette of medicines you can take that will adjust your physiology and hunger.

And it's amazing how well it squares with the understanding of the basic biology, you know, and that's a perfect opportunity for me to really just say what is in my mind and clearly in the minds of everyone listening and watching, which is thank you so much for this absolutely encyclopedic and exceptionally clear explanation of feeding and thirst and

and salt regulation and these new drugs that are in everyone's minds and everyone's hearing about. I've learned so much today. I know everyone else has. You run an incredible laboratory. I've tracked your career for a very long time. Every paper is spectacular, and you're in a very competitive field, and you've contributed in enormous ways to our understanding of these important processes. And I don't just say that as a formality. I know that to be true, given that we

you know, are from the same field and have known each other for a long time. And I'm familiar with your work at a deep level. Today has just been an absolute privilege and a gift to learn from you. And I know everyone feels the same way. So thank you for taking time out of your busy research schedule and the other important areas of your life to come here and educate us all. I learned so much basic and practical knowledge. And I know everyone

everyone else did as well. Thank you so much. Thank you. This has been really fun. I'm really glad we had a chance to do this. We talked about some of my favorite topics, so it's always a pleasure and talk with another neuroscientist about these things is fantastic. So, well, please come back again. Um,

Meanwhile, thanks for everything you do. All right. Thanks. Thank you for joining me for today's discussion with Dr. Zachary Knight. To learn more about his research or to support his laboratory's work, please see the links in the show note captions. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel.

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