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

welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday [Music] life I'm Andrew huberman and I'm a professor of neurobiology and Opthalmology at Stanford School of Medicine my guest today is Dr Zachary Knight Dr Zachary Knight is a professor of physiology at the University of California San Francisco and an investigator with the Howard Hughes Medical Institute for those of you that don't know Howard Hughes medical investigators are selected from an extremely competitive pool of applicants and have to renew in order to maintain their investigatorship with the Howard Hughes Medical Institute

every 5 years or so placing him in the most elite of categories with respect to research scientists his laboratory focuses on homeostasis in particular what drives our sense of hunger what drives our sense of thirst and what controls therm regulation which is the ability to maintain body temperature within a specific safe range today we mainly focus on Hunger Dr Zachary Knight explains the biological mechanisms for craving food for consuming food and believe it or not you have brain circuits that actually determine how much you're likely to eat even before you take your very first bite

and he explains the biological mechanisms for satiety that is the sense that one has had enough of a particular food or food group Dr Knight also explains the role of dopamine in food craving and consumption which I think every everybody will find very surprising because it runs countercurrent to most people's understanding of what dopamine does in the context of eating and other Cravings today's discussion also includes a deep dive into glp1 glucagonlike peptide and the novel class of drugs such as OIC and monjaro and other related compounds that are now widespread in use for the

reduction in body weight Dr Knight explains how glp1 was first discovered and how these drugs were developed how they work and importantly why they work and how that is leading to the next generation of so-called diet drugs or drugs to treat obesity diabetes and related syndromes we also discussed thirst and the intimate relationship between water consumption and food consumption and we also talk about the relationship between sodium intake water intake and food intake by the end of today's conversation you will have learned a tremendous amount about the modern understanding of hunger thirst and salt intake

as well as this modern class of drugs such as OIC and related compounds all from a truly world-class investigator in the subjects of researching hunger thirst and thermal regulation before you begin I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford it is however part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme I'd like to thank the sponsors of today's podcast our first sponsor is better help better help offers Professional

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again that's waking up.com huberman to access a free 30-day trial and now for my discussion with Dr Zachary Knight Dr Zachary Knight welcome great to be here today we're going to talk about Hunger appetite thirst other motivated behaviors the role of dopamine the vagus nerve these are terms and topics that a lot of people hear nowadays and for which there's a ton of interest but just to March Us in sequentially could you describe some of what's happening in the brain and our body as we get hungry decide what to eat and and decide that we've

had enough to eat you I think most people just assume that okay that my stomach's full is what we say I've had enough um or we self-regulate it for some other reason you know caloric restriction or or monitoring in some cases what's happening in the brain in terms of the circuitry um and what have you discovered about what that process looks like in terms of its um kind of universality across people and then maybe how it sometimes differs between people okay there's a lot in that that I'll try to unpack and I can remind of

some of the Nuance but just in other words as a biologist as a neuroscientist how do you think about this thing that we call hunger and Fe absolutely absolutely so I think a very high level a good way to think about the regulation of food intake by the brain is that there's two systems uh short-term system and a long-term system that are primarily localized to different parts of the brain operate on different time scales one on the time scale of a meal so 10 20 minutes uh and the other on the time scale of sort

of weeks to months to years and tracks levels of body fat and these two systems sort of interact so that so that these short-term behaviors we do eating are matched to our long-term need for energy and so um uh uh I think one of the uh uh one of the initial experiments that really led to this idea is this great experiment by Harvey Grill um about 50 years ago uh it's called the desate rat and so essentially what he did was he made a a cut in the rat brain so he took these rats in

the lab made a cut so that he separated the brain stem so the most posterior part of the brain from the entire forbrain basically got rid of you know 80% of the rat's brain so this basically creating these zombie rats right all they have is a brain stem and asked you know what can these rats still do you might imagine they can't do a lot of things right because they basically have lost most of their brain um but he discovered that one thing they can still do is regulate the size of a meal and so

um so very informative experiment and so um and and you have to be careful how we talk about this because the way this meal works is you have to actually put food into their mouth and then they'll swallow it as you put food into their mouth um but eventually at some point they'll start spitting it out and that basically is an indication that in some sense they're becoming saded uh and and they're uh they're just using the brain stem that they have left they're able to sense those signals from the gut and uh Drive the

termination of a meal and he did other experiments showing that many of these signals that come from the gut gastric stretch hormones that come from your intestine in response to food intake like cck these desate rats that just have a brain stem um if you inject those or manipulate the gut in in those ways it can in an appropriate way change how much the rat eats now what can't the rat do when it doesn't have a forebrain and the thing it can't do is it can't respond to longer term changes in energy need meaning if

you fast the rat for a couple days this desate rat then start putting food in its mouth the amount that it eats doesn't change so basically it doesn't eat a larger meal the way you would if you were fasted for several days and then re refed and that experiment along with other Evans has led to the idea that in the brain stem and in the most posterior part of your brain there are neural circuits that control sort of a meal and then the time scale of 10 minutes or 20 minutes deciding when a meal should

end and in the forbrain primarily in the hypothalamus there are neural circuits that then track what is my overall level of energy reserves what is my level of body fat things that would fluctuate on time scale of say days when you're fasting and those forbrain centers feedback to talk to the brain stem and modulate those brain stem circuit that are controlling the size of a meal to sort of match these two time scales so that's at the highest level how I think about the neural circuitry that controls feeding um there's obviously a lot more going

on underneath that but f ating you mentioned body fat and that somehow the brain is tracking the amount of body fat um that caught my ear uh because while it makes total sense I'd like to know how that happens if we happen to know the mechanism and the second question is why body fat and not body fat and muscular mass or body fat and overall body weight what is being signaled between body fat and the Brain that allows the brain to track body fat and why do you think body fat is the critical signal I

realize it represents an energy Reserve but certainly there are other things about the bodily state that are important yeah well there are certainly other things about the bodily state that are important and there are other things about physiology definitely that are regulated other than body fat um but body fat is is unique because it represents this energy Reserve so the neural circuitry that regulates eating behavior is in some ways very unique because it has this reserve of energy so if you we also study thirst in my lab and drinking and you don't have a reserve

of water in your body right um and that's true for basically everything else but for fat we have this this this reserve of energy and so it's very important that uh the brain know uh how much remains and then adjust Behavior Uh uh uh in coordinance with that so that so that you know you know how urgent it is to get the next meal um and so the thought is that the major signal of the level of body fat that we have is leptin it's this hormone uh it was discovered it was cloned in 1994

actually by my post-doctoral adviser a scientist named Jeff Friedman at Rockefeller University although its history goes back way before 1994 so the story behind leptin is that um there's a a facility called Jackson Labs that you I'm sure familiar with in Maine that um since the 1920s has been raising mice and selling them to academics basically who study physiology and behavior and so they breed thousands of mice they sort of nonprofit organization distributes mice to the scientific community and at some point in the 1950s um they spontaneously just because they were breeding so many mice

they came across some spontaneous mutations um mutant mice that were extremely fat like the fattest mice they had ever seen these mice just eat constantly they're just enormous three times the size of of a normal Mouse and um it's all body fats they're just justu these huge uh uh uh uh fat mice and they came across several different um mut Mutant strains that um all had the phenotype in the sense that they were all extremely fat all extremely hyperphagic but they could tell even in the 1950s that these mutations were on different chromosomes they didn't

know anything about how to identify the genes at that point that was just science fiction but they knew they were chromosomes and they were on different chromosomes and so they labeled one obese one of these mous trains obese and the other one diabetes but they're basically the same and so people wonder for a long time what what what's going on in these mice then there was a scientist at Jackson Labs Doug Coleman who had the idea what if we do an experiment where we connect the circulations of these two different strains of obese mice and

test the hypothesis that maybe there's a circulating factor a hormone that is produced by one of these strains and that controls appetite because at that point insulin was known glucagon was known there were some hormones that were known that were involved in metabolism so it was logical that there could be a hormone that uh perhaps regulates body fat levels and what they found which was was remarkable when you attach the OB strain to the DB strain so you basically connect their circulation so hormones are are are transmitted between the two um the OB mouse that

strain dramatically loses weight in fact within a couple weeks it looks like a normal Mouse it just stops eating it loses almost all of its body fat and it essentially in all respects becomes a normal Mouse the DB Mouse nothing really happens it Still Remains obese and Still Remains hyperphagic and based on just that piece of data Doug Coleman hypothesized that what was going on is these two mutations were mutations in a hormone and a receptor the OB Mouse had a mutation in the recept in the hormone that comes from fat so it couldn't produce

this hormone that comes from fat and signals to the brain how much fat you have and the DB Mouse has a mutation in the receptor so it can't sense the hormone um and that was just an idea it was hypothesis um but you know in the 1980s as technology advanced as it became you know there's molecular biology had been invented it became possible to clone genes um a number of people tried to identify what are the genetic mutation that are occurring in these mice that make them so obese and Jeff Bally cloned leptin and showed

that in fact Doug was exactly right the the OB mutation is a mutation in this hormone leptin uh and later uh Millennium Pharmaceuticals showed that the the DB mutation is in fact a receptor and it was an important Discovery for a couple ways for a couple reasons one because this OB Gene is just expressed in fat it's exclusively impressed expressed in adapost tissue and uh how much it's expressed is directly proportional to how much body fat you have so as you gain weight the expression of this hormone increases in a linear manner and then it's

secreted into the blood so the level of leptin in your blood is a direct readout of your body fat reserves this receptor for leptin leptin receptor the the functional form of it is expressed almost exclusively in the brain and it's expressed in all of the brain regions that we knew from previous work were important for appetite so basically the expression of this receptor gives you a map in the brain of the neurons that control hunger and so what happens is basically when you lose weight uh the levels of leptin in your blood fall because basically

you've lost adapost tissue the absence of that hormone sends a signal to all these neurons that have leap in receptors in the brain they're not getting that signal that uh I'm starving and it basically that initiates this entire homeostatic response to starvation so a big part of that is um obviously increased hunger but it's also decreased energy expenditure decreased body temperature um even decreased fertility um because you don't want to reproduce if you're starving less spontaneous movement less spontaneous movement all of this um and so um and so the thought is which I think is

absolutely correct is that this this hormone leptin is is part of this negative feedback loop from the fat to the brain that basically tells you about your level of body fat reserves and how urgent it is to find the next meal fascinating as I recall um Amin Pharmaceuticals own the patent for leptin in hopes that it would become the Blockbuster diet drug the logic being that if you were to take this hormone somehow or activate this pathway that the brain would be tricked into thinking that there was more body fat more energy reserves than there

was and then people would uh basically be less hungry eat less and lose body fat yes what happened with that do we know why it did not work yeah so that's a great question so um there was a lot of excitement when leptin was Clon because it was thought basically we've cured obesity um there was an auction for the patent amen one I think it was something like $20 million upfront Payment Plus royalties which at the time was I mean still is a lot of money but even more money nowadays it would it would be

um a drop in the ocean compared to what companies will invest into potential diet drugs ex exactly so but but you know at the time um and still a lot of money today um and uh they did a clinical trial gave obese people leptin subcutaneous injections of this hormone and they didn't lose a lot of weight um and the question was why and so what was subsequently field is that the challenge with leptin is that individuals who are obese um do not have low levels of leptin for the most part they actually have high levels

of leptin and so what they have is a state of leptin resistance so it's analogous to someone who has type two diabetes it's not because they lack insulin it's because they actually have over time a high level of insulin and so Target tissues stop responding to insulin and the thought is that it's the same way in obesity and leptin now subsequently they went back and did um an reanalysis of that clinical trial and ask what if you take all of these people and stratify them according to their starting leptin level so some people have relatively

low levels of leptin some have higher some have really high levels of leptin and then ask if we reanalyze the data um how uh how effective is leptin and as you might expect the people with the lowest levels of leptin they lost the most weight when you gave them this drug and the peop with the highest levels of leptin lost the least weight so there is a rationale there for why um for for a scenario in which leptin could work either among the subset of people who just have for some reason lower levels of leptin

these aren't people with mutations like the OB Mouse they have some leptin they just don't have unusually high levels or alternatively after weight loss so after you've lost a lot of weight your leptin levels plummet they become very low and that part of the reason it's a big part of the reason it's so difficult to keep weight off is because those leptin levels are so low and so it's been thought for a long time that that that is a scenario where treat treating people with leptin uh uh could be really useful to help them keep

the weight off why it never made it as a drug for that application I really don't understand it has something to do I think with the pharmaceutical industry with the economics with a bunch of other issues that aren't necessarily scientific um but I think there's still in the future is a possibility that it could come back for that indication especially now that we have these gp1 drugs and now there's just millions of people losing so much weight and perhaps they want to transition to a different kind of drug uh to keep the weight off well

we are definitely going to talk about glp1 OIC and um some of the related compounds in a in a few minutes but before we do that I'd love to get to this issue of what's happening in the brain as we get hungry approach a meal decide what to eat and decide when we've had enough are there separate circuitries or at least separate neurons for each of those steps and um if you would uh could you walk us through what that process looks like since we do it every day most people do it every day unless

they're fasting multiple times per day what's going on in our brain and body as we think about and approach a meal consume a meal and decide enough sure so um there are different neurons that are preferentially involved in different aspects of those processes so so I think people we often divide feeding behavior and many other kinds of motivated behaviors into repetitive and consummatory phases so appetitive is the phase of the behavior where you're for example searching for food it's foraging it's all the actions that lead up to the actual Behavior itself which then we call

the consum at Phase that's actually putting the food in your mouth and eating it and the general thought is that these four brain circuits in the hypothalamus are more important particularly in hypothalamus but other parts of the forebrain as well are more important for the repetitive phase and the brain stem circuits are more important for the consummatory phase the actual putting it in your mouth and licking chewing swallowing and all that within the hypothalamus there's a population of neurons called agrp neurons so it's just an acronym agrp and stands for a gy related p but

it doesn't really matter um they're absolutely critical for that repetitive phase for the searching for food for the desire to find food and consume it when you're hungry um May sorry just to um touch on the agrp neurons and this repetitive phase are they known to connect to areas of the brain and body that stimulate the desire to move because I think about um when I get hungry if I'm at my desk or something um I need to get up and find food need to walk to lunch or go to the refrigerator are they somehow

linked to the circuits that um promote Locomotion well they have to promote those things um but they're not directly linked to any of those circuits they're linked directly to other forbrain circuits involved in motivation so the way we think we think about you know what these kinds of neurons like adrp are doing they're not directly talking to the motor circuits to tell you to move your legs or arms to pick up the sandwich or whatever they're rather creating this General problem that the animal has to solve which is that I'm hungry I need to get

food it would be really if I could have a sandwich and then the animal uses all of its mental capacities right to solve that problem so they're just there to set the goal not so much to direct the solution and so uh but these hrp neurons there are a few thousand neurons at the base of the hypothalamus so basically the the the most ventral the most bottom part of the forbrain um so tiny population of cells but outsized importance for the control of feeding Behavior so if you stimulate these cells in a mouse or a

rat that's not hungry um the animal will voraciously eat like get starving uh if you silence these cells U animals will starve to death so you can basically give them food they just won't eat it voluntarily until basically they you have to euthanize them because they're uh they've lost so much weight um and the activity of these these agrp neurons uh um is thought to track the body's need for energy one reason that's thought is that um uh they express these receptors for leptin this hormone that I was just talking about that that comes from

fat and signals the level of body fat Reserves and leptin inhibits agrp neurons so as you might expect if you have lots of body fat um then uh a neuron that expresses that controls hunger should be less active than if you have very little body fat so that's one mechanism by which leptin controls hunger um we my lab have investigated the role of these agrp neurons um uh 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 uh something I think we wanted to know for a long time um was not really addressable until about 10 years ago because just the technology didn't exist because these are such a tiny population of cells so deep in the brain um so one of the very first experiments we did in my lab was to investigate that to ask for the first time what happens to these arrp neurons when an

animal eats and so uh one of my first graduate students yuming Chen he uh he used a technology called fiber fetometry which allows us to put a fiber optic into the mouse's brain so then then we could record fluoresence 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 very one of the very first experiments he did we said let's make the animal hungry these ARR pons will be very active because the animal's hungry and then let's

give it some food and see what happens during a meal and our expectation was that these arrp Neons would gradually decline in activity as the animal eats and levels of hormones and the Blood start changing uh feeding back to inhibit these neurons what he found was really surprising I remember that when he made this discovery basically him running into my office and saying Zack I I I gave the mouse the piece of food but the weirdest thing happened the neurons shut off almost immediately and I said you man you've made a mistake it's okay you're

just starting off in graduate school this happens go back and repeat the experiment and then we'll discuss it but he did it several times he said you know is that every single time I do this happens I give a Hungry Mouse food and the ARR panun within just a few seconds uh their activity has uh greatly diminished back to the level it would be in a Fed Mouse even before they take the first bite of food and so yuming then went to do a series of experiments to try to understand what was going on and

what he basically showed by changing the kind of food he gave them or the accessibility of the food or how hungry the mouse was and measuring the response of these arrp neurons was that what the neurons were doing was predicting the mouse looks at at the at the food it looks at how palatable it is imagines how hungry the mouse is how accessible it is and then within a few seconds these neurons predict how much food the mouse is going to eat in the forthcoming meal and so essentially these neurons know how much the mouse

is going to eat before the mouse even takes the first bite and uh you can show this in very simple by very simple analysis in which you you give the mouse different foods and you look at how much these arrp neurons drop when the mouse sees and smells the food and then you plot that again so this this drop happens in 3 seconds 4 seconds something like that then you look at how much does the mouse go on to eat in the next 30 minutes and you can just draw a straight line this was one

of the first results from my lab and it was really surprising to all of us and I think everyone um but it Illustrated a theme that we've now seen again and again which is that these circuits that control internal State control things like hunger and thirst what they're constantly doing is predicting the future they can sense these signals from the body that tell you about what's happened but those signals are slow and and you don't want to wait 20 minutes from the food that you ingested to reach your stomach and then slowly start entering your

intestine to figure out what was the nutrient content of the meal you want to try to figure that out as soon as you can right and so the animals learn presumably through just experience that okay something that smells like this and looks like this that has about this many calories and I know I'm this hungry so I'm going to eat about this much and then that information is all transmitted to these circuits to start the process of satiation before the meal begins is it satiation or it's um ceasing of foraging so that the animal or

if I translate to a person decides okay now I'm going to consume this sandwich this package of food yeah that's a great question so um we don't fully know the answer so 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 the muscle just sit there and eat so you can't fully separate although we like to make this distinction between repetitive and consummatory and we know that that that in different parts of the brain there's more important for one versus the other the reality is the entire behavior is linked and you can't fully separate them so there's a number of ideas about what what this means so one idea that I

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

idea is is it's involved in these what we call spol phase responses that are necessary to prepare you for a meal right so this the famous example of this is Pavlov right basically uh trains the dog to associate the Ring of the bell with the uh uh uh presentation of food and then eventually The Ring Of The Bell alone causes the dog to salivate in the absence of any food and salivation is one example of a stolic phas response the purpose of that is to have enzymes in your mouth that basically are going to digest

the food and get them there right before you need them but there's all sorts of other things like basically the secretion of insulin occurs in response to food cues changes in gastric acid gut motility all these things are getting ready for the for the meal to happen and so another idea is is it could be part of that but probably it's doing all of these things as many of you know I've been taking age G1 for more than 10 years now so I'm delighted that they're sponsoring this podcast to be clear I don't take ag1

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your order plus a year supply of vitamin D3 K2 again that's drink a1.com huberman it's so interesting I have a number of questions but I think the one that I'll uh put at the top of the list is the other night we were out to dinner in New York and um I was very hungry I hadn't eaten much that day and I was looking forward to a nice steak uh they brought out bread french bread it was French restaurant I took one bite I realized it was absolutely delicious French bread the butter was fantastic and

so I had some bread and butter which I love yes then they brought more and then they started bringing out I don't know who ordered them cuz I didn't appetizers and I realized that this was going to be a much more extensive calorically dense meal and suddenly my appetite for the appetizers I it sort of went down because I I knew knew there was more food coming right yes had I not known that there was more food coming I think I would have consumed more of the appetizers which also looked great so clearly there's something

going on with these agrp neurons the moment you're sort of um integrating based on new information exactly um on the other end of the spectrum um I did a solo episode about eating disorders in anorexia nervosa in particular and one of the things that I learned from experts in that field the psychiatrist who work on this and the scientists who work on this is that um people with anorexia are unbelievably tuned to the caloric content of food huh that their visual system and presumably other systems um have become like almost um uh hyper accurate calculators

of the amount of calories in food they've devoted a lot of cognition to it it sometimes can you know border on or or be placed within the obsessive realm but that they see food and they they they can tell you a tremendous amount about the caloric amounts with these Foods even food combinations to uh you know with a in a very small margin of error okay um so and and that drives in in that condition obviously uh food avoidance yeah um so I have to assume that these agrp neurons are involved in this kind of

thing one represents a regulation in the case of the example I gave and in the other case a let's just call it what it is because anorexia nervosa is the most deadly of the psychiatric conditions sadly a pathologic disregulation a maladaptive disregulation so what is known about these AGP neurons in humans meaning do they exist in humans um presumably they express the leptin receptor um sounds like they are able to integrate information both cognitive um based on immediate experience visual or factory but also a lot of Prior experience um you know a hamburger patty I

don't can't tell you how many calories it has all know that it's mostly protein and some fat um you know what are these neurons doing what do they have access to they sound like you know when anytime I hear about hypothalamus I think very basic drives but you're talking about a pretty sophisticated analysis of a real-time event yeah that is driving fairly nuanced behavioral decisions and updating that which is which is a big deal you know we're both neuroscientists but for everyone listening and watching this is a big deal this is as nuances deciding whether

or not somebody is Friend or Foe or deciding whether or not you you you like a movie or you don't I mean this is this is some um some pretty sophisticated processing this isn't eat don't eat or eat less eat more these aren't switches exactly um these are dials exactly yeah so there's there's a lot there I'll try to unpack that um so the first thing I'd say is they are present in humans and humans uh do humans have hrp neurons human arrp neurons Express the leptin receptor and we think the functions are very similar

um so one of the nice things actually about studying these kinds of things like basic mechanisms of hunger thirst because these things are so important for survival they've been under really strong selection right and so many of the components of these systems are genetically hardwired meaning these are cell types that have a single purpose in this case to control hunger they're labeled by specific genes and those are conserved through Evolution um we also know that this pathway this AGR Pam pathway um is important in humans due to human genetics so uh just to add a

little bit more information here there's a companion set of neurons called palc neurons that promote satiety so there sort of the yin and yangang of hunger arrp neurons promote hunger pomc neurons promote satiety they're intermingled in the same part of the hypothalamus they they're axons that project to the exact same Downstream brain regions then it's thought that these two neurons compete with each other uh to control appetite and that competition occurs through neuropeptides that they release one of which is a an Agonist for a downstream receptor and the other one of which is an antagonist

um we know from Human genetics that the these um that among severely obese people mutations in this pathway agrp palc neurons and their direct Downstream targets are quite common so so and so is it fair to say that that some amount of obesity is genetic in in nature at the level of neuronal firing or circuitry I think a lot of body weight regulation is genetic it's highly heritable um 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 um among those people something on the order of 10% have mutations in this pathway and it can either be this this hormone palc um or an enzyme within those cells that processes pomy into the right form or in the down this is the most common mutation in the downstream receptor for pomy it's called the melanocortin 4 receptor and so um so among the severely obese people have sort of genetically inherited severe

obesity from childhood uh something on the earth 10% have mutations in this pathway so it's very clear that this uh that this this pathway is involved in body weight regulation in humans most obesity although there is a very strong genetic component um uh is not associated with single gene mutations like this Associated effects of many mutations um but we know that even in in that sort of polygenic obesity that has many different uh genetic causes um that uh uh the brain is important and one of the reasons we know that is if you look at

the genes through genetic Association studies that have been associated with body weight and there's been lots of genetic Association studies try to find mutations that are associated with whether you're lean or obese something on the order of a thousand genes have been linked to body weight regulation um and the vast majority of those are expressed in the brain and they're highly enriched for brain processes which makes sense because body weight is controlled by food intake right and the brain controls behavior and also the brain controls energy expenditure so so maybe it's not so surprising but

it's clear that um that that mutations in in in genes in the brain uh are important for body weight and which is consistent with the results of you know twin studies so if you look at monozygotic versus diotic twins the estimates for the heritability of body weight is something on the order of 80% we should explain monozygotic dizygotic which I've talked about before on the podcast just to brush people just identical versus fraternal twins basically and so um uh and by comparing their uh basically their um their body weight when they become adults you can

get a sense for how much of this is genetic versus environmental and um something on the order of uh 80% is thought to the variation between individuals is thought to be have a genetic component wow um so I I don't think most people appreciate that and a lot of the debate we hear nowadays is um because there are things that people can do to lose body fat exercise eat differently Etc maybe Embrace pharmacology if if that's um appropriate um there seems to be this to me silly debate as to whether or not people should be

eating better and exercising or um assuming that all of the Obesity they might have um arises through genetic causes um and therefore take a prescription drug I mean why wouldn't it be a combination of things yeah like to me it just seems like why wouldn't people um Embrace some are 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 uh the moment we assign a genetic source to something we're removing um personal

responsibility but of course there are people I know people who have struggled with their weight their entire lives for whom some of these new Pharmaceuticals like OIC have provided them the opport to finally be able to uh lose weight and feel better and exercise safely yeah for instance I I completely agree with that um 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 of body weight that's the idea that you know if you look at people say 75 years ago right they were much leaner right and you look at people today and there's been this starting sometime around you know the 1970s there's this explosion in body an increase in obesity is that when that's when it started mid 7s sort of 1970s is a lot start snacking so there's lots of there's lots of explanation oil snack by the way I don't think that's the reason folks I I think there are a lot of reasons

but the theories that that abound right now on social media are I have a list of the theories as to why the OB obesity is increased you get everything from seed oils to snacking to uh smartphones to uh conspiracies to it's wild it's wild the range of of hypothesis is wild yeah I mean the the challenges I mean some of them could be true but it's just very hard to test those things experimentally because they're happening in the whole population right but so I think the thing that people find hard to wrap their heads around

because it is a little bit of a confusing idea is that how can it be that in say 50 or 75 years there's been this explosion in obesity which is the environment has changed but human genetics has not changed in that amount of time it's just not fast enough for people to evolve so it can't be due to mutations in humans what about devolve my understanding is that within a species um evolving new traits is very slow yes but mutations arise like the Obi Obi mutation and then you can get very fat versions of a

of an animal very quickly right all you need is a you know if if it's a um if it's a recessive alal you need two copies and then next thing you know you've got a mouse that's four times larger than a typical Mouse and and it's all explained by increased body weight so that happen can happen very quickly within a species what's rare to find uh is an entire new branch of a species that has a a very uh a new adaptive function that seems more rare so 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 signific baby baby boomers right that's me right and then whatever is YZ Millennial I lose track after exactly so so I think the thing that people find hard to WRA their heads around is how can it be that this is how this is that that that increase in body weight is clearly environmental right because that's all that's changed the environment it's nothing has changed genetically yet it's also true what I

said that body weight is extremely heritable it's one of the most heritable features and something on the order of 80% 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 how can you explain that the idea is this there's a distribution of body weights among people so in any given so 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 primar by genetics so you may be the person who has the Thrifty genes so that basically cause you to save energy and so you would be more on the obese side or you may be may be a person who has different genes that cause you to be a little bit less hungry so you would be on the leaner side what environment does is then it shifts that whole distribution so that basically the mean shifts so that everyone becomes or most people become heavier and so sort of phrase that people sometimes use

is that is that um genetics loads the gun and environment pulls the trigger so basically genetics s your sets your propensity and then environment can 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 uh just various other things that you mentioned seed oils who knows if that's important um uh uh certain people had these latent mutations that made them say very sens sensitive to

to palatable food and in an earlier time they may have been lean but now because they have that latent capacity to be sensitive to to ultr processed food they now gain tons of weight in 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 you know in prison and just only feeding them 1500 calories I mean we've done those kinds of experiment this this famous experiment the Minnesota starvation

experiment right they basically this is didn't put people in prison but this is in World War II they took a bunch of healthy volunteers fed them 1600 calories a day just asked what would happen if you basically semi- starved people and unsurprisingly they lose an incredible amount of weight all they think about is food they basically their body temperature goes down their heart rate goes down they just become obsessed with food and you you could always do that for anyone right but but um 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 great number of other people will as well because the explanation for the increase in obesity um has not been described with that level of accuracy in detail with respect to the interactions between genetics and the environment is it fair to say that what's changed in our environment is the free availability of food you know I was walking through an airport yesterday and every 20 meters or so there's a vending machine or a

restaurant um the cost of calories yeah 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 um it's one of several plausible hypothesis and it would be surprising to me if it didn't contribute but the reality is these population level questions it's just so hard to actually know because you can't do an experiment right we can't create a parallel so Society where we manipulate one of these variables and see if the people become obese so

I think probably the availability of food of the free availability the low cost is one part of it another part of it is probably although again it's it's it's it's not proven is that these ultr processed foods have a number of features that um make them make people prone to gain weight and this's really beautiful work I if you know about this from Kevin Hall at the NIH who's investigated this he's really in my opinion the best person doing this kind of human obesity research today and he does these experiments where he takes people into

the NH into the hospital hospitalizes them for several weeks so he can exactly control what they eat and he did this this beautiful experiment where basically he had chef prepare two kinds of food one Ultra processed and the other not ultr 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 as this non Ultra processed dish what's

an example of an ultra processed dish like a outof package macaroni and cheese exactly that kind of stuff with bacon kind of thing exact versus um some pasta sitting next to a vegetable and some exactly a nice piece of salmon or something exactly exactly um and uh um took people into the into the hospital basically allowed them to eat just as much as they would like first of the ultr processed meals so they had the selection of ultra processed meals for a couple weeks and then switch them to the 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 and what he found is that even though um uh uh people rated the foods as equally palatable they ate more of the ultr processed food and they actually gained weight when during that two we period when they were being given the ultra processed foods and 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

pref 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 could be part of it another idea is that you know a big thing about Whole Foods is that they take more energy to digest and they have more volume so

one of the Striking things from that study is if you just look at the pictures of the meals they're the same number of calories but there's so much more food seemingly on the nonprocessed food versus the ultr 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 so I think that that's another

H plausible hypothesis but the truth is we don't really know I have a hypothesis and I don't want to force you into speculation but given that you've studied and discovered that the neurons and circuits involved in appetitive and consummatory behaviors can learn based on experience and expectation 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 um let's call them elimination diets where people will just eat meat yes or will go onto a vegan diet

or do some time restricted feeding or do any number of different things that have been shown to promote weight loss provided people obey the laws of thermodynamics and consume fewer calories than they um than they burn yeah right I do believe in calories in calories out and there are a number of different routes to get there and some are more painful some are less painful and it depends on the individual lifestyle exercise and on and on but let's just suppose for a moment based on Kevin's work on highly processed foods versus Whole Foods that there's

a learning that takes place when we eat yes and that this learning takes place over time such that our brain and appetite start to link the variables of taste macronutrients proteins fats and carbohydrates sort of knowledge about macronutrients a piece of fish is mostly protein has some fat a bowl of rice is mostly carbohydrate has some protein yeah put a pat of butter on it has some fat also right it's sort of obvious but taste macronutrient content calories which we already know people with anorexia are exquisitely good at counting with their eyes so it's possible

they represent again a pathologic stream of this and micronutrient content maybe even amino acid content like how much Lucine is there now most people aren't thinking about how much Lucine is in a meal but we know that Lucine is important for certain aspects of muscle metabolism it's um 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 and so on and that when people eat mostly nonprocessed 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 G sounds disgusting right broccoli rice and a chicken breast blend together just sounds horrible but eating them separately if there's some olive oil and a little Pat of butter involved like that sounds pretty good but a highly processed food in some ways is a blending together of macronutrients micronutrients if there are any um and other features of the food that neurons in the brain seem to pay attention to and then giving it a unified taste a Dorito right um a candy bar that we attach

to the product we attached to the name of the processed food to the packaging but I could imagine and here's the hypothesis that that is quote unquote confusing to our neural circuits in a way that doesn't match up well with our thermodynamic requirements of how much we're burning versus how much we need to eat whereas when I eat a piece of steak and a vegetable I actually want less carbohydrate afterwards if I eat the carbohydrate first for me it's difficult because I love the taste of carbohydrates especially when they're combined with fat but there'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 and I'm guessing it's not just because um they're trying to be healthier that might be what stimulates the the shift but that the brain starts to learn the relationship between food volume smell taste um 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 there's a linking of nutrients calories and taste in a way that's more appropriately matched to the energetic demands of the organism this case us humans that highly processed foods bypass yeah okay now I realized 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 a discussion that I would like to think can at least stimulate some additional thinking about a landscape in this case nutrition and and feeding behavior that

for a lot of people is just really confusing and here's why and this is the last thing I'll say I have several friends who have been very overweight their entire lives for whom the following diet has worked exceptionally well I'm not a diet coach I'm not a nutritionist I don't pretend to be one I say eat proteins like meat fish eggs vegetables and fruit and do that for a couple of months and then add back in starches as you um 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 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 in terms of what they actually need and without fail they all say oh you know on I went to this party and I had a piece of cake and it didn't taste good to me after three

or four bites so that's interesting too so I just would like your thoughts on this we're not defining any new diets I don't sell any diets I don't do any of that but I find it amazing that when people start eating minimally processed Whole Foods I have to assume that their brain changes as it relates to appetite craving and just kind of a an unconscious understanding about what food is providing them or not and that highly processed foods basically bypass all of this and just get you to consume more perhaps in hopes of getting something

that you probably aren't getting at all or that you need to consume a lot of this food in order to get yeah there's several interesting ideas there so there's two that come to mind just thinking about what you just said so the one is the idea of what's going on when these people uh consume simpler diets more of of Whole Foods and and one one thing I think that's very likely going on is this phenomenon of sensory specific satiety is being engaged and so um uh sensory specific satiety is just the idea that as you

expose yourself repeatedly to a certain flavor or taste you um you basically lose appetite for that you get specific loss of appetite for that flavor or taste this is why as you said basically if you start off eating the protein after a while I don't want any more salmon but I would like some carbohydrates now because you have the sensory specific satiety and so um it's well known actually that if you simplify your diet make your diet really simple so there's just a few things then 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 and so I think a lot of diets actually it's not about the specific macronutrient or the specific food it's just that they're reducing the variable the the variety in the diet eventually you just get sick of eating the same thing and you know this is the thought behind that idea is that it's it's important evolutionarily so that you eat a diverse diet it's the reason probably that you want sweets after you've eaten a Savory

meal and so on a second idea though that comes to mind is just as you mentioned this idea of learning and and so much about our our preferences for food are they're not an a they're driven by learning right and so so you know there are some things that are a so if you put sugar on a baby's T tongue you know it'll smile indicating that it likes it and if you uh put something bitter it'll frown and a rat will do the same thing a neonate rat but most of flavor and the perception of

food is not just sweet or bitter it's this much more complex Sensation that involves smells it involves tastes and then it involves how those tastes and smells interact with the post-ingestive effects of the nutrients so the sensing of those nutrients in your stomach and in your intestine primarily in your intestine are thought to then feed back and then change your preference for these foods and so you know there's lots of examples of this that you can just imagine from everyday experience most people the first time they had a beer or the first time they had

a glass of coffee found it repulsive 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 they're medicine we actually somehow change our very perception of how that flavor is we actually come to savor that flavor we previously found disgusting and it's because our sensation of what is what is whether something's good or bad depends on an internal State and so it's an interesting idea you know perhaps

if these Ultra processed foods that have so many different ingredients and such an unnatural combination perhaps this process of learning about the nutrient content of different foods and flavors becomes impaired because it's just the brain is not used 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 Flav I can connect this flavor to an amino acid content but something that's so diverse it might be harder to do and isn't it the case that the neurons in the gut

and the hormones that are produced by the gut as we digest food and that the neurons in the brain that can control appetite and feeding have to be tuned to macronutrient content because those are the U primary colors of of nutrients and nutrients are uh the way in which we can persist um on a day-to-day basis right I mean I'm not trying to sound more sophisticated where simpler terms would suffice what basically saying is that the neurons in our brains that control these behaviors both eating and cessation of 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 uh or to lentils um but rather to amino acid content essential amino acid content in particular essential fatty acids and in the case of carbohydrate whatever is going to replace whatever glycogen we might have depleted right I mean like if we really break it down into biology eating is for a purpose and my understanding is that the purpose of eating is to uh replace those things as needed um rather than to uh you know taste Savory

or taste um absolutely absolutely absolutely those are just those those things those sensory cues are just markers that tell the brain what might be in that substance I think if you if you look at broadly at this difference between calories and macronutrients and micronutrients I would say what you see is that most of the circuits that are controlling hunger are primarily calorie specific so they they can like for example an arrp neuron I can put sugar fat or protein into the stomach of a mouse and to an equal extent inhibit an agrp as long as

they have equal calories really yeah so a little drop of olive oil into the belly that has of an animal that has um let's drop let's say a little bit more let's say um 120 calories of olive oil is equipotent to 120 calories of chicken breast at the level of these agrp neurons it is so we they don't care about they don't care about no they're really concerned about they're really concerned about energy um there are circuitries that are more concerned with macronutrients individually although I don't think we know nearly as much about how that

works and I think the evidence is clear that the the strongest offended Mac macronutrient by far is protein so protein um you know I don't think really sugar and fat intake are strong strongly defended in the sense that you can you you're fine if you go without eating sugar right basically you can synthesize sugar from other from amino acids for example um and you don't develop an a specific sugar appetite in the same way you do for example if you deprive yourself of hunger you develop a protein hunger or essential I think the difference is

that you know proteins consist of essential amino acids there's this I forget if it's nine I think amino acids that um uh your body cannot synthesize you absolutely need them or you will die and so um whereas sugar and fat can be interchanged with other macronutrients so um and then there's other things also that you absolutely need to ingest like sodium chloride right so sodium so uh uh there's very if you deprive an animal of of sodium they will develop this salt appetite that's incredible basically and that's completely innate um uh but that's I think

salt appetite and and and protein appetite are the things that are probably the most strongly regulated at the level of the macro micronutrients 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 that means the electrolytes sodium magnesium and potassium in the correct amounts and ratios and nothing you don't which means no sugar now I and others on this podcast have talked about the critical importance of hydration for proper brain and body functioning even a slight degree of dehydration can diminish cognitive

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hydration and your electrolytes with no sugar if you'd like to try element you can go to drink element spelled l mn.com huberman to claim a free element sample pack with the purchase of any element drink mix again that's drink element.com / huberman to claim a free sample pack if we could talk about body weight homeostasis for a moment that I think that would be useful so let's say somebody decides they want to lose some weight they caloric restricts slightly either by exercising more or eating less or both their body weight drops by a bit let's

say they lose 10 pounds eight of which are body fat they lose a little bit of lean mass also they're now at a new lower body weight are the arrp neurons motivated to have them seek out more food in other words are they hungrier and more motivated to find and eat food or do these agrp neurons learn hey body weight is lower and I don't need to push to find so much food so often no I mean the idea is that the hrp neurons are more active when you lose weight and that that chronic activation

of those neurons in part because leptin levels are lower in the blood because you've lost weight is that drive that that that counterregulatory drive that drives you to then consume more food but then how do people ever keep weight off well so part of the answer is they don't I mean so so there's so really I I I I would argue like I have these friends who were very heavy most of the excess weight was body body fat for a long time they seem to be doing great yeah uh eating the way that I described

before and by the way I'm not a proponent of any one particular diet I have vegan friends carnivore friends Etc but but that pattern of eating I described before has been enormously successful for them I haven't run a you know a randomized control trial that's not my job to do that in the realm of nutrition but they're doing great they claim to be sad they are so happy with the way things are going and um I I don't hear that they're constantly hungry I hear that they're constantly saded well so I would say that that

you know there have been efforts for a long time to develop diets that would help people consistently lose weight and it has been very unsuccessful um there are some people who for various reasons can't can successfully lose weight and keep it off and I don't know that I have a good answer for what's going on in those individual cases how they are the exceptions to the rule what about them is different that makes sense some also quit drinking alcohol yeah so there's other things so you know I think so behavioral regulation is better when you're

sober as opposed to environment but you know so what this is sort of getting at is what is the counterregulatory response to weight loss and so this has been studied um it was first studied um uh in the context of energy expenditure and um because energy expenditure is actually surprisingly easier to measure in humans than food intake because people don't tell you accurately what food they eat if they're free living humans they have to fill out a questionaire but um and the idea is that um for every uh kilogram of weight you lose so it's

about 2.2 pounds I think um your energy expenditure decreases by about 30 kilo calories a day now so not a ton but that is significant right 30 calories and then if you lose as you said 10 lb then that's 100 50 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 liell about 25 years ago that did this um 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 in the people that lost all the way is about 25% lower than the people people who never were obese and so those people who lost the weight we call them the reduced obese or that's what they were called in those studies and the idea is that 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 the 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 solow metabolism they were always destined to be obese and then you just basically you're 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 um but there have been studies looking at at least a year and it doesn't seem to come back within a

year that difference in energy expenditure now the question is is that really the big effect is that why it's so hard to lose weight energy expenditure or is it because you're hungrier and that's actually much harder to measure um but there was another really nice study Again by Kevin Hall investigating this um used a really clever approach this drug so basically what he wanted to do was is um he reasoned that um you can meure people's body weight and you can measure people's energy expenditure and because calories in calories out if we can measure body

weight and energy expenditure accurately we can then back calculate how much that person was actually eating um so let's see what happens when you have people lose weight how does their food intake change but the trick to this is you need to do it in such a way that you don't just tell them to go run on a treadmill because if you tell someone to go around a treadmill and lose way then basically there's all these they're thinking about the fact that they're doing this you need to do it in some way overtly so you

increase their energy expenditure cause them to lose weight but without them realizing that's what's happening so they gave them these uh drugs these sglt2 Inhibitors and it's a pill you can take they're used for diabetes they block this this this protein sglt2 in the kidney that is necessary for glucose to be reabsorbed into the blood and so basically what happens 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 these people would lose some weight and then measure how

their food intake changes and what that showed is that for every two pounds or so of weight you lose your hunger goes up by 100 calories per day so basically you've got a 30 kilo calorie decrease in energy expenditure 100 kilo calorie decrease in appetite for every two pounds you lose on average some people will be exceptions right they won't experience that at all for aspects of their physiology we don't understand um and so 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 gp1 glucagon like pep TI one OIC monjaro and similar drugs um my understanding of the back history on these is that a biologist obsessed with hila Monsters uh a reptile that doesn't need to eat very often discovered a peptide within their bloodstream called extendin yeah that um allowed them to eat very seldom a curbed appetite in the hila monster of all things and and it has a analog homologue you know we don't know uh I don't know the sequence homology exactly but there's a similar peptide made in mice and in humans that

suppresses appetite um if you would could you tell us uh what is known about how glp1 Works to suppress appetite where in the body indor brain sure and uh your sort of read of um these drugs and what's happening there um good bad exciting sure ugly sure be happy to anything else so um the story of glp1 so the he monster is an important turn and I'll talk about that it actually goes back before that quite a ways so so I should take a step back and say you know these were developed as drugs for

diabetes right and so and know diabetes is a condition where basically have elevated blood glucose either because you don't produce enough insulin or because your insulin is is not effective and so back in in sort of the 1920s right around the time insulin was discovered um there was this phenomenon discovered known as the incretin effect um and uh what it was intin intin not the effect not the effect you can observe the effect in numerous places in daily life and online just kidding so it's it's called the incretin effect you can think of it as

increase insulin because that's what the effect is um and the idea was that if you take glucose by mouth if you consume glucose orally um 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 uh the glucose causes more insulin to be released and causes you to to lower your body sugar more accurately more more more strongly interesting um which is a little bit counterintuitive because in the pancreas right so insulin is released

from the pancreas from the beta cell the pancreas senses the glucose concentration in the blood directly and so it suggest that that insulin is being released not just in response to changes in blood glucose but in response to a second factor and so they call that an incretin and through various experiments it was it was uh shown that this incretin effect comes from the intestine that there's some substance being produced by the intestine that when you eat a meal uh 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 because if you inject too much insulin you can kill yourself by making yourself hypoglycemic right so this have to be very careful but the thing about the incretin effect is it's not causing insulin release directly but it's rather boosting the natural insulin release that comes when glucose is higher in your blood so it's sort of an amplifier on the natural insul insulin release so basically in the years that

followed whenever someone would find a new hormone they would test it is it this incretin and there's lots of failures they weren't the incretin um but then so there's this other hormone that comes from from the the um pancreas called glucagon right and so glucagon which also discovered in the 1920s glucagon is kind of the anti-insulin so um when blood sugar goes low glucagon is released in order to cause your liver to release glucose into the blood so glucose glucagon and insulins are these two opposing hormones glucagon was known for a long time but but

people discovered in s of the 1980s that the glucagon Gene is expressed in other tissues other than the pancreas and it's differentially processed the protein is differentially processed to produce different hormones hormones other than glucagon and they discovered there was one in the intestine and so they called it glucagon like peptide because it came from the same gene but it's just slightly different it's cut up slightly differently and this hormone was an in creedon so basically if you uh put it on beta cells um 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 increte that's that's been found it's it's called jip Gip and that will be important talking about some of these other drugs also a hormone that comes from the intestine and so um the challenge with making glp1 into a drug is that it has an extremely short halflife so it has a half life about 2 minutes in the blood um 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 because just degraded too fast and the reason it's degrade is because there's an enzyme dpp4 is what it's called that degrades gp1 so the first thing people tried was let's make Inhibitors of that enzyme so we can boost this natural gp1 signal and those are improved uh uh uh diabetes drugs they're called gpon you've probably heard about them Genovia is the most common one and those boost the level of gp1 the natural glp1 in the in the produced from the intestine by about three-fold and

they're effective in treating diabetes not people lose weight people do not lose weight and that's one of the key reasons that we know that the natural function of gp1 is not really to control body weight because you can boost the level three-fold with these dpp4 drugs millions of people have taken them they do not lose weight that's a great question so but you know a three-fold 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 uh uh

is more stable in the blood and that's where this this lizard that you're talk you mentioned comes into play it produces a stabilized form of glp1 and its venom no one knows why one hypothesis is that it's something to do with the lizard uh as you said basically having this long time period between meals and it needs to regulate its blood glucose who knows if that is true but it turned out to be fortuitous because then this glp1 from this lizard it has a half life of like 2 hours and so the first glp1 drug

that was approved was just this molecule from this lizard basically and it um it's called exenatide and it's approved in 2005 for works well for diabetes um has a half life of two hours you inject it and um uh doesn't cause a ton of weight loss but two hours is good but it's not so great so then pharmaceutical industry tries to can we you know basically improve this even further and so they start engineering this hormone making mutations attaching lipid tails to make it binds to proteins in the blood that would stabilize it chemistry jockey

stuff yeah exactly and I think the next big Advance was this Compound L glutide um and L glutide was approv for diabetes in 2010 and for and then for weight loss in 2014 and so lug glutide has a half life of about 13 hours in the blood no now you're getting up to something serious we've gone from 2 minutes 2 hours 1 hours and you get better effects on on on aspects of blood glucose and diabetes control and they started to see that some people were losing weight very variable responses not everyone loses weight on

L glutide and one of the things they noticed that I think is just is fascinating to sort of example of how drug Discovery works in the real world um you know a lot of these people who take log glutide now it has this longer halflife they start to get nauseous and that would limit how much of the LI glutide they could take and it's a known side effect of these gp1 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 and these side effects would reappear but then they go away and then once you got up to the highest doses then people really started losing weight and so there's a couple things that are pharmaceutical industry realized wow these are potentially really effective weight loss drugs and also

this nausea which we thought was a was you know a killer people are able to just get used to it and then it just goes away it under goes the word is Tac aaxis so the idea is that the receptor uh that's affecting the the in the gut that's causing this these effects undergo some sort of down regulation with with chronic chronic exposure so L glutide you know was it's been around it's been on the market for 14 years now um was used but still you're only getting sort of like 7 to 10% weight loss

which is good but not like you know amazing Rive um but then semaglutide came along um and that that was approved for diabetes in 2017 and semaglutide is OIC or also Al also uh marketed as uh wig oie for weight loss and semaglutide now has a half life of seven days so now we've gone from two 2 minutes 2 hours 13 hours 7 days and you can really jack up the concentration with a 7-Day uh uh halflife and then they saw people started really losing weight and so and some of those trials people lost you

know 16% of their body weight which previously had been unattainable with in what time frame uh typically takes about a year okay and most of the loss and body weights from body fat or from other other compartments the typical number is that if you um 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 be offset by resistance training Andor consuming a higher protein diet yeah you can almost completely eliminate that if you eat enough protein and do serious weightlifting um obviously not the whole population is interested in doing that and there's been a lot of discussion of how serious a side effect this is um you 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 counterargument that has been made which I think is also kind of convincing is that

true you're losing some muscle but you're also losing all this fat and you no longer need as much muscle when you're not carrying around as much body fat so people who are heavier naturally have more muscle because they need to to move their body right and so yeah the the calves on very um obese people are often enormous exactly and then they lose weight and exactly the and I mentioned the calves in particular because um 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 this musan muscle mass loss is although the pharmaceutical industry is all in now on making drugs that basically are going to prevent that so that's that's something that will be will be happening probably in the future is it a sorry to interrupt it is the um weight loss on these drugs the consequence of reduced appetite um or some other aspect of metabolism and if it's the consequence of reduced appetite um is that occurring at the level of the brain and gut um or culmination so it's almost entirely reduced appetite and

it's almost entirely incurring at the level of the the brain which neurons it's thought that the key targets of of uh 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 Posta so where back in the brain stem back in the brain stem so these are actually the neurons in that desate rat story I was telling earlier these are the brain regions that are preserved in the deser rat the deser rat still has these very coddle brain stem structures um they're two very

special brain regions because they get direct input from the vagus nerve so the vagus nerve is the nerve that inates your stomach and intestines and heart and lungs and it's sort of the major pathway from gut to brain and provides most of the sensor of the neural input from gut the brain telling you about things like this your stomach distension how many nutrients are in your intestine breathing all that stuff and almost all of those vagal nerves terminate on these two structures in the brain stem when I hear Posta I think about nausea because I

was taught that Posta contains neurons that can stimulate vomiting um and this seems to link up well at least in The Logical sense with the idea that stimulating activating receptors in these neurons within postma might explain part of the transient nausea side effect do of OIC and and related drugs yeah so the current thought is that a lot of the nausea is coming from activating the neurons in the area Posta 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 that's going to change the whole brain so it's not just those regions but you know 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 do they so you can visualize where do

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 they're um there's an abundance of The receptors for the these compounds in Posta and um NTS or is it because the bloodb brain barrier is somehow weaker at that location uh it's because the blood brain barrier is weaker so basically it's a region uh so what's known as a circumventricular organ meaning it's a 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 um 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 barrier is weakened I really appreciate that you mentioned the half-life issue with glp1 and the fact that these um dpp4 antagonist did not lead to weight loss despite increasing circulating glp by three-fold um this is relevant um to a number of different claims that people

make that a given food or a given drink um increases glp one um I've actually said before you know I'm a big consumer of Y brate my uh father's side is Argentine and it's a known appetite suppressant but it contains caffeine and other stimulants that might explain some of that and it's not a robust appetite suppressant to the point where most people would you know rely on it as a weight loss compound it's but anyway it's my preferred source of caffeine but I've um said before um you know 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 stimulatory effect right so you can't separate because it's it's a complex compound this year thing it's got lots of things in it but also um you know I've uh observed you being vocal on social media uh when people have said hey this thing increases uh gop1 um you quite appropriately I think um said

wait you know OIC and drugs like that increase glp 1,000 fold when you talk about a food or drink or maybe a supplement increasing gp1 it's very unlikely to increases gp1 to that level meaning unless you're getting into the hundredfold OR thousandfold increases um probably uh not right to talk about glp1 being the source of any appetite suppressive effect yeah that's 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 you know 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 it three-fold um these These gp1 agonists are really a pharmacologic effect effect that only happens with drugs so you get a thousand to 10,000 fold higher concentrations of these drugs in your blood than uh the natural hormone and so it's just there's no diet is 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 a essentially a peptide hormone yeah um if we were talking about different peptide hormone you know pick one um you know oxytocin or uh estrogen testosterone they're not really you know broadly speaking um most people would be concerned about thousandfold dosing of something like that and obviously there are clinical indications where that's important however my observation of the ever expanding literature on

gp1 agonis um is that there seems to be improvements in like reduction in um alcohol consumption um and by the way why would uh increasing gop1 reduce um uh craving for alcohol that it seems like there's an ever expanding list of things that glp1 agonism is good for yeah um but we are talking about Su I would say super physiological levels when one takes it and again I'm not um against it nor for it I'm just paying attention to the literature so I would say that that's absolutely right when you're increasing the level of hormone

a thousandfold you need to be careful see what's happening um but at the end it's an empirical question what what what does it actually do to a person and it can only be answered through experiments and I think the nice thing about these gp1 drugs that a lot of people don't realize is they've been around approved since 2005 the earliest ones and even something like OIC which maybe only entered the public Consciousness in the last year or two right it's been around for sevenish years I think so so and big clinical trials with these drugs

and so um and the evidence so far is that they seem to be incredibly safe and as you said not just incredibly safe but um they seem to have all these unexpected health benefits that that were seems to be in some cases even unrelated to weight loss and so so you know because of the reasons you mentioned one of the things the FDA requires from these pharmaceutical companies for diabetes drugs is um these large cardiac uh outcome trials so basically where you measure stroke and where you measure uh uh heart attacks and and death from

from any cardiac cause um big trials like 20,000 people four years cost like a billion dollars to run and the data from the semaglutide the OIC trial came out last year and as expected reduced the rate of heart attacks Strokes all cause mortality according to cardiac uh uh for for cardiac reasons but was really surprising was a lot of that seemed to happen before the people even lose weight lost weight so there was already a difference between the placebo group and the semag glte group before the people on the drug had lost a significant amount

of weight and there was no correlation between the amount of weight they lost and how well they were protected from heart disease and that's led many people to think that some of these effects actually could be due to other things the gp1s are doing that we didn't expect and so one thing is there's an idea emerging that that they are anti-inflammatory so um these brain regions the area postre and the NTS are also really important for this this reflex known as the inflammatory reflex that basically acts starts with the vagus nerve goes to these brain

regions of the brain stem and then goes back down to the body to basically suppress to prevent outof control inflammation and so it's thought that these drugs perhaps have an anti-inflammatory effect that explains some of that um sounds like the patent on these drugs just got extended by another hundred years that's a that's a that's a bio uh Pharma joke I mean just to put context on it um 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 um

approved clinical use in which case it can be remarketed only as a um brand name not generic version so a lot of companies once they do the uh safety testing and uh and all given everything they put into the R&D into the research and development there's a very big incentive to not necessarily find new drugs but finding new uses for the same drugs and not allowing generic versions into uh into the picture and that's why it's likely to be based on these um uh what sounds like additional uses of um OIC related compounds a long

time before there's generic OIC available I 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 almost every major pharmaceutical company now has a gp1 program really and uh some of them are really exciting actually um so so I mean the general Trend in this area is what people call glp1 plus 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 so one compound is from Eli Lily which makes this other so there's this other drug on the market that we haven't talked about but tepati which is know as mojarro for diabetes and zap Bound for obesity which is even better really in almost every respect a better drug than than OIC um so people lose more weight so it's about 21% weight loss at a year um fewer side effects um at least at comparable doses that seems to be because this

this other drug uh tepati um it has two Targets not one so so whereas whereas OIC is just um gp1 receptor Agonist tepati is a dual Agonist of glp1 and this other in that we talked about Gip Gip and it seems like having that Gip agonism actually EXs as an anti nausea effect that sort of counteracts some of the nausea caused by the gop1 in the area Posta there are Gip receptor neurons in the area Posta this nausea Center to sort of allows you to crank up the dose of the gp1 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 years so Eli Lily the company that makes this drug chatid muaro um they have a triple Agonist that's in phase three clinical trials now so this is now three hormones in one it's the glp1 which all these drugs have the Gip which is the anti-nausea component and then glucagon itself and so these these three hormones all combined in one pill and what the glucagon does is it increases

energy expenditure this is a well-known effect of glucagon and um so you're basically eating less your nausea is as bad and now you're just burning more calories at Baseline the results from this strug are incredible so basically um there's been one phase 2 trial published and people lost 25% of their body weight at the end of the of the uh uh uh I think it was 48 we period and they were still losing weight so we don't know where the end point we don't know what the what the maximum is so there are bigger Longer

trials going on now to figure that out but but at that point when you get Beyond 25% body weight you're talking about basically bariatric surgery right which is currently the best thing we have you know like these these surgeries people people do qu stomach staple removing a portion of the stomach removing a portion of the gut so really it's a pharmacologic version of bariatric surgery the other one that I think is really exciting there's this compound from Amgen it's called just right now it's just a code it's like AMG 133 but um it's like tepati

in the sense that targets both glp1 and Gip so it's a dual dual dual uh targeted but unlike tepati which activates the Gip receptor this amen 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 lot of debate about what's going on there but the way this Amgen compound activates um the uh Gip receptor or inhibits the Gip receptor rather is that uh it's an antibody so all these other things were peptides but this is a much bigger sexual protein this

is an antibody and because it's an antibody it has a much longer lifetime even than something like semaglutide which is 7 days so it last a month in 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 um at the end of this they stopped and people maintained the weight loss for 6 months that's impressive potentially because of the long-lasting effects of this antibody or potentially because of other things that we don't understand so and those are

just two there's all sorts of other crazy things happening so really I think it's just it's just created this explosion of of interest in Pharma um once basically it's one of these things you know it's you know once you see that something can be done all of a sudden that changes everyone's perspective and so now obesity drug Discovery has gone from something that 10 years ago everyone wanted to stay away from because there were so many nightmare stories about drugs that turn out to be not safe till now everybody's sort of Allin on this yeah

I remember in college the fenfen 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 in part to bring us back into the brain and in part because it's directly relev to what we've been discussing um about OIC and glp1 um there are other neurons in the brain that regulate feeding um and there are other peptides involved in appetite control for which I would say Niche communities have started to indulge in um and by

the way people were taking glp1 analoges long before they were FDA approved in kind of Niche communities these aren't communities I'm a part of but every once in a while I'll stick an ear into one of these communities and hear what people taking and a big thing right now um in these communities is the use of other peptides um that are in the melanocyte simulating hormone pathway and you mentioned melanocortin um receptor containing neurons um could you tell us a little bit about what these neurons do um in the absence of any pharmacologic stimulation and

then why it would be that uh people would uh perhaps um stimulate these Pathways um with these drugs not that we're recommending that but I do think that um given that some of these neurons are also involved in sexual behavior and FDA approved for the treatment of um hyposexual function in women um things like that you know there is FDA approval for 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 uh feeding appetite and weight control are likely

to enter the picture uh with more prominence um in the not too distant future so Alpha msh as scientists call it the hormone you were just referring to is um is a product of uh Palm the Palm C Gene so in the same way that we just talked about glucagon can be processed into different things in some Gene in some in some cells it's made into the glucagon hormone and other cells is made into gp1 pal C that that Gene can be processed to produce different hormones and one is Alpha msh which is very important

for feeding control and so these these Palm C neurons they're in the aru nucleus of the hypothalamus same region where these agrp neurons I talked about earlier are located and there's sort of these these these two uh uh uh these two sets of neurons that have opposing effects on body weight regulation and so Alpha msh inhibits food intake and arrp neurons promote food intake um and where they converge is is at this receptor the melanocortin 4 receptor um which is uh uh important for body weight regulation and so Alpha msh is an Agonist it turns

on that receptor and the arrp peptide is an antagonist it turns it off um and so you know there's a lot of human genetics as I as I mentioned earlier implicating this pathway in uh body weight regulation there have been a lot of efforts um over many years to turn Alpha msh into a drug um and it's been very difficult um there is one drug that's now approved it's called I think I'm going to get the name wrong it's like set MTI or something like this um it's an mc4 receptor Agonist um it's mainly used

relatively small populations of people that for example have mutations in this pathway it's not used as a widespread as as as a drug and the challenge has been um really side effects so um there's an increase in blood pressure that happens sometimes with these medicines partly because the this pathway controls not only appetite but also autonomic tone and sympathetic nervous system activation um uh so you know it's just taking a step back from everything we've talked about today um I talked about this the short-term system and the long-term system that controls energy balance and body

weight the long short-term system in the brain stem the long-term system in the hypothalamus the long-term system being leptin and Alpha msh and agrp when I was coming up learning about this stuff 15 years ago 20 years ago um you know it was uh 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 brain stem the animal would would just compensate and there were these famous experiments where they would take cck which is a hormone just like

gp1 inject it into rats inject it several times a day and cck is known to decrease the size of meals and it would decrease the size of meals but the rats would never lose any weight because they just eat more meals to compensate and they would just perfectly compensate by eating more meals and so the lore was it's just impossible the animal will always compensate unless you hit this body weight set point regulating area which is the hypothalamus the long-term system um but then what the pharmaceutical industry discovered which I guess maybe shouldn't be so

surprising but I guess it was to some people is that if you just hit that receptor that short-term system 24 hours a day 7 days a week and never let it stop then you will lose weight right and so the short-term system alone is enough to cause body weight regulation on the other hand the long-term system with Alpha msh and and arrp neurons and pomy and all this stuff has been a challenge to pharmaceutically Target um because you know leptin we discussed didn't really work um and so I think there's going to be as as

you mentioned a reemergence of interest in considering this other pathway now that we've seen the the the success of the of the gp1s and I think one area where it may emerge is um 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 gp1 drug to lose the weight and then at some point you might stop that drug and switch to a a more hypothalamus Center leptin based drug to

keep the weight off so basically use the gp1 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 it's hard to say because you know the gp1 drugs have just a lot of benefits even Beyond weight loss so people might not want to stop taking them um but that's one idea very interesting I'd love to talk about dopamine sure we hear so much

about dopamine being involved in pleasure I like to think I've had at least a small level of impact act 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

you had a beautiful paper publish in nature entitled and we'll put a link to this in the show note captions uh dopamine subsystems that track internal States um and I love this paper for a variety of reasons but if you could give us the high points of of your discoveries on dopamine as it relates to feeding I think um I know in fact that people would find it very Illuminating sure fantastic um so uh yeah the question of what dopamine does with respect to feeding is a great question and a difficult question I think to

answer there's a lot of miscon conceptions I think um the evidence is dopamine probably isn't so much involved in the pleasure of food that taste that's some The honic Experience um one reason we think this is because you can make mice the Richard paler did this decades ago that don't have any dopamine and they still show the same sort of effective responses to food so you put something sweet in their mouth they kind of they like it right um what dopamine seems to be important for with respect to food is two things um one is

the motivation to engage in work to get food particularly when it's high levels of effort so um if you ask a mouse to press a lever to get a pallet of food uh if it doesn't have any dopamine it won't do it and if it has low levels of dopamine it'll just work a little bit so you dopamine is important for sort of energizing action and 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 and what that paper of ours is about is the idea that this learning actually happens on two different time scales 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 qes in the environment predict something like food availability right so you see a McDonald's sign and you know that uh that means there's some tasty food in in in there and so dopamine is is is involved in that process of sort

of learning what what that external Q means and that's a very fast time scale process so in the laboratory um for example we will play a tone and then give an animal a sip of a of a solution that has calories in it for example and 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 that's a dopamine dependent process um but there's a second sort of much slower time scale learning about food which isn't about where

I go to get a hamburger but rather about what the experience of eating the food the Oro sensory experience its taste its flavor its texture how that relates to the post-ingestive effects and I should say that this seems extremely relevant to the McDonald's example because um in your experimental situation the tone is analogous to the golden arches of the McDonald's sign but in my experience uh and forgive me but most of the food that I've consumed from McDonald's does not taste good um relative to other like really delicious hamburgers or french fries or something like

that I mean it's um so you're saying dopamine is required to link the signal the golden arches or the tone to the presence of food at a particular location exactly but not to the experience of pleasure from that food exactly which squares very well with my experience of McDonald's and I probably haven't had a bite of McDonald's in 20 plus years I would have to be pretty hungry I haven't either and I it's funny the Golden Archers thing is just something that people in Neuroscience talks about dopamine use and so now I've started subconsciously just

talking about golden arches even though I also haven't eaten McDonald's in decades in and out burger better tasting uh from what I understand probably better sourcing we're not going to get into all this in detail but everyone has their preferences but um but I do think it's interesting because what we're talking about here is related I think to this notion of Highly processed food packaging the commodation of food just 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 an important distinction that people make is the distinction between wanting and liking I don't know if you've talked about this previously on the podcast an lmy my colleague at Stanford came on the podcast talked about dopamine is about wanting as opposed to enjoying exactly so in most cases yeah so liking is this the subjective honic pleasure in the moment of eating it but wanting is just it's what you want and these can be uncoupled all the time you could want things that at the end of the day you don't actually enjoy it when you

get it I feel like a lot of life is like that indeed and and so uh and so um and so dopamine is very powerful at making you want something but not necessarily like it so that's one element but then there's this other element that that that is important but very much less studied but I find much more interesting which is how you connect this this the sensory cues associated with food its taste its flavor um its smell uh with the consequences for the body and this is so important because um so much of whether

we like or dislike a particular food or drink is related to its post-ingestive effects you come to like things for example that have calories so this is one of the reasons that adults will eat vegetables and other Savory Foods that children find disgusting even though they're a little bit bitter you learn through experience this makes me feel good to eat this and even maybe at a completely subconscious level there's also a level of learning that occurs um 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 this other much slower learning occurs and the reason I say it's slower is because because the time between when you taste the food and when it actually gets into your intestine and releases the the hormones that might drive this is quite slow separated by tens of minutes um but how that works hasn't been clear there's been an idea that dopamine might be involved um but it hadn't really received a lot of attention and so we set out to investigate what is the role of dopamine in these post-ingestive responses and

sort of map out for the dopamine system how does the dopamine system respond not when you see the golden arches which is usually the kinds of experiments that have been performed but rather when you deliver nutrients directly to your stomach or when you deliver water directly to your stomach if you're thirsty and so on and what we saw was that there are these different populations of dopamine neurons that are tuned to respond to signals from inside the body and so there are some that respond when nutrients are in the stomach and intestine um there are

others that respond when in a thirsty Mouse when the blood is rehydrated when you basically satiate your thirst and we showed that the um the purpose or at least at least a purpose of that activation is to cause you to learn about the effects of what you just ate basically to create this connection between the flavor of something and its post-ingestive effects so that sort of that that delayed dopamine signal uh 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 one of the sort of interesting things about that paper that was not the direction we initially expected to go in is that um for food I think it's kind of intuitive there are lots of flavors to food you have to learn you know 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 like how do you have to learn anything to do with drinking a glass of water but it actually is a learning a learning question

in part because for many animals probably most animals thirst is something that's associated with eating not drinking there's this study I love um of rabbits in New Zealand so so you there's not a lot of people studying what animals how they get their fluids in the wild cuz who cares but it's kind of interesting and so in New Zealand uh uh this huge rabbit problem because they're invasive P species that that that was introduced in 1800s and they're just eating all the all the land and so there's lots of money to study rabbits just understand

their ecology and so um group of researchers did this experiment where they made this big pen outside where they put a bunch of rabbits in the rabbits couldn't escape but they had all their natural food it was like an outdoor area and they also put a trough of water so the rabits always had access to water just like clean water then they could measure how much water the rabbits drank and what they basically found is that nine months out of a year rabbits drink Zero Water they drink absolutely zero because they get all of their

water from food the only time they drink is during the winter when all of the greenery has sort of become shriveled and then they can't get water from that anymore and so it's just kind of interesting aspect of of how many animals are very different from the way we think about ingestive Behavior but but 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 a food and say if you've never had any

experience oh yeah this is something that's very water rich and this will rehydrate me when I'm thirsty and this one is not and so James the graduate student who led this project uh basically investigated this by uh giving mice different fluids and then measuring how the dopamine response and he showed there was this delayed dopamine response after the mice had drank the fluids uh uh that correlated with rehydration of the blood so a whole bunch of dopam neurons get strongly activated when the blood is rehydrated and he hypothesized this might be a signal this delayed

this delayed activation of dopam neurons that allows animals in the wild to learn uh uh uh that food I just ate is is 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 uh he showed that basically uh uh these dopamine neurons are critical for them learning that Association so so that's the story of that I

love it and I'll tell you why um 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 back and forth and I generally

would only eat two or three times a day you know anyway there's only so many hours in the day um and I found it to be incredibly satiating um and I found that I felt great and I can imagine any number of different reasons for that and there are these theories that you probably recall that the the diet that was being um promoted in the 90s where people would either eat carbohydrates or proteins separately like there was some wackiness out there and as I say that I'm sure I'll get assaulted in the comments probably not

wacky I'm sure there's some enzymatic basis for why that would be useful if you enjoy it go for it um you know um I I don't have a feeling about it one way or the other but one thing I noticed was that um low water content containing meals um either by virtue of the foods that they include or by virtue of the fact that they're not diluted so to speak um it's a different taste experience to eat those Foods than it is to eat like a big salad or something of that sort um in any

event I don't do that any longer I just sort of stopped but it was a fun experiment um 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 um in all seriousness um to what extent do you think humans uh overeat or undereat depending on the water content of the food it's an interesting question so you know there is this advice that you should um if you're hungry first drink something

drink some water and see if you're still hungry and the idea is that um perhaps uh uh humans can't always I mean we our our interceptive sense our ability to sense what our body needs is not perfect and sometimes we could be confused and we could really be thirsty when we're hungry and hungry when we're thirsty and there's some evidence that that could help um I would say it's probably not a huge effect in most of modern day life but but uh it's an interesting idea mhm yeah um this brings us to the topic of

thirst something that your laboratory has worked on extensively and the topic of osmolarity yeah of um salt consumption and things of that sort um in Broad terms how do these things link up meaning are there instances in which what we really need is salt and we end up eating a bunch of Parmesan cheese I got teased Yesterday by my team because occasionally when I'm on the road I I don't like most of the foods available in most airports and stuff so I'll bring a a chunk of really nice parmesan cheese I just break off a

piece and eat it I'll have half a cucumber and I'll have a can of um not a can of tuna but they're these 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 um and I'd rather eat that in most cases until I can get to a decent um meal than like what's put in front of me on an airplane most of the time um so I get teased about this but I notice 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' had a couple extra glasses of water maybe I'm just craving salt and I'm confused and I'm over consuming this cheese yes when in fact what I'm going for is the salt as you point out um our understanding of exactly what we need is fairly crude and oftentimes we overshoot the margin especially when foods are in combination so um salt water and let's just say calories how how do we

um accurately or inaccurately um pursue those at the level of biology okay so I was drawing tough questions I but you're your feels like my qualifying exam so um so uh well there are separate system this thought to be separate systems that control salt appetite thirst for water and hunger for calories and so they involve different brain regions for the most part different neurons different signals from the body um in general hunger and thirst are pretty separable the I would say the the the instance where they interact is in phenomenon such as dehydration anorexia this

is the idea that if I give you some dry food but I don't give you any water um 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 um so we prioritize hydration yes you will at some point you will prioritize uh hydration that's related also to the concept of prandial drinking so many animals including humans drink most of their water during meals because you basically want to counteract the osmolites that are in your

food um salt balance though and and thirst so the The Thirst for water and the desire for salt are much more tightly linked because um 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 osmolality the blood which you can just think of in simple terms as sort of the the total concentration of all the salts um uh it's a little more complicated than that but it doesn't really matter and uh uh uh you also specifically need to maintain the sodium

concentration at the right level and so um uh and there are really powerful innate mechanisms that drive both I think thirst is very intuitive to people you get dehydrated uh you lose water you become thirsty um and uh we know now that that that there are very small set of neurons in a few brain regions that control that um and uh they they the way they they're thought to work is they contain Osmos sensors 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 and 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 wow um 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 um half an ounce sip of sea water inadvertently yes it's extremely aversive it is it's like like you just you you want to drink

some nons salty water some nice clean water yes exactly immediately yeah so I should I should emphasize that there's two components to the fluid homeostasis system to the water homeostasis system one is this desire to drink but the other is of course the kidney and so the reason that drinking the salt water won't put you in a really bad situation is your kidney would then filter out a lot of that salt and cause you just to pee it out and then you'll be fine um 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 uh allowing you to replenish the blood with water at various intervals um and so um yeah I mean the experiments led to the discovery of this third circuitry are amazing it was this guy B Anderson working in the 1950s and he just had this hypothesis that there was an Osmos sensor in the brain right which is very I think you know there was some evidence to 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 um infusing small amounts of salt into various places in their brain reasoning that if there was an Osmos sensor sorry to I was wild I mean I I wasn't chuckling at ingest like it like I you know I feel for the goats I I feel for everyone involved in that experiment but what a wild experiment just to put salt directly into the brain concentrated saline solution yeah good and he found this tiny region in and around the hypothalamus that if you

um if you infuse salt in this region the goats will they'll drink like eight liters of water in five minutes just crazy right and then he and so he read okay this must be the osmo sensor and then he went back and uh stimulated those neurons and just same thing go just drinks like crazy and so now we know there's this couple small regions in around the hypothalamus one's called the sub fornical organ another one's called well it doesn't really matter what they called but basically uh uh uh that have these Osmos sensors 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 uh uh 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 absorbed into your blood for the blood to be rehydrated and then for these Osmos sensors that Bank

Anderson discovered in your brain to be uh uh to be sort of sense that and return to normal activity but of course if you had the experience of drinking a glass of water you know that you can quench your thirst within minutes right and so how does that work within seconds even so one of the other sort of experiments we did early in my lab was to to ask that question um by basically recording for the first time the activity of these neurons that bank had discovered by putting the salt in the ghost we went

back to them now in mice mice have the same neurons you have the same neurons and recording their activity when a thirsty mice drinks and asks what happens and um what we saw was that the neurons don't wait until the blood is is rehydrated um they also don't do what the arrp neurons 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 mouse takes a lick of water their activity goes down a little bit and

basically they track in that way the volume of water that's passed through the mouth um they also get the signal from the blood relaying the osmolarity of the blood and they compare these two and basically when the mouse is drank enough in order to in order for the animal to predict that the blood osmolality is going to return to normal then the animal stops drinking beautiful yes just beautiful right like the brain is essentially predicting with it sounds like a high degree of accuracy how much water one needs to drink linking it to the the

pleasure and uh of ingesting good clean water under conditions where we're thirsty in anticip PA of adjusting blood osmolarity in 20 minutes exactly I mean it's um yeah I mean this is the kind of thing that just it Delights me because it just means the brain as a predictive organ is just is so accurate it also explains some uh some sort of funny aspects of thirst that you may have noticed from everyday experience so so you know one one idea is that just cooling your mouth can sort of quench your thirst right so if you're

in the hospital and you're not allowed to drink any fluids they'll give you ice chips to suck on to sort of quench your thirst so why is that and so one idea is that perhaps because water is usually cooler than your body that sensation of water pass it always cools your mouth and so you learn or maybe it's a Nate that just cooling of my mouth means that basically I'm going to be rehydrated so Chris this was experiment done by grum Chris Zimmerman Chris um did the same thing where he was recording these thirst neurons

just put a cold piece of metal on the mouse's tongue and you can see when you do that these thir go down in activity and then you remove the cold piece of metal and they go back up amazing so a lot of these these sort of oddities of everyday experience have to do with how the system is evolved to make the prediction uh about what's going to happen to the body I mean few things are as rewarding as the sensation of drinking really nice clean cold water when one is very thirsty when my lab was

in San Diego I used to take my dog um hiking in Palomar Mountain and one day you know I really screwed up he was a Bulldog Mastiff they overheat easily and it was a lot warmer than we thought we ran out of water it was a actually 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 what is I was told with spring water and it came out you know really cold and you could just see him fill back up with life

yes I filled back up with life knowing he was filling back up with life and it was it was unlike the the kind of reward that one experiences with food when you're hungry absolutely it's like that that basic critical need for water absolutely um under conditions where you're clearly hydrated is like nothing else it's it's delicious in a way that no food is delicious I would like to actually say something about this so 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 um they'll lever press hundreds of times to make it stop the same neurons that the neurons I talked about that control hunger the arrp neurons they actually don't so much um they won't really do much of anything to shut them off that raises the question why do the animals eat then when you stimulate the hunger neurons and we think the primary thing that the hunger neuron 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 you know dehydration and thirst is really just unpleasant and animals just want to avoid that and so I think that distinction is is is very real I think there are two different motivational mechanisms for hunger and thirst hunger is mostly about the reward of food thirst

is mostly about this is just really unpleasant and removing that unpleasant exactly and you had a paper which I was going to ask you about so I will entitled The forbrain Thirst circuit drives drinking through negative reinforcement yes um and I'm guessing that paper illustrates exactly the point you just made so it's a forbrain circuit um so does that mean that there's some elements of learning and cognition around this or are we broadly speaking about the for brain for instance the hypothalamus being in the in the for brain so yeah it's interesting um so so

The Thirst circuit for whatever reason is mostly in the forbrain so um the neurons that so we talked about the NTS and the area Posta being important for hunger and sign signals from the gut those are the a arosta 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 forbrain one is called the sub fornical organ the other one is called the ovlt but they're just acronyms but um so why it evolved

to have The Thirst neurons more in the forbrain and the the neurons that sense nutrients more in the hind brain is a little bit unclear and so there is definitely an element of learning but um a lot of this is those neurons are also just directly sensing the blood and sensing changes in in both the concentration of salt in the blood and then also hormones like Angiotensin the drive thirst I was going to ask you this earlier but it seems appropriate to ask now a colleague of mine at Stanford in the psych ology Department uh

Dr Ali crumb who studies mindsets um has done some interesting experiments where people are told that a given milkshake is calorically dense other people are told that a milkshake is calorically sparse um both groups independently consume the milkshake um and then they measure things like um hormone responses in the bloodstream that are associated with satiety and and what she finds is that um even hormone responses um to the same Shake meaning the same amount of calories fat sugar Etc can be significantly modulated based on what we're told mhm um and it extends into some other

perhaps even more interesting areas in my opinion whereby if people are told that let's say a given meal that has a small piece of fish uh serving a vegetables and a a carbohydrate is yes perhaps a little bit calorically sparse compared to what one would normally eat at a given meal but they're told this is a highly nutritious meal this is good for you yes 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 um 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 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 um and I think this is important given the Obesity crisis you know to say nothing of these drugs that are coming out uh 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 um pain of caloric restriction what are your thoughts on on that yeah um well I 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 arrp hunger neurons how they can sort of see the food or get input about the sight smell of food and in that way predict how many calories the mouse is going to eat but I mean this is

a mouse right this is all based on a mouse and a mouse has you know a thousand times fewer n than you do as a person right so the computational capacity that the human brain has to make these predictions um 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 nutritional State and how information that you're given can change uh uh uh the expected physiologic outcomes I mean you're right I mean

there's there's there's just this whole other element that it's very hard to study because it's happening in the brains of humans and we can't do these kinds of experiments um but I'm sure that's very important I mean so I talked a little bit about about these flavor nutrient conditioning experiments these are the experiments where essentially an animal learns to uh uh uh consume a certain flavor because it learns it's going to be associated with nutrients later sort of the Paradigm for how you learn to consume bitter vegetables because they're good for you and you get

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

any pressure for it to be prescriptive um how do you approach eating um 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 um has it shaped um kind of how you think about food cravings your own you don't have to reveal what those are even if they exist um how you uh observe the eating behavior of others um and yeah what how has knowledge

uh shaped your your feeding Behavior well I try not to think too much about my agrp neurons when I'm eating because I would hope I would hope I think it gets it gets um I think you know the circuitry is so complex and we're just beginning to see what's happening so I wouldn't I wouldn't use that kind of information at this stage in we're just beginning too prescriptively but I think I think there is a set of you know basic recommendations from physiology and Neuroscience very simple things you've probably talked about with people on your

podcast before um for sort of shaping your diet to be healthier to limit food intake so um one we've already talked about is limiting consumption of ultra processed food eating more Whole Foods for lots of different reasons um because it's they're more satiating because they're 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 is protein consumption making sure you get adequate protein consumption both because there's this concept of protein leveraging so if you don't eat a minimum amount

of protein that's going to cause you to eat more calories just to try to achieve that minimum amount of protein also just because protein's more satiating and also because there's this idea ofer effect of food and so you basically burn more calories metabolizing protein than sugar or fat how about consumption of fluids um during meals you know you I've heard it said before that um you know we're not supposed to consume too many fluids because it's going to dilute the enzymes that that allow us to digest our food I've heard other people say that's complete

um I think that's I've never that's a myth I think I mean I think um drinking water I mean so humans don't have a perfect capacity to determine whether they're hungry or thirsty and so drinking water will ensure your you're not eating because you're hung uh because you're thirsty um and uh so and there's there's no idea of diluting it I don't think that and you distension itself even even though water provides a very limited distension signal the expansion of your stomach and intestines is one important way that you that you uh terminate feeding and

so um and so there is some component of that where you can get distension just from drinking water I say sorry I blur it out interesting because I didn't realize that a fluid consumption um only provides a limited signal for dis it's not fluids 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 is gradually

absorbed if you drink something like a glass of orange juice it will empty much more slowly and if you drinking something that's really high in fat really high in calories it'll empty extremely slowly over hours and that's because there's a negative feedback loop from the intestine that controls gastric emptying so as those first nutrients leave your um uh 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 uh it's just your your intestine can only metabolize nutrients so fast and so if there's calories then it slows down gas scamping a lot but water just kind of goes through what a beautiful system like there's regulation at at every point right hypothalamus brain stem got a rate of emptying based on the difference between water and orange juice it's just awesome yeah and that's part of the reason I think it's so hard to outsmart the system right because you know these you know these neurons are making predictions based on the

sight and smell of food but then the gut is doing its own thing it's calculating it separately and relaying that information so at every step there are these checks basically they are just confirming that what you thought happened the first time is actually what's really going on and so and it's which makes sense because it's so important for survival these homeostatic systems are the product of you know so much natural selection which I think at least partially explains why thousandfold increases in peptide hormones like glp1 are required to see significant long- lasting changes in weight

exactly um 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 of um let's call it anti-obesity drugs is headed I'm very optimistic I mean I think look I me I think that it's you couldn't have asked for more so far at this stage with these with these glp1 drugs um incredible uh weight loss unexpected health benefits really safe as far as we can tell I mean there it's always possible that

some new uh 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 so um 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 are going in five years people have so many different options it won't just be OIC or mro there will be five different 10 different drugs that they can choose from um that have slightly different

side effect profile slightly different efficacy perhaps used for people with slightly different metabolic conditions um and so it'll really be a whole pallet of of medicines you can take that will adjust your physiology and hunger and it's amazing how well it um squares with the understanding of the basic biology you know and um and that's a perfect opportunity for me to uh really just say what uh is in my mind and clearly in the minds of everyone listening and 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 you know in everyone's minds and everyone's hearing about um I've learned so much today I know everyone else has uh you run a incredible laboratory I've tracked your career for a very long time every paper is is spectacular and you're in a very competitive field and you've contributed in enormous ways to our understanding of these important processes and I don't just say that as a formality I I know that to be true given that we you know um are from the same field and

uh have known each other for a long time and I'm familiar with your work at at a at a deep level um today is just been an absolute uh privilege and and a gift to learn from you and um 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 uh everyone else did as well thank you so much thank you this has

been really fun I'm really glad we had a chance to do this we talked about some of my favorite topics so it's always a pleasure and talk with another neuroscientist about these things is fantastic so well please come back again um meanwhile thanks for everything you do all right thanks thank you for joining me for today's discussion with Dr Zachary Knight to learn more about his research or to support his laboratory's work please see the links in the show note captions if you're learning from Andor enjoying this podcast please subscribe to our YouTube Channel please

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