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

24:40So that's one mechanism by which leptin controls hunger. We, 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 it's the technology didn't exist because these are such a tiny population of cells so deep in the brain.

25:17So 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. And so, on my first graduate student's, Yoming Chen, he used a technology called fiber photometry, which allows us to put a fiber optic into the mouse's brain so that the epidemic 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.

25:49These AGRP neurons will be very active because the animal is 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 and the blood start changing, feeding back to inhibit these neurons. What we found was really surprising. I remember that when he made this discovery, he basically am running into my office and saying, exact, I gave the mouse the piece of food, but the weirdest thing happened, the neurons shut off almost immediately. And I said, Yoming, you've been in a mistake.

26:17It's okay, you're just starting off in graduate school. This happens, go back and repeat the experiments, and then we'll discuss it. But he did several times, he said, every single time I do this happens, I give a hungry mouse food and the AGR P neurons within just a few seconds, their activity has greatly diminished back to the level that would be in a fed mouse, even before they take the first bite of food. And so Yoming then went to do a series of experiments, 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 in measuring the response of these AGR P neurons was that what the neurons were doing was predicting.

26:53The 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. 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 in very simple by very simple analysis in which you give the mouse different foods and you look at how much these AGR P neurons drop when the mouse sees and smells the food. And then you plot that again, so this drop happens in three seconds, four seconds, something like that.

27:22Then 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 lap and it was really surprising to all of a sudden I think everyone, but it illustrated a theme that we've now seen again and again, which is that these circuits the control internal state, 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.

27:56You 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 that has about this many calories and I'm known as 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. That's a great question. So we don't fully know the answer.

28:30So one interpretation of the data I just showed you is what you 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 repetitive 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, they're also just sit there and eat. So you can't fully separate, although we like to make the distinction between a repetitive and consummatory and we know that in different parts of the brain, there's more important for one versus the other.

29:05The 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 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, that in biology it's always hard to answer why something happens. You can figure out what does happen, but then you can, the reason why it evolved that way is challenging.

29:40Another idea is it's involved in these, what we call, cipholic phase responses, that are necessary to prepare you for a meal. So the famous example, this is Pavlov, basically, trains the dog to associate the ring of the bell with the presentation of food, and then eventually the ring of the bell alone causes the dog to celebrate in the absence of any food. And, celebration is one example of a cipholic 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 also some other things, like basically this creation 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.

30:20So another idea is it could be part of that. But it probably is doing all of these things. As many of you know, I've been taking AG1 for more than 10 years now. So I'm delighted that they're sponsoring this podcast. To be clear, I don't take AG1 because they're a sponsor, rather they are a sponsor because I take AG1. In fact, I take AG1 once and often twice every single day, and I've done that since starting way back in 2012. There is so much conflicting information out there nowadays about what proper nutrition is. But here's what there seems to be a general consensus on. Whether you're an omnivore, a carnivore, a vegetarian, or a vegan, I think it's generally agreed that you should get most of your food from unprocessed or minimally processed sources, which allows you to eat enough, but not overeat, get plenty of vitamins and minerals, probiotics, and micronutrients that we all need for physical and mental health.

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32:23And 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 was French restaurant. I took one bite. I realized it was absolutely delicious. French bread. The butter was fantastic. So I had some bread and butter, which I love. Then they brought more. Then they started bringing out, I don't know who ordered them because I didn't appetizers. I realized that this was going to be a much more extensive, chlorically dense meal. Suddenly, my appetite for the appetizers went down because I knew there was more food coming. Had I not known that there was more food coming, I think I would have consumed more of the appetizers, which also looked great.

33:06Clearly, there's something going on with these AGRP neurons for a moment. You're integrating based on new information. Exactly. On the other end of the spectrum, I did a solo episode about eating disorders in anorexia nervosa in particular. 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 almost hyperaccurate calculators of the amount of calories in food. They've devoted a lot of cognition to it.

33:51It 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. That drives in that condition obviously a food avoidance. 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. 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.

34:32What is known about these AGRP neurons in humans? Meaning do they exist in humans? Presumably they express the leptin receptor. Sounds like they are able to integrate information both cognitive based on immediate experience, visual, olfactory, but also a lot of prior experience. A hamburger patty, I don't can't tell you how many calories it has. All I know is that it's mostly protein and some fat. What are these neurons doing? What do they have access to? They sound like, when any time you hear about hypothalamus, I think very basic, dries, but you're talking about a pretty sophisticated analysis of a real -time event that is driving fairly nuanced behavioral decisions and updating that, which is a big deal.

35:22We're both neuroscientists, but for everyone listening and watching, this is a big deal. This is as nuanced as 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. These are switches. These are dials. Yeah, so there's a lot there. I'll try to unpack that. The first thing I'd say is they are present in humans. Humans have age air penarons. Human age air penarons express the leptin receptor. We think the functions are very similar. One of the nice things 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.

36:11Many 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 age air penaron pathway, is important in humans due to human genetics. Just add a little bit more information here. There's a companion set of neurons called pom cenerons that promote satiety. They're sort of the in and yang of hunger. Age air penarons promote hunger, pom cenerons promote satiety. They're intermingled in the same part of the hypothalamus.

36:47They'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. 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 among severely obese people, mutations in this pathway, age, RP, pom cenerons, and their direct downstream targets are quite common. So anyway, is it fair to say that some amount of obesity is genetic in nature at the level of neuronal firing or circuitry?

37:29I think a lot of bodyweight regulation is genetic. It's highly heritable. There's a question of how much of it is due to single genes and the number of 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 pom c, or an enzyme within those cells that processes pom c into the right form, or in the most common mutation in the downstream receptor for pom c, it's called the melanocortin -4 receptor.

38:10And so among the severely obese people have sort of genetically inherited severe obesity from childhood. Something on the order of 10 % have mutations in this pathway. So it's very clear that this pathway is involved in bodyweight regulation in humans. Most obesity, although there's a very strong genetic component, is not associated with single gene mutations, like this is 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, so if you look at the genes through genetic association studies that have been associated with bodyweight, and there's been lots of genetic association studies trying to find mutations that are associated with whether you're lean or obese.

38:55Something on the order of 1 ,000 genes have been linked to bodyweight regulation. And the vast majority of those are expressed in the brain. They're highly enriched for brain processes, which makes sense because bodyweight is controlled by food and take, 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 bodyweight, which is consistent with the results of twin studies. So if you look at monosegotic versus diosegotic twins, the estimates for the heredibility of bodyweight is something on the order of 80%.

39:28We should explain monosegotic, diosegotic, which I've talked about before in the podcast, just to show people that. Just identical versus fraternal twins, basically. And so, and by comparing their bodyweight 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 of the variation between individuals is thought to be have a genetic component. So I don't think most people appreciate that. Yeah, 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, etc.

40:06Maybe embrace pharmacology. Yeah. 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? To me, it just seems like why wouldn't people embrace 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.

40:47But 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 Ozempik, have provided them the opportunity to finally be able to lose weight and feel better and exercise safely, 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 starting sometime around, you know, the 1970s, there's this explosion in body weight and increase in obesity.

41:28That's when it started mid -70s. Sort of the 1970s, isn't it? A lot of that started. Snacking. So there's lots of explanation. There's lots of explanations. Sinoils. Snacking. By the way, I don't think that's the reason folks. I think there are a lot of reasons. But the theories that that abound right now on social media are that I have a list of the theories as to why the obesity is increasing. Get everything from seed oils to snacking to smartphones to conspiracies to its wild. Yeah, it's wild. The range of hypotheses is wild. I mean, the challenges, I mean, some of them could be true, but it's just very hard to test those things, which are happening in the whole population, right?

42:05But 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. Just not fast enough for people to evolve. So 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?

42:38All you need is if it's a recessive allele, you need two copies. And the next thing you know, you've got a mouse four times larger than a typical mouse, and it's all explained by increased body weight. So that haven't can happen very quickly within a species. What's rare to find is an entire new branch of a species 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 significant. We want to baby boomers.

43:14Generate X. And then whatever is YZ -moaning. Exactly. I think the thing that people find hard to wrap their heads around is how can it be that this is how this is that that increase in body weight is clearly environmental, right? Because that's all this change is the environment. The thing is changed genetically. Yet it's also true what I said that body weight is extremely hierarchical. It's one of the most heritable features and something on the order of 80 % the only thing 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.

43:42How can you explain that? The idea is this. There's a distribution of body weight 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 to basically cause you to save energy. And so you would be more on the obese side or you may be maybe 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 shift so that everyone becomes or most people become heavier.

44:19And 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. They're 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 various sensitive to palatable food.

44:55And 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 still because of genetics, but it also requires the environmental component. I mean, you just take a step back, right? You can make anyone lean, but just putting them putting them in prison and just only feeding them 1500 calories. I mean, we've done those kinds of experiments. This is a famous experiment, the Minnesota starvation experiment, right? They basically is, they put people in prison, but this is in World War II.

45:23They took a bunch of healthy volunteers, fed them 1600 calories a day and just asked what would happen if you basically sent me starved people and unsurprisingly they lose an incredible amount of weight. All they think about is food, they basically the 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.

46:05Is 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, right? Getting high quality nutritious food that tastes great is expensive. Yeah, I would argue. But getting calories is fairly inexpensive. Yeah. 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, right?

46:45We can't create a parallel society where we manipulate one of these variables and save the people become obese. 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 them make people prone to gain weight. And this really beautiful work, if you know what this is from Kevin Hall at the NIH who's investigated this, he's really my opinion, the best person doing this kind of human obesity research today. And he does these experiments where he takes people into the NIH into the hospital, hospitalized them for several weeks so he can exactly control what they eat.

47:24And he did this, 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 raiders to people to test, they would say, this is about equally palatable. So I like the, this ultra -processed dish as much as this non -ultra -processed dish. What's an example of an ultra -processed dish like a 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 some nice piece of pizza and some something.

47:59Exactly, 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 we find 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.

48:32And then when you switch them, they lost weight. So the idea being that you can have two sets of food that you sort of 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 a big thing about whole foods is that they take more energy to digest and they have more volume.

49:04So 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 on 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.

49:32I 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 repetitive and consummatory behaviors can learn based on experience and expectation, 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 into 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 than they burn.

50:20I do believe in calories and 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, macro nutrients, proteins, fats, and carbohydrates, sort of knowledge about macro nutrients, a piece of fish is mostly protein, has some fat, a bowl of rice is mostly carbohydrate, has some protein, put a pad of butter on it, has some fat also, right, it is sort of obvious.

51:10But taste, macro nutrient content, calories, which we already know people with interrexia are exquisitely good at counting with their eyes. So it's possible they represent again a pathologic extreme of this. And micro nutrient content, maybe even amino acid content, like how much loosing is there. Now most people aren't thinking about how much loosing is in a meal, but we know that loosing 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.

51:51And 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, broccoli rice and a chicken breast blend together just sounds horrible eating them separately, if there's some olive oil and a little pad of butter involved, that sounds pretty good. But a highly processed food in some ways is a blending together of macro nutrients, micro nutrients, 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, adorito, a candy bar, that we attach to the product, we attach to the name of the processed food to the packaging.

52:37But I could imagine, and here's the hypothesis, 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, it's for me, it's difficult because I love the taste of carbohydrates, especially when they're combined with fat. But there's seems to be an easier time regulating food intake when people step back and say, I'm going to consume minimally processed whole foods.

53:14And 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, 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 case us humans, that highly processed foods bypass.

53:56Now, 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 and at least stimulate some additional thinking about a landscape, in this case, nutrition and feeding behavior, that for a lot of it was 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.

54:31I 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.

55:17So 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 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.

55:51There's several interesting ideas there. 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 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 all, I don't want any more salmon, but I would like some carbohydrates now because you have this sensory specific satiety.

56:34And 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 variety in the diet. Eventually you just get sick of eating the same thing. And this is 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.

57:09A second idea, though, that comes to mind is just as you mentioned, this idea of learning. And then so much about our preferences for food are, 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, you know, 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 and 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 tastes, and then it involves how those tastes and smells interact with the post -injustive effects of the nutrients.

57:49So 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, you know, there's lots of examples of this that you can just match for every day experience. Most people, the first time they had a beer or the first time they had a glass of coffee, found it repulsive, right? 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.

58:14We 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 what is what whether something is good or bad depends on an internal state. And so it's an interesting idea, you know, perhaps if these ultra -process 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, 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.

58:54And 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 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 busy saying is that the neurons in our brains that control these behaviors, 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.

59:50And in the case of carbohydrate, whatever is going to replace whatever glycogen we might have depleted, right? I mean, like 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 taste savory or taste. Absolutely. 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.

1:00:30So they can, like for example, an agiar penuron. I can put sugar, fat, or protein into the stomach of a mouse and to an equal extent inhibit an agiar penuron as long as they have equal calories. Yeah. So a little drop of olive oil into the belly that has of an animal that has, let's drop, 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 agiar penurons, it is. So they don't care about the macronutrients. No, they're really concerned about the wrong rules. 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.

1:01:16And 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 other 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 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 neither, or you will die.

1:01:53And so, whereas sugar in fact 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 there's very few deprive an animal of sodium. They'll develop the salt appetite that's incredible, basically, and that's completely innate. But that's, I think, salt appetite and protein appetite are the things that are probably the most strongly regulated at the level of the macronutrients. I'd like to take a brief break and acknowledge one of our sponsors, Element. Element is an electrolyte drink that has everything you need.

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1:03:03To make sure I'm getting proper amounts of hydration and electrolytes, I dissolve one packet of Element in about 16 to 32 ounces of water when I wake up in the morning, and I drink that basically first thing in the morning. I'll also drink Element dissolved in water during any kind of physical exercise I'm doing, especially in hot days when I'm sweating a lot, losing water and electrolytes. They have a bunch of different great -tasting flavors of Element. My favorite is the watermelon, although I confess I also like the raspberry and the citrus. Basically, I like all the flavors. Element has also just released a new line of canned sparkling Element.

1:03:34These aren't the packets you dissolve in water. These are cans of Element that you crack open like any other canned drink like a soda, but you're getting your hydration and your electrolytes with no sugar. If you'd like to try Element, you can go to drinkelementspeltlmnt .com slash Huberman to claim a free Element sample pack with the purchase of any Element drink mix. Again, that's drinkelement .com slash Huberman to claim a free sample pack. If we could talk about bodyweight homeostasis for a moment that I think that would be useful. Let's say somebody decides they want to lose some weight. They chloric restrict slightly either by exercising more or eating less or both.

1:04:15Their bodyweight 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 bodyweight. Are the AGRP neurons motivated to have them seek out more food? In other words, are they hungrier and more motivated to find an eat food? Or do these AGRP neurons learn, hey, bodyweight is lower and I don't need to push to find so much food so often? No, I mean, the idea is that the AGRP neurons are more active when you lose weight and that chronic activation of those neurons. And part because leptin levels are lower in the blood because you've lost weight is that counter regulatory drive that drives you to then consume more food.

1:04:56But then how do people ever keep weight off? Well, so part of the answer is they count. I would argue I have these friends who were very heavy. 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. By the way, I'm not a proponent of any one particular diet. I vegan friends, carnivore friends, etc. 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.

1:05:32They 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 that there have been efforts for a long time to develop diets that would help people consistently lose weight. It has been very unsuccessful. There are some people who for various reasons can successfully lose weight and keep it off. 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. So I'm also quit drinking alcohol. Yeah, so there's other things.

1:06:07So if you gave your regulations better when you're so opposed to changing your environment. 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 if they're free living humans. They have to fill out a questionnaire. But 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.

1:06:48Now, 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 Libel about 25 years ago that did this. Take people 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.

1:07:28And 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 this now this chronic deficit. They have to eat 25 % less than someone who looks the same as them, is 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 little slow metabolism. They're 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.

1:07:59But there have been studies looking at it at least a year and it doesn't seem to come back within a year, that difference in energy expenditure. Now a 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's 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 and calories out, if we can measure body weight and energy expenditure accurately, we can then back calculate how much that person was actually eating.

1:08:40So 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 somebody to go around a treadmill in those ways, then basically they're thinking about the fact that they're doing this. You need to do it in some way covertly. So that you increase the 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.

1:09:08They block this protein SGLT2 and the kidney that is necessary for glucose to be reabsorbed into the blood. And so basically it happens to 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 will 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.

1:09:40Some 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 GOP1, Gleukugon like peptide 1, OZM -Pik -Mongerro and similar drugs. My understanding of the back history on the users that a biologist obsessed with Helomonsters, a reptile that doesn't need to eat very often, discovered a peptide within their bloodstream called extended that allowed them to eat very seldom, a curved appetite in the Helomonster of all things.

1:10:25And it has an analogue, homologue, you know, we don't know. I don't know the sequence homology exactly, but there's a similar peptide made in my身 and humans that suppresses appetite. If you would, could you tell us what is known about how GOP1 works to suppress appetite, wear in the body and or brain, and your sort of read of these drugs and what's happening there. Good, bad, exciting, ugly. Sure. We haven't been happy to anything else. So the story of GOP1, so the Helomonster 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, you know, these were developed as drugs for diabetes.

1:11:09And diabetes is a condition where basically a 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 is this phenomenon on discovery and it's the increase in effect. And what it went into? Increasing. Increasing. Increasing. Not the creature effect. Not the creature effect. Observe the creature effect in numerous places in daily life and online. Just kidding. So it's called the increase in effect. You can think of it as increase insulin because that's what the effect is.

1:11:43And 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 more 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.

1:12:18And so it's suggested 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 increase in. And through various experiments, it was it was shown that this increase in effect comes from the intestine that there's some substance being produced by the intestine that when you eat a meal, if sugar goes through your intestine, that boosts this insulin response to glucose in the blood. And people immediately realize this could potentially be very valuable. And the reason is that you know, you can treat diabetes with insulin injections, but insulin is dangerous, right?

1:12:49Because if you inject too much insulin, you can kill yourself by making yourself hypoglycemic, right? So this is to be very careful. But the thing about the increase in effect is it's not causing insulin release directly, but it's rather boosting the natural insulin release that comes when glucose is higher in your blood.

1:13:06So basically in the years that followed, whenever someone would find a new hormone, they would test it is it this increase in and there's lots of failures. They weren't the increase in. But then so there's other hormone that comes from the the pancreas called glucagon, right? And so glucagon, which 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 but but people discovered in sort of the 1980s that the glucagon gene is expressed in other tissues other than the pancreas.

1:13:44And 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 came from the same gene, but it's just slightly different. It's cut up slightly differently. And this hormone wasn't increasing. 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 there I should say there was one other increase that's that's been found.

1:14:15It's it's called GIP. 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 GLP1 into a drug is that as an extremely short half -life. So it has a half -life about two minutes in the blood. And so even if you inject people with GLP1, it won't really be useful for anything. You don't decrease appetite, you don't affect blood sugar, 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 GLP1. So the first thing people tried was let's make inhibitors of that enzyme so we can boost this natural GLP1 signal.

1:14:53And those are approved, uh, uh, diabetes drugs are called gliptens. You've probably heard about them genuvias, the most common one. And those boost the level of GLP1, the natural GLP1 in the in the in produce from the intestine by about threefold. And they're effective in treating diabetes. That's the fact that people lose weight. People do not lose weight. And that's one of the key reasons that we know the natural function of GLP1 is not really to control body weight because you can boost the level threefold with these DPP -4 millions of people have taken them. They do not lose weight. That's a great question.

1:15:26So, 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 GLP1 that is more stable in the blood. And that's where this, this lizard that you're talking, you were mentioned, comes to play. It produces a stabilized form of GLP1 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's true, but it turned out to be fortuitous because then this GLP1 from this lizard, it has a half -life of like two hours.

1:16:01And so the first GLP1 drug that was approved was just this molecule from this lizard, basically. And it's called Exynatide as approved in 2005 for works well for diabetes, has 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 pharmaceutical industry tried to say can we you know, basically improve this even further? And so they start engineering this hormone and making mutations, attaching lipid tails to make it binds this proteins in the blood that would stabilize it. Chemistry jockey stuff. Yeah, exactly. And I think the next big advance was this compound lyraglutide.

1:16:42And lyraglutide was approved for diabetes in 2010 and for and then for weight loss in 2014. And so lyraglutide 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 on aspects of blood glucose and diabetes control and they started to see that some people were losing weight. Very variable response. It's not everyone loses weight on lyraglutide. And one of the things they notice that I think it's just as fascinating to sort of example of how drug discovery works in the real world.

1:17:14You know, a lot of these people would take lyraglutide. Now it has this longer half -life. They'll start to get nauseous. And that would limit how much of the lyraglutide they could take. And it's a known side effect of the GLP1 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, you know, 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.

1:17:41And these side effects would reappear but then they go away. And then once you got after the highest dose is then people really started losing weight. And so there's a couple of things that are pharmaceutical industry realized, well, these are potentially really effective weight loss drugs. And also this nausea, which we thought was, you know, a killer, people are able to just get used to it and then it just goes away. And it goes the worst tackle for access. So the idea is that the receptor that's affecting the in the gut that's affecting causing these effects, it undergo some sort of downregulation with chronic exposure.

1:18:12So they're a glutide, 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 seven to 10 % weight loss, which is good, but not like, you know, amazing, impressive. But then semi -glutide came along. And that was a proof for diabetes in 2017. And semi -glutide is ozemic or also also marketed as wig -o -v for weight loss. And semi -glutide 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 start really losing weight.

1:18:53And so, and some of those trials, people lost 16 % of their body weight, which previously had been unattainable. Right? In what time frame? Typically takes about a year. 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.

1:19:30Yeah, you can almost completely eliminate that if you're in enough protein and do serious weight lifting. Obviously not the whole population is interested in doing that. And there's been a lot of discussion of how serious the 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's 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. You're not carrying around as much body fat.

1:20:01So people who are heavier naturally have more muscle because they need to move their body. Right? And so 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 must lean muscle mass losses, although the pharmaceutical industry is all in now on making drugs that basically are going to 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?

1:20:41And 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 incurring 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 post -trauma. So we're going back in the brainstem. Back in the brainstem. So these are actually the neurons in that deserabat rat story I was telling earlier. These are the brain regions that are preserved in the deserabat rat.

1:21:14The deserabat still has these very coddle 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 sensory or the neural input from gut to brain telling you about things like this, your stomach distension, how many nutrients are near a testin, 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.

1:21:53And this seems to link up well, at least in the logical sense, with the idea that stimulating and activating receptors in these neurons within post -trauma 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 in the area of post -trauma, 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.

1:22:24It'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 they actually go, they're enriched in these structures in the brain stem. So that's why people think that this is probably where they're acting. And is that because 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?

1:22:59It'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 get only get into areas of the brain where the blood brain barriers weakened. I really appreciate that you mentioned the half -life issue with GLP1 and the fact that these DPP4 antagonists did not lead to weight loss despite increasing circulating GLP by threefold.

1:23:39This is relevant to a number of different claims that people make that a given food or a given drink increases GLP1. I've actually said before, I'm a big consumer of your Brahmate, my 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. But anyway, it's my preferred source of caffeine, but I've said before, there's some evidence that it can increase GLP1, but based on what you've said, the increases in GLP1 that it creates are very unlikely to produce the kind of appetite suppressive effect that would lead to any significant weight loss in somebody that's obese, presumably, that are separate from any caffeine stimulator.

1:24:28They're exact. You can't separate because it's a complex compound this year of the Montet 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 GLP1 quite appropriately, I think, said, wait, you know, ozemic and drugs like that increase GLP1. Thousandfold, when you talk about a food or drink, or maybe a supplement increasing GLP1, it's very unlikely to increase GLP1 to that level, meaning unless you're getting into the hundredfold or thousandfold increases, probably not right to talk about GLP1 being the source of any appetite suppressive effect.

1:25:14Yeah, 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 twofold change in your GLP1 by eating a different food, one food versus the other. But as we know from those DPP4 inhibitors, it's not going to really change your appetite because the drugs increase at threefold. These GLP1 agonists are really a pharmacologic effect. Effectively, it only happens with drugs. So, you get the thousand to ten thousandfold higher concentrations of these drugs in your blood than the natural hormone.

1:25:52And 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, not you know, pick one, you know, oxytocin or estrogen testosterone, they're not really, you know, broadly speaking. Most people would be concerned about thousandfold dancing of something like that. And obviously, there are clinical indications where that's important.

1:26:27However, my observation of the ever expanding literature on GLP1 agonists is that there seems to be improvements in like reduction in alcohol consumption. And by the way, why would increasing GLP1 reduce craving for alcohol? It seems like there's an ever expanding list of things that GLP1 agonism is good for. But we are talking about soup. I would say super -physiological levels. That's when one takes it. And again, I'm not against it. More for it. I'm just paying attention to the literature. So, I would say that that's absolutely right. When you're increasing level of hormone, a thousandfold, you need to be careful and see what's happening.

1:27:13But at the end, it's an only answer to experiments. And I think the nice thing about these GLP1 drugs that a lot of people don't realize is they've been around and improved since 2005, the earliest ones. And even something like ozempic, which may be only entered the public consciousness in the last year or two, right? It's been around for seven -ish years, I think. So, 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.

1:27:48And so, 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, cost like a billion dollars to run. And the data from the semiglutide, the ozempic trial, came out last year. And as expected, reduced the rate of heart attacks, strokes, all -cause mortality, according to cardiac, for cardiac reasons. But what was really surprising was, a lot of that seemed to happen before the people even lose weight, lost weight.

1:28:27So, there was already a difference between the placebo group and the semiglutide group, before the people on the drug, it 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 that GLP ones 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 of post -stream and the NTS, are also really important for this this reflex, known as the inflammatory reflex, that basically acts and starts with the vagus nerve, goes to these brain regions and the brainstem and then goes back down to the body to basically suppress, to prevent out of control inflammation.

1:29:10And 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 bio -forma 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 all given everything they put into the R &D and to 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.

1:30:01And that's why it's likely to be based on these, what sounds like additional uses of ozemic related compounds a long time before there's generic ozemic available. I think it will be a while. I don't know the exact status of the patents, but I'm guessing it's going to 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 GLP1 program. And some of them are really exciting, actually. So, so I mean the general trend in this area is what people call GLP1+. Which means you take the GLP1 agonist, which is already giving you 15 % weight loss or so, and then you add additional things to that to give it additional properties.

1:30:45So, one compound is from Eli Lilly, which makes this other, so there's a drug on the market that we haven't talked about, but Terzepatide, which is known as Ongaro for diabetes and zepabound for obesity, which is even better, really almost every respected better drug than the ozemic. 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, whereas ozemic is just GLP1 receptor agonist, Terzepatide is a dual agonist of GLP1 and this other ingredient that we talked about, GIP.

1:31:27And it seems like having that GIP agonism actually acts as an anti -nauzia effect. The sort of counteract some of the nausea caused by the GLP1 in the area post -stream, there are gip receptor neurons in the area post -stream of the syn nausea center. So, it sort of it allows you to crank up the dose of the GLP1 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 the Terzepatide and Slash Mujaro, they have a triple agonist that's in phase three clinical trials now.

1:32:00So, this is now three hormones in one. It's the GLP1, which all the strokes have, the GIP, which is the anti -nauzia component, and then GLP1 itself. So, these three hormones all combine in one pill. And what the GLP1 does is it increases energy expenditure. This is a well -known effective GLP1 agon. 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 the stroke are incredible. So, basically, there's been one phase two trial published, and people lost 25 % of their bodyweight at the end of the, I think, was 48 -week period, and they were still losing weight.

1:32:39So, we don't know where the end point. We don't know what the maximum is. So, they're bigger, longer trials going on now to figure that out. But at that point, when you get beyond 25 % bodyweight, you're talking about, basically, bariatric surgery, which is currently the best thing we have, these surgeries, people do. It's a stomach state. We're moving a portion of the stomach. Moving 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 right now, it's just a code.

1:33:07It's like AMG133. But it's like, TheraZephytide, in the sense that targets both GLP1 and GIP. So, it's a dual targeted. But unlike TheraZephytide, 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.

1:33:46This 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's like a month, then the blood or something. And so, you can 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, 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.

1:34:15So, really, I think it's just created this explosion of interest in pharma. Basically, one of these things, 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, remembering college, the Fenn Fenn debacle, where a diet drug was released, and people had cardiac issues start dying. So, it was pulled from market, and then it was essentially a quiet field for a long time.

1:34:49In part, to bring us back into the brain, and in part, because it's directly relevant to what we've been discussing about ozemic and GLP1. 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 GLP1 analogues long before they were FDA approved in kind of niche communities. These aren't communities I'm a part of, but everyone's a while sticking here 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 stimulating hormone pathway.

1:35:36And 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 them. 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, 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 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.

1:36:26So alpha -MSH, a scientist called the hormone you're just referring to, is a product of pumps, the POMC gene. So in the same way that we just talked about glucagon can be processed into different things in some genes and some cells that's made into the glucagon hormone and other cells that's made into GLP1, POMC, that gene can be processed to prove different hormones. And one is alpha -MSH, which is very important for feeding control. And so these POMC neurons are in the arqueot nucleus of the hypothalamus, the same region where these agiar pinarons I talked about earlier are located and there's sort of these two these two sets of neurons have opposing effects on body weight regulation.

1:37:04And so alpha -MSH inhibits food intake and agiar pinarons promote food intake. And where they converge is at this receptor, the Melana -Cortin IV receptor, which is important for body weight regulation. And so alpha -MSH is an agonist that turns on that receptor and the agiar P peptide is an antagonist that turns it off. And so you know there's a lot of human genetics as I mentioned earlier implicating this pathway in body weight regulation. There's 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 a set Melanatide or something like this.

1:37:49It'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, sympathetic nervous system activation. So it's just taking a step back from everything we've talked about today. I talked about this short -term system in the long -term system. The controls on energy balance and body weight.

1:38:29The long - short -term system in the brainstem, the long -term system in the hypothalamus, the long -term system being leptin and alpha -MSH and agiar P. 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 GLP1, injected into rats, injected several times a day.

1:39:02And 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'd just eat more meals to compensate. They're just perfectly compensated by eating more meals. And so the lore was, it's just impossible. The animal always compensated unless you hit this body weight set point regulating area, which is the hypothalamus, the long -term system. But then with 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.

1:39:32And 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 HGRP neurons and pumps in all this stuff has been a challenge to pharmaceutical target. Because you know, leptin, we discussed, didn't really work. And so I think there's going to be, as you mentioned, a reemergence of interest in considering this other pathway now that we've seen the success of the GLP ones. And I think one area where it may emerge is in considering their combination, perhaps at different stages of weight loss. So perhaps, you know, 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 one drug to lose the weight.

1:40:12And then at some point, you might stop that drug and switch to a more hypothalamus center leptin -based drug to keep the weight off. So basically, use the GLP one 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 you know, the GLP one drug has just a lot of benefits even beyond weight loss. People might now want to stop taking them. But that's one idea. Very interesting.

1:40:43I'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 does lots of things. But it certainly is believed that dopamine is involved in our either craving for food or pleasure from food. What's the real story on dopamine as it relates to food and eating behavior?

1:41:22You 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 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 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.

1:41:59That taste, the hedonic experience. One reason we think this is because you can make mice, the Richard Paul Leonard did this decades ago, that don't have any dopamine. And they still show the same sort of effective responses to foods. He puts something sweet in their mouth. They kind of, 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.

1:42:38So dopamine's 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 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 in there.

1:43:18And 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 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 hamburger, but rather about what the experience of eating the food, the oro sensory experience, its taste, its flavor, its texture, how that relates to the post -injustive effects.

1:44:01And 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. Exactly. 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.

1:44:39Exactly. Squares very well with my experience of McDonald's. And I probably haven't had a lot of fun with the D -Hongri. I haven't either. It's funny, the golden arches thing is just something that people in neuroscience talk about dopamine use. And so now I've started subconsciously just talking about golden arches, even though I also haven't eaten McDonald's in decades. In and out burger, the better tasting from what I understand, probably better sourcing. We're not going to get into all this in detail, but everyone has their preferences. But I do think it's interesting, because what we're talking about here is a related, I think, to this notion of highly processed food, packaging, the commodization of food.

1:45:16Which is the idea that we are drawn to food for things other than the taste that we expect for. There's all this context. That's right. So I think an important distinction that people make is its distinction between wanting and liking. I don't know if you've talked about this previously on the podcast. On a 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 you want. And these can be uncoupled all the time.

1:45:48You can 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 in 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 -injustive effects.

1:46:26You come to like things for example that are 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 my drive, this is quite slow, separated by tens of minutes.

1:47:01But 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 -injustive 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.

1:47:35And so there are some that respond when nutrients are in the stomach and intestine. There are others that respond when in a thirsty mouse, when the blood is rehydrated, when you basically say, shade 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 -injustive effects. That sort of the delayed dopamine signal after ingested food and fluids is sort of reinforcing this connection between the flavor of what I just ate and that it was something good for me.

1:48:11One of the sort of 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.

1:48:44There'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 a huge rabbit problem because they're invasive pests species that was introduced in 1800s and they're just eating all the land. So there's lots of money to study rabbits to understand their ecology. And so 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.

1:49:13It 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 drank 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 digestive behavior.

1:49:43But that fact that animals have to get water from food raises this question, how do they know which foods are rehydrating? That's presumably they have to learn that because you can't just look at 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 basically investigated this by giving mice different fluids and then measuring how the dopamine response. And he showed that there was this delayed dopamine response after the mice had drank the fluids.

1:50:16The 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.

1:50:52So 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 two or three times a day, you know, anyway, there's only so many hours in the day.

1:51:30And 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 diet that was being promoted in the 90s where people would eat either carbohydrates or proteins separately. Like there was a whackingness out there. And as I say that, I'm sure I'll get assaulted in the comments. It's probably not whacking. I'm sure there's some enzymatic basis for why that would be useful. If you enjoy it, go for it. You know, I don't have a feeling about it one way or the other. But one thing I noticed was that low water content containing meals either by virtue of the foods that they include or by virtue of the fact that they're not diluted, so to speak.

1:52:18It'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 under eat, depending on the water content of the food? It's an interesting question. So, you know, there is this advice that you should, if you're hungry, first drink something, drink some water and see if you're still hungry.

1:52:56And the idea is that perhaps humans can't always, I mean, our inter -oceptive sense or 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 could help. I would say it's probably not a huge effect in most of modern day life, but it's an interesting idea. Yeah. This brings us to the topic of thirst, something that your laboratories 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?

1:53:38Meaning, 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 and most airports and stuff. So, I'll bring a chunk of really nice parmesan cheese. I'll 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 they're wonderful. A 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 what's put in front of me on an airplane, most of the time.

1:54:18So, 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. 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 when in fact what I'm going for is the salt. As 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?

1:55:01Okay. So, I would draw into tough questions. I know, but your, your, your, your, feels like my qualifying exam. So, so, well there are separate systems. This ought 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. Though I would say the instance where they interact is in phenomena such as dehydration and erexia. This is the idea that if I give you some dry food but I don't give you any water, event 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, my fluid balance even if I eat less calories.

1:55:49So, we prioritize hydration. Yes. You will at some point, at some point you will prioritize hydration. That's related also to the concept of pran deal drinking. So, many animals, including humans drink most of their water during meals because you basically want to counteract the osmolytes that are in your food. Salt balance though and in thirst, so the, 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, you want to have the right osmolyte of the blood which you can just think of in simple terms as sort of the total concentration of all the salts.

1:56:29It'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 so, 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. And we know now that that they're a very small set of neurons in few brain regions that control that. And the way they they're thought to work is they contain osmosensors. So, they contain same basically these neurons are sensors for the osmolality of the blood and they're activated when the blood osmolality gets too high.

1:57:10And it's incredibly sensitive system. So, 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 a let's just say a half an ounce sip of seawater inadvertently. Yes. It's extremely immersive. It is. It's like, like you just you you want to drink some non -saltty water. So, nice clean water. Yes. Exactly. Immediately. Yeah.

1:57:51So, as 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 the 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 cause you just to pee it out and then you'll be fine. And so, those two work in balance. The kidney is controlling how much of the salt gets reabsorbed into the blood. And then this desire for thirst, this desire to drink, allowing you to replenish the blood with water at various intervals.

1:58:22And so, yeah, I mean the experiments led to discovery. This thirst circuitry are amazing. It was this guy, Bench Anderson, working in the 1950s. And he just had this hypothesis that there was an osmosensor in the brain, right? Which is very I think, you know, there were some evidence suggested, but it was not really really a 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 osmosensor, then I was wild. I mean, I wasn't chuckling at it just like it like, you know, I feel for the goats.

1:58:54I feel for everyone involved in the experiment. But what a wild experiment just to put salt directly into the brain. The concentrated saline solution. Yeah. And he found this tiny region in and around the hypothalamus that if you if you infuse salt in this region, the goats will drink like eight liters of water in five minutes, just crazy, right? And then he and three weeks, okay, this must be the osmosensor. And then he went back and stimulated those neurons. It's the same thing. The goat just drinks like crazy. And so, now we know there's this couple small regions in around the hypothalamus.

1:59:24One's called the subfornical organ. I know that one's called what doesn't really matter with 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.

1:59:54And then for these osmosensors that banked Anderson discovered in your brain, to be to be sort of sense that in 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 others, but when a 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 banked and discovered by putting the salt in the goat, 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.

2:00:29And what we saw was that the neurons don't wait until the blood is rehydrated. They also don't do what the agiar pinarons do, is 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 mouth 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 that really relaying the osmolarity of the blood and they compare these two. And basically when the mouth is drank enough in order to the nerve for the animal to predict that the blood osmolarity is going to return to normal, then the animal stops drinking.

2:01:04Beautiful. Yeah, it's just beautiful. That's incredible. The brain is essentially predicting, it sounds like a high degree of accuracy, how much water one needs to drink, linking it to the pleasure and of ingesting good clean water under conditions where we're thirsty in anticipation of adjusting blood osmolarity in 20 minutes. Exactly. Yeah, I mean this is the kind of thing that just delights me because the brain as a predictive organ is just so accurate. It also explains some sort of funny aspects of thirst that you may have noticed from every day experience. So one idea is that just cooling your mouth can sort of quench your thirst.

2:01:48So if you're in the hospital and you're not allowed to drink any fluids, they'll give you ice chips to suck on the 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 passes, 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 is an experiment by Greta St. and Chris Zimmerman. Chris did the same thing where he was recording these thirst neurons, we just put a cold piece of metal on the mouse's tongue.

2:02:15And 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 is evolved to make the prediction about what's going to happen to the body. 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, High Game Palomar Mountain in one day, I really screwed up. He was Bulldog Mastiff. They overheat easily and it was a lot warmer than we thought.

2:02:49We 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 I was told 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.

2:03:27I would like to actually say something about this. 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 the control hunger, the HGRP neurons, they actually don't care so much. They won't really do much of anything to shut them off.

2:03:55That raises the question, why do the animals eat them when you stimulate the hunger neurons? And we think the primary thing that the hunger and neurons stimulation does is it make 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. Animals just want to avoid that. So I think that distinction is very real. I think there are two different motivational mechanisms for hunger and thirst.

2:04:25Hunger 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 entitle the four brain, third circuit drives drinking through negative reinforcement. And I'm guessing that paper illustrates exactly the point you just made. So it's a four brain circuit. So does that mean that there's some elements of learning and cognition around this? Or are we broadly speaking about the four brain, for instance, the hypothalamus being in the four brain? So the third circuit for whatever reason is mostly in the four brain.

2:05:00So the neurons that, so we talked about the NTS in the area post -stream being important for hunger and signals from the gut. Those are the eight area post -stream 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 four brain. One is called the sub four -nical organ. The other one is called the OVLT, but they're just the neurons that sense nutrients more in the high brain 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, the triathletrist.

2:05:46I was going to ask you this earlier, but it seems appropriate to us. Now, a colleague of mine at Stanford in the psychology department, Dr. Ali Krum, who studies mind sets, has done some interesting experiments where people are told that a given milkshake is colorically dense. Other people are told that a milkshake is colorically sparse. Both groups independently consume the milkshake and then they measure things like hormone responses in the bloodstream that are associated with satiety. And what she finds is that even hormone responses to the same shake, meaning the same amount of calories fat, sugar, etc, can be significantly modulated based on what we're told.

2:06:33And 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 colorically sparse compared to what 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 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 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.

2:07:35And 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 age -rp hunger neurons, how they can sort of see the food or get input about the the side smell of food, and that way predict how many calories the mouse is going to eat.

2:08:16But I mean, this is a mouse, right? This is all based on a mouse. 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, 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 traditional state and how information that you're given can change the expected physiologic outcomes. I mean, you're right. I mean, there's there's just this whole other element that is very hard to study because it's happening in the brains of humans, and we can't do these kinds of experiments.

2:08:52But 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 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.

2:09:22So if you put nutritional labels where you show the different numbers of calories, then basically they sort of adjust their expectations and nothing happens. 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 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 how you think about food cravings your own?

2:10:02You don't have to reveal what those are even if they exist, how you observe the eating behavior of others. And yeah, how is knowledge shaped your your feeding behavior? Well, I try not to think too much about my AGRP neurons when I'm eating. 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 in there. We're just beginning to prescriptively. But I think there is a set of basic recommendations from physiology and neuroscience. Very simple things. You've probably talked about people on your podcast before shaping your diet to be healthier, to limit food intake.

2:10:48So one we've already talked about is limiting consumption of ultra -process 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.

2:11:17Also just because proteins 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? You know, you 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 complete. I think that's myth. I've never, 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.

2:11:50And so drinking water will ensure you're not eating because you're hungry, because you're thirsty. And so and there's no idea of diluting it. I don't think that meant distension itself, even though in the water provides a very limited distension signal, the expansion of your stomach and intestines is one important way. Interesting. You that you terminate feeding. And so and so there is some component of that where you can get distension just from drinking water. I say as I have blurted out, interesting because I didn't realize that a fluid consumption only provides a limited signal for distension.

2:12:21Not fluid, it's water. And so the idea is that 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 glass of orange juice, it will empty much more slowly. And if you drink 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.

2:12:51So 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 your intestine can only metabolize nutrients so fast. And so if there's calories, then it slows down gastric emptying a lot, but water just kind goes through. What a beautiful system. There's regulation at every point. Hypothalamus, brain stem, gut, rate of emptying based on the difference between water and orange juice.

2:13:32It's just awesome. And this part of the reason I think it's so hard to outsmart the system, right? Because these neurons are making predictions based on the site and smell of food, but then the God 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 the what you thought happened the first time it was actually really going on. And so it makes sense because it's so important for survival, these homestatic systems, the product, you know, so much natural selection. Which I think at least partially explains why thousand fold increases in peptide hormones like GLP1 are required to see significant long -lasting changes in weight.

2:14:09Exactly. 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 what's called 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 GLP1 drugs. I'm incredible weight loss, unexpected health benefits, really safe as far as we can tell. I mean, there is always possible that some new side effect will emerge. But these drugs are millions of people and they've been in a lot of people for a long time now and nothing seems to have shown up.

2:14:55So 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 working out. In five years, people have so many different options. It won't just be ozm -pick or redriro. There will be five different, ten 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.

2:15:23And it's amazing how well it squares with the understanding of the basic biology. 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 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.

2:16:15And I don't just say that as a formality. I know that to be true given that we 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 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.

2:16:51We 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. 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 Endor and join this podcast, please subscribe to our YouTube channel. Please also subscribe to the podcast on both Spotify and Apple by clicking the follow button.

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