The Peter Attia Drive - #212 - The neuroscience of obesity | Stephan Guyenet, Ph.D.

Episode Date: June 27, 2022

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Stephan Guyenet is a neuroscientist focused on the neuroscience of obesity and energy homeostasis.  He is the author of the book, The Hungry Brain and founder/director of Red Pen Reviews. In this episode, Stephan explains how obesity has changed phenotypically over the course of human history as well as what might explain the dramatic increase in prevalence of obesity in the last few decades. He talks in depth about the role of genetics, the brain, and hormones like leptin play in the regulation of fat mass. He dives deep into two common theories of obesity—the carbohydrate-insulin model and the energy balance model and provides his take on which theory has stronger evidence. Additionally, he provides insights on how we’re hard-wired to think about food and the consequences of modern foods designed for maximal pleasure. Finally, he goes through the factors that affect body weight, set points, and provides takeaways for people wanting to take advantage of what we know about the brain’s role in regulating our body weight. We discuss: Stephan’s neuroscience background and his focus on the nuances of obesity [2:15]; How obesity has changed for humans throughout history [8:00]; The association between obesity and adverse health outcomes, the “obesity paradox,” and confounders when relating BMI to longevity [14:00]; The sharp increase in obesity across demographics [23:30]; The hypothalamus and its role in obesity [30:00];  The role of the hormone leptin in obesity [40:00]; The genetic component of obesity [46:30]; Understanding the tendency of humans to store fat through an evolutionary lens [57:00];   The hedonic aspect of food, and how the brain reacts to modern, highly-rewarding foods [1:03:30]; How we are hard-wired to think about food [1:14:30]; A review of the “Carnivore diet” [1:21:45]; The energy balance model, carbohydrate-insulin model, and unifying the theories around adiposity [1:34:15]; Body weight set points: a hypothetical comparison of two individuals [1:41:45]; Takeaways for people who want to lose weight and keep it off [1:48:30]; Evidence that favors the energy balance model of weight gain [1:56:00]; The synergistic effect of fat and carbohydrates and observations that a low-fat diet or a low-carb diet can cause weight loss [2:04:30]; Red Pen Reviews [2:11:00]; More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn

more now, head over to peteratia MD dot com forward slash subscribe. Now, without further delay, here's today's episode. I guess this week is Stefan Guyanae. Stefan is a neuroscientist and a passionate communicator about the science of primarily obesity, but many aspects of health. His research has focused on neurodegeneration early in his career and then more recently the neuroscience of obesity and energy homeostasis. His scientific publications have been cited more than 3600 times. He's the author of a book in 2017, The Hungry Brain. He's also the founder and director of Red Pen Reviews, which publishes informative,

consistent, and unbiased reviews of popular health and nutrition books. He is a review editor at Frontiers in Nutrition. In this episode, we talk about his background and what led him to get to where he is today. We talk about obesity and how it's changed phenotypically over the last thousand years and specifically looking at U.S. rates of obesity over the past probably 150 years. Talk about what the brain has to do with obesity, the role of leptin and the genes that regulate fat mass and obesity, about the hedonic aspects of food and how our taste today is different than obviously what our ancestors tasted and how energy and chlorogenic density relate to taste and how we potentially select foods. We discuss the carnivore diet and red pens review of the carnivore diet.

We speak about the energy balance model, the carbohydrate insulin model, and unifying theories around etepocity. So without further delay, please enjoy my conversation with Stefan Guyane. Hey, Stefan, thanks so much for making time. I've been looking forward to this for such a long time. Probably since I started a podcast, which has been, now we're coming up on four years, always knew we'd have to sit down. So I'm glad we're finally doing this. I'll be it not in person, but that's more an artifact of my laziness. I think a lot of people listening

to this will be familiar with you and your work, but I think a number of people won't be. So let's talk people a little bit about your path to where you are now, which is sort of being one of the most thoughtful people on the nuances of obesity. What did you study in college? Were you a neuroscience major? Biochem, but I had a neuroscience in mind when I was doing biochem. My idea at the time is that it would provide a foundation for going into neuroscience later,

which I'm not sure that reasoning really works out so well, but I worked out okay in the end. And did you go straight from your undergrad to Mike Schwartz's lab, or did you do your PhD with Mike Schwartz or a postdoc? Postdoc. Okay, so where did you do your PhD? PhD was with Alasbada at the University of Washington studying neurodegenerative disease.

Interesting. So tell me about that. Was that a detour that was always part of the plan, or at that point were you not yet fully interested in obesity? I think more of the plan or at that point where you're not yet fully interested in obesity? I think more of the latter, so I've always been fascinated by the brain, but I didn't know which area of neuroscience I wanted to get into. For a long time, I became interested in neurodegenerative disease for a few different reasons. One, they're just absolutely horrible diseases, and to my grandmother had Alzheimer's disease. And in grad school, I was studying neurodegenerative disease, but I wasn't studying Alzheimer's disease.

I was studying a class of neurodegenerative diseases called triplet repeat diseases that includes Huntington's disease, or polyglutamine repeat diseases, would be another name for them. So Huntington's disease is the most common. That's the most common, heritable, neurodegenerative disease. It's an absolutely awful disease with almost 100% penetrance, correct? I mean, it's a deterministic gene. Well, it's actually more complex and interesting than that. It's the genetics of it are real interesting because they are non-mindelian

because the length of the CAG repeat actually changes intergenerationaly. The weird thing about it is there's these CAG repeats that code for polyglutamines, polyglutamines stretches in the protein, they are unstable in replication. And so what you tend to see is an enlargement of these polyglutamine repeats from one generation to the next. So it has this really weird non-mendelian pattern. Okay, you ask specifically about penetrance. I think the penetrance actually is pretty high. So in other words, if you have a polyglutamine repeat in the wrong protein of a certain length, yes, very high likelihood, you're going to develop the disease. But like anything, it is not 100% fixed, but I don't think we

really understand what makes it not fixed. I was studying one of the less common ones called SCA7, Spino-Cerabella, Ataxia Type 7. You know, it's an interesting disease. It's a neurodegenerative disease with some relevance to other more common neurodegenerative disease. I used to joke that there were probably more scientists studying it than people with the actual disorder. I don't think that's actually true, but I think you get the point of the joke.

And I just wanted to study something with greater impact. I've always been interested in fitness and nutrition kind of on a personal level. So when I started learning about the neuroscience of obesity during my PhD work, I got really into it because that was a way to satisfy my criteria for something that's impactful. It's hard to imagine much that's more impactful than that in the world we live in. It's very common. It relates to my interest in fitness and health, and it has a strong relationship with neuroscience.

Once I figure that out, which I think to a lot of people is not obvious the relationship with neuroscience, that's the topic we'll get into. But once I figured that out, I started realizing that not only was this really fascinating, but there was a ton of information in the space that was incredibly enlightening that was not making it to the public. What year did you finish your PhD? 2009, I think. And Mike Schwartz was also at the University of Washington, correct? Correct. What point, as you were wrapping up your PhD, did you connect with Mike, or at least become

familiar enough with his work that you thought, you know, this is kind of my finishing school? I'm not sure. I don't remember exactly what all the options were that I was considering, but I was particularly interested in obesity. And staying at the same institution after your PhD is atypical. It's something that I wanted to do in part for personal reasons. I'm not really a big fan of the typical academic thing of,

it's almost like a military life, you're moving around like five or more times before you finally settle down. So that was part of it's almost like a military life, you know, you're moving around like five or more times before you finally settle down. So that was part of it, but Mike was also a really good fit. And there are other labs that could have been a good fit in other places, but Mike's lab was a really good fit and he was willing, so I did that. I feel like the first time you and I met

would have been at a conference in 2012. Did you just finish your postdoc? Were you wrapping it up then? That would have been close a conference in 2012. Did you just finish your postdoc? Were you wrapping it up then? That would have been close to the end of it. Yeah, I was a postdoc until 2013. So it would have been approaching the end of it. Wow, it's hard to believe it. That's 10 years ago.

I still remember all that stuff pretty well. So let's tell people a little bit about the problem that you work on today. I think everybody knows directionally that obesity is a significant issue, but you can probably quantify this for people a little bit better and help people understand maybe even over a few thousand years how things have changed in terms of let's just talk about the phenotype. We're going to obviously talk about the environment and the triggers, but let's just talk phenotypically how have we as a species? You know, we've been around what, maybe six million years in our current

rendition. But let's change over the last thousand years in terms of our phenotype. If we're comparing the body shape of people in modern affluent societies, like the United States, to what the typical human would have looked like a thousand years ago, I think it's clear that we're much fatter today on average with the much higher percentage of obesity. And a thousand years ago, there was obesity. I mean we have evidence even from Egyptian mummies that among the wealthy there was obesity, not to say that it necessarily was super common, but I don't think it was that uncommon among the wealthy, I think probably for similar reasons that we have obesity today, but certainly the prevalence was much lower. And when we start to

get into the more modern historical period where we start to actually get data on this, the first data that we can find on this in the United States, or at least that I have found, that is somewhat informative, are from Civil War veterans from 1890 and 1900. They did height and weight measurements on middle-aged Civil War veterans. So these people were, I think, almost exclusively white men. However, if you compare to the same demographic, so middle-aged white men today, you see that there was almost no obesity back then, and today the obesity rate

is something like 45% for that same demographic. And just to be clear, we're defining obesity in the most traditional way, which is the use of body mass index, and we're defining it as a BMI of more than 30. Correct. And so the advantage of BMI is it's really easy to measure, and you can calculate it from these really simple measures that go back a long time. Unfortunately, they didn't have Dexa machines in 1890, which would have been, of course,

a more informative way of looking at it. But using measures that we can compare over long periods of time, like body mass index, I don't remember the exact numbers, but it was like a few percent low single digits of people actually classified as BMI over 30 at that time, 120, 130 years ago. And then if we look toward more recent data, the first really good data we have starts in the 1960s for the United States.

That's when the NHES surveys started, which later became NHANES. And in those surveys, what you see is by the time they started measuring it, it had already gone up from that previous time in the late 1800s, early 1900s. So you're saying stuff, and there really wasn't a lot of longitudinal data from 1900 to 1960 to check what that trend line was doing. It was sort of this big effort in 1900 and then another big effort didn't take place till about 1960. I don't know that I'd call it a big effort but the biggest that I'm aware of in the late 1800s,

early 1900s, true representative national sampling started in the 1960s and then got better through the 70s and now we have this NHANES survey methodology that is the best source of evidence that we have. It started getting good in the 60s. And what were those levels there, Sethan in the 1960s? I don't remember the exact figure but it's like 12% of US adults had obesity at that time. Something like that in the earliest measures. And do you have a sense of, because I'm sure this is going to become more relevant today? adults had obesity at that time, something like that in the earliest measures. And do you have a sense of,

because I'm sure this is going to become more relevant today? What is the term that's used if BMI is over 35? Isn't there an extreme category of obesity? More bit obesity is that defined as 35 or 40 or something? The terminology has changed to try to avoid stigma. It has been extreme obesity or morbid obesity. I can't remember what the current term is for it, but yeah, there's a category over 35 as well. There's a class system, so class one, class two, class three. So I think that corresponds

to 30, 35, and 40 if I'm not mistaken. So basically, this progression was not just at the kind of median level, because I'm not mistaken. So basically this progression was not just at the kind of median level, because I'm sure the median BMI was also moving, the mean BMI was also moving, the fraction over 30 and presumably the fraction over whatever that highest threshold is, be it 35 or 40.

Yes, and actually the most extreme changes happened in more severe obesity. Very, very few people had BMI's over 35 in the earliest measures, and then now it's like something like 9% or 10% today of adults. So there has been more movement at the extreme end than at the mean, yes. And that's what happens when a distribution spreads out, which is what happened. If you look at the distribution of BMI's, it used to be a lot tighter, and it just got less tight.

So there are still people who are lean. There are still people in every BMI category, just like there used to be, but since it has spread out, you get a disproportionate increase at extreme values. What about underweight? What was the fraction of underweight in 1900? If we would define that as a BMI below,

I don't know what underweight is, is it below 18 or below 20? And then how has that changed over time? Typically, the cutoff is 18.5, and I don't know the answer to your question. I think it was higher than it is today, but I'm not sure about that. When did people first make the connection that there is an association between obesity and adverse health outcomes? When you think back to a thousand years ago, or back with the Egyptian aristocrats, obesity

probably would have been a sign of affluence, and I don't think anybody would have looked down upon it too negatively back in medical school. I remember learning about gout and how gout emerged around this time. And it was really this disease of excess, right? Alcohol, excess, sugar, excess, protein would manifest itself in gout, and this was the ultimate rich man's disease, Basically a sign of affluence. So I can't imagine people were to upset to be obese back then and of course today We take it for granted despite some of the political pressure to Understandably try to destigmatize obesity and somehow now suggest that it's completely healthy

I think the reality of it is it's pretty unambiguous that obesity is indeed associated with poor health outcomes. When did that become clear? I'm not real knowledgeable about the deep history of this, but I know I've heard that there were physicians in ancient Greece, in India who recognized that being very heavy was associated with health problems, such as having sweet tasting urine, for example, sign of type 2 diabetes or any kind of diabetes. And then there were these insurance life tables in the early 1900s that suggested that people who had obesity had shortened life spans and greater risk of certain diseases. But it actually became pretty controversial with a series of studies that was published. Catherine Flegal was intimately involved in this work, suggesting that there was actually not

the relationship people thought there was between body mass index and mortality. So these studies, this was labeled as the obesity paradox because what they found is that there wasn't really much of an association between obesity and poor health outcomes. And often if you look at the relationship between BMI and mortality, if you just look at a graph of it, the native, the lowest point on that graph was in the overweight range, or sometimes even on the low end of the obese range, depending on what the study was. And they were finding this in metanalces of millions and millions of people.

And so suddenly people were saying, well, maybe higher body fatness is not bad, maybe it's actually protective. So there's been this big debate about it. I think what has emerged in recent years, especially the last 10 or 15 years. And by the way, let me take a step back. The reason this is called the paradox is because there's all this evidence that excess body fat contributes to all kinds of diseases. Type 2 diabetes, cardiovascular disease, certain cancers. And so how could it be protective for mortality

when it's driving all these diseases that are the leading causes of mortality? So that's why it's called the paradox. The research that has come out since then is suggesting that it's probably not a paradox as paradoxes often or not, and that it's an artifact of those observational data. There are probably a few different things going on,

but the biggest one is that people who are sick often lose weight. There are many different health conditions that can cause a person to lose weight. Type 2 diabetes, it's not well controlled, you can be losing weight. Certainly, renal failure, COPD, things like that. Yeah, those are great examples. Alzheimer's disease, cognitive decline, those things can cause a person to lose weight. So there are many health conditions that can cause a person to lose weight.

And essentially, the concern was that makes leanness look worse than it really is because you're getting all these people in the lean category that are lean because they're sick. They're not sick because they're lean. Some people have called that reverse causation. David Allison corrected me. It's technically confounding. You and David and I had a nice email exchange about that because we did discuss this. I'll share with you a very glib example. I had shoulder surgery less than three weeks ago. In the 18 days since I've had my shoulder operated on, I've lost nine pounds.

I don't know what my BMI was before versus after. I probably went from BMI of 26 to BMI of 24. So on paper, that looks good. I would argue there is nothing about me today that is superior in health to where I was 18 days ago. Of those nine pounds I've lost, I'd be willing to bet seven of it is lean body mass. Again, it's a silly example, but it illustrates that one can see an improvement in BMI with probably a deterioration in body composition and an increase in morbidity.

Absolutely. BMI is a crude measure. No doubt about it. It's useful. You talked about this with David Allison in your episode, and I think you guys had a nice conversation, Absolutely, BMI is a crude measure. No doubt about it. It's useful. You talked about this with David Allison in your episode, and I think you guys had a nice conversation, but Cliff's notes is it's useful for a population level study as it can be useful for screening, but it's a crude measure. So how do you get around this issue

of confounding or reverse causality? There are some methods that have been developed for this. One of them that I particularly like was developed by Andrew Stokes and his colleagues, and that is the maximum attained weight method. Instead of using the exposure variable, instead of looking for BMI right now and seeing that how that correlates with mortality

risk right now, you say, what's the heaviest you've ever been? And how does that correlate with your health outcomes? Essentially, that's saying like, whatever health condition you've developed that might have caused you to lose weight, works screening that out. We're looking before that. And when you look at it that way, you get a sharpening of the association between BMI and mortality, and you find that the native, the lowest point, shifts to a lower BMI. So essentially, whereas before it looked like

maybe overweight was the best, now you see that in the lean range looks the best. And there's a stronger difference, a larger difference between being lean and having obesity in terms of mortality. So it really sharpens things up. And the reason that happens is because when he looked into this, you're excluding a bunch of people

who were formerly in the obese or overweight category and went into a lower category. And those people, if you look at their health outcomes, they're terrible. So those people who used to have obesity and now just are overweight or are lean, those people have massively elevated rates of chronic disease and of mortality.

They're essentially bringing all this excess mortality into lower weight categories. Why is that, Seven? Because that's almost sounds like the worst news you could ever hear, right? It would suggest that if your BMI is 33, all hope is lost that your fate was sealed the moment you hit that BMI, you know what? Just dig in and eat more hog and does because if you bring that BMI down to 26, you don't assume the health of the 26. You bring the health of the 33, which that doesn't sound right either, right? No, it's not right.

And this is another limitation of the observational data. It's hard to lose weight. It's hard to lose a lot of weight. It's hard to keep it off. It's hard to go from 35 to 25 BMI. That's a lot of weight loss. Most people, frankly, are not able to achieve that and maintain it. Through voluntary means. And so these people who are losing weight, it's predominantly unintentional weight loss.

This is not people who start a diet and lifestyle plan and lose a bunch of weight. This is predominantly people who are losing weight unintentionally. And as a doctor, I'm sure you know this, when a person starts losing a bunch of weight for no reason, that's probably not a good sign, right? Absolutely. Even if they start off overweight and they're lean, maybe they even look good, that's probably gonna start ring alarm bells.

So if you look at studies that have measured the impact of intentional weight loss on mortality, this has been done both for diet and lifestyle weight loss, randomized controlled trials. So we're talking about good quality of evidence, and also for bariatric surgery, you see a reduction in all cause mortality. That's also going to ask you, I was going to say, how does bariatric surgery and how does some agglutide affect this? It's too soon to say, but when we start to look at, I was going to say, how does bariatric surgery and how does some agglutide affect this? It's too soon to say.

But when we start to look at what I think is the most impressive weight loss drug out there, and then of course when you think about ruin-wide gastric bypass, which has been around for a while, it'll be interesting over time to see if that can flip that paradigm. We have data for type 2 diabetes. For people with type 2 diabetes, for somagletite, and it does reduce all the cause mortality in meta-analysis of randomized control trials. So it will be interesting to see whether that extends to people without type 2 diabetes. Obviously, people with diabetes are probably going to benefit the most from that kind of drug class in terms of the physiology of it, but there are promising signals that at the

very least it's probably not going to kill you. We go from the 60s to the 70s to the 80s. When does it really, from an epidemiologic standpoint, just completely take off? If I remember what you said, I'm going to go back in the 60s, we might have been at 12% obese. And today it's hard to imagine such a low figure, given 40 to 45% today. 43 is the latest.

Not that I don't believe it, it's just hard to fathom that nearly half of the US adult population could have a BMI above 30. When did it really hit its stride? This is an interesting question. Probably a lot of people listening will have seen graphs of Enhan's data where it kind of spikes around 1980.

But the interesting thing about that is that point around 1980 is actually the average date of that survey. But it was actually a multi-year survey. It was a survey that started, I believe, in 76 and ended in 84, something like that. I don't remember the exact years, but it was a range. That's how the N-hands used to be. Today, the range is much narrower, but at the time, it was a broader range. And so, what we're seeing is we can turn that into a point and put it on a graph, but really it represents a range of years. So we don't know exactly when it happened,

but if you look at the average value for that, it's I think 1978 is the average value for that survey, the average year, but we don't know exactly where in there, it started to turn up, and we don't really know how sharp it was because we don't have that resolution. It looks real sharp on the graph.

Again, when you make it a single point, it looks sharp. But we don't really know exactly how sharp it is. Anyway, I'm kind of putting a lot of nuance into this, but to answer your question and it's... Well, it is actually an important point because I know that many people, I've probably been guilty of this myself 10 years ago, would also look at changes in macronutrient composition that occurred around the same time and say, boy, it's hard to uncouple those. But in reality, if they occurred over a different time scale, it might make that correlation

a little less robust. We have a sharper focus on the changes in dietary intake because we have annual data from the Economic Research Service, USDA Economic Research Service. The data on BMI are less sharp. So I would say that those two changes are absolutely compatible and on a logical level. I'm sure they're related.

You see big changes happening around the same time in the diet. To give a kind of simpler, hopefully more satisfying answer, sometime around between the late 70s and the early 80s, we see an uptick, an apparent uptick in the obesity rate. So the rate starts to increase, goes up and up and up, and then there's a couple of places where it slightly goes down for a year or two, and then it keeps going up. It looked like it was going to plateau or maybe start going back down, but really in recent years, it's really just been skyrocketing. So essentially from somewhere in the late 70s to early 80s to now, we went from something like 15% of obesity to 43% of US adults and I want to point out something else too that I think is relevant.

One way I like to think about this is the lifetime risk. So that's just the population prevalence. That includes people who are 20 years old. That's a snapshot. That's includes people who may be growing into it. Exactly. If you look at the lifetime risk, I don't know what the exact figure is, but I think it's well over 50%. So I think more than half of US adults will be classified as actually having obesity at some point in their life if the current context is maintained. And you see the same thing for type 2 diabetes.

The prevalence of all diabetes is something like 10 or 12%, but if you look at the lifetime risk, it's like double that. Maybe even more, I can't remember what the exact figure is, but it's mind-blowing. The number of people who will, at some point in their life, develop type 2 diabetes. If you take a 50-year look at the change in type 2 diabetes prevalence, so the snapshot, I believe it's a five-fold difference in risk over 50 years. The past 50 years. So you go back 50 years ago and look today, just the prevalence delta is 5x. I could believe that. So you have to then look at what does that rate of change tell you about lifetime prevalence. What does it tell you about a person who is only five years old today, or a person who's 15 years old today? I haven't done the math, but I would completely agree that their lifetime risk is probably at least

one in five of having type two diabetes. This has been quantified. I tweeted out a paper about this a while back, and unfortunately I don't remember the top line figure, but there are actual data on this. What about the rest of the world? Where are they in relation to us? We probably led the way, along with a handful of other developed nations. But one of the things that seems to have changed is this is no longer a condition of affluence, at the individual level.

It really hinges on how we define the term affluent. Because if you go to the very poorest people in the world, there still is not a lot of obesity in those places. Places that are really challenged with food security, where the diet is very limited, like subsistence farmers in sub-Taharan Africa, you're still going to see that there's a low prevalence of obesity in those places. Sorry, I think what I meant was at the individual level.

So if you look at the United States from the bottom 10% of the population economically to the top 10% of the population economically, is there a difference in obesity there? Bottom 10 to top 10, you would see a difference. If you're looking in turtiles, so just bottom third to top third, there's very little difference actually. If you start slicing and dicing it by very little difference actually. If you start slicing and dicing it by sex and race, then you will start to see larger differences emerged. For example, women who are in the top turtile are leaner than women in the bottom turtile, but there's no difference for men in terms of income. So you can start to find patterns when you slice and dice, my overall feeling though is that there

is no demographic in the United States that has not gotten a lot fatter over the last few decades. Even though if you look at certain demographics particularly with regard to education, you're going to see gradients emerge, but even among highly educated people, you're going to see a higher prevalence today than there was 50 years ago. So, let's not bring this up to your work. What did you do when you got to Mike Schwartz's lab? How did you begin your re-education around neuroscience as it applies to everything that

has to do with obesity, which let's just talk about this. There's an input side and an output side. Rudy was on the podcast, God's probably been two, three years ago, so maybe it's worth a refresher on the neurobiology of how the different parts of, for example, the hypothalamus can regulate, energy expenditure, can regulate appetite,

and what we can learn under very, very controlled experimental settings with animals, and then how we can start to think about how that applies to humans with a primitive brain in a modern world, sort of speak. I want to take a little step back before getting into that and say, answer the question of, what does the brain have to do with obesity at all? Just to make sure we're bringing everybody along. I think it's not obvious to everyone what the brain might have to do with obesity, but I think if you start to think about it, it becomes pretty obvious that the answer is just about everything. And the reason is that the brain is the organ that generates behavior. If you think that behavior of any kind relates to body fatness, how much we eat, how we use our bodies, how we sleep, whether we're stressed or not, if we think any of that relates

to body fatness, then we think the brain is laying a role. I think most people would agree that food and take quantity and quality is pretty important. There, the second reason is that the brain actually contains a regulatory system for body fat, for body fatness, I should say, body fat mass. And it's the only known system in the body that does that. And it's located primarily in a part of the brain called the hypothalamus, which is, forget who described it this way. It's maybe it was permanent cancer.

It's like a water bubble gum on the bottom of your brain near where your optic nerves cross. So it's this little tiny part of the brain that specializes in homeostasis, maintaining the stability of body systems. I was described as a walnut. A walnut, okay. So just to give you an example, it's the part of the brain that regulates body temperature. And there's a thermostat in there, effectively a thermostat and thermometers. There are

thermometers that measure your core temperature, there are thermometers on your skin that measure future threats to your core temperature. Like if you jump into a cold lake, your core temperature doesn't instantly drop, but your brain knows that it will drop because of the temperature sensors in your skin. And so it can respond adaptively. And then that system in the hypothalamus engages a suite of behavioral and physiological responses to maintain temperature homeostasis. On the physiology side, you get waves of constriction, you get non-shivering

thermogenesis through brown fat, you get shivering, and then through the behavioral side, you want to get out of the cold water, you want to put a sweater on, you want to drink some hot tea, you want to adopt a heat-conserving posture. And through this coordinated physiology and behavior, you get incredible regulation of temperature, of core temperature, I should say, plus or minus one degree Fahrenheit, when the exterior temperature could be varying by 50 degrees. It's an incredible regulatory system, and the body fat regulatory system, unfortunately, is not so precise But I give that as an analogy just to give you a sense of what the hypothalamus specializes in

There's also a regulatory system for body fatness and a nice name for that is the lipos stat So lipofat stat the same and Really we've known about it since stat, the same. And really we've known about it since 1840. Or we've known there was something going on since 1840 when the Viennese physician Bernard Moore published a case study about a woman who had extreme obesity, rapid onset, extreme obesity. He did an autopsy after her death and she had a tumor in her hypothalamus. And to this day, hypothalamic obesity is a thing that we have to deal with with people with tumors or other damage to the hypothalamus, it often causes extreme obesity. And what's the nature of the obesity? How much of it is due to hyperphasia, excess eating? How much of it is due to loss of activity or even just a shutdown of metabolic rate?

If you look at probably the closest experimental analog of hypothalamic obesity that sort of human like hypothalamic obesity would be VMH lesion. So this is something that's been done since I think the 20s. They go in with a very precise instrument called the stereotaxic instrument in animals and they lesion this part of the hypothalamus called the ventramedial hypothalamus. They're trying to replicate the damage of hypothalamic obesity. As soon as the anesthesia wears off these animals are cramming food into their faces. As soon as the anesthesia wears off, these animals are cramming food into their faces. And if there's no food in their cage, they'll eat bedding. They will just like put anything they can get a hold of into their bodies. And they will continue binging until they have rapidly gained a large amount of weight,

and then it will start to plateau off. But they have extreme hyperfagia. The first experiments that were done on this showed that if you restrict them to a normal level of calorie intake, so that of a non-lesient animal, it prevents the fat gain, suggesting that I should rephrase it. It prevents the weight gain, so they were just weighing them at the time, suggesting that it's primarily phenotype of hyperfagia. However, later experiments that were more precise found that it doesn't completely eliminate

the weight gain. It only eliminates about 80 percent of it. And so there is a component coming from energy expenditure, primarily hyperfagia, but there's also an energy expenditure component that's smaller. It's funny. I just remember in medical school, one of the neurobiology professors saying, if you were asked to give up a piece of your brain, if you had to give up like one cubic centimeter of brain tissue, you just fight like hell to make sure you preserve your entire hypothyroidism. I agree with that. I would say the brain stem and the hypothalamus probably not places you want to lose. Let's go a little bit further. You referred to the lipostat.

So say a little bit more about what we've learned about this lipostat and what circulating factors might play a role in governing this and what's been learned through some of the work that was done using parabiosis. I'm going to give you the simple version. There is a more complex version that is emerging, but I'll start with the simple version, which is that it is a negative feedback system similar to your home thermostat, similar to the thermostat in your brain, in that the hypothalamus measures levels of a circulating hormone called leptin that circulates in proportion to your body fat mass.

So the same way your home thermostat measures the temperature in your home, your hypothalamus is measuring the level of leptin in your circulation. Still some controversy about how exactly or where that measuring happens, but the signal gets to the hypothalamus. And it uses that to determine whether you essentially have the amount of fat that your hypothalamus wants you to have. So the same way that your thermostat has a set point and your internal thermostat and your body has a set point, your hypothalamus has a certain idea of how much fat it wants you to have on your body.

If you deviate from that, it starts to engage a coordinated series of physiological and behavioral responses to restore the previous level of body fat. This system works better at protecting against fat loss than it does against fat gain. And certainly over long periods of time, we see that the average person in a country like the US tends to gain fat, the life of stat is not stopping them, or at least it's not preventing them. It might be resisting, but it's not stopping

the process of weight gain. But we see that it actually is quite vigorous at defending against weight loss. This is part of the cruelty of the unfairness of how obesity works is that your set point where your defended level of body weight controversy about what to call that, but whatever it is, it goes up. A person with obesity, their body, defends against weight loss as if they were starving, just like a lean person losing weight, their body and brain would defend against weight loss.

It's literally a starvation response. It's the same behavioral and physiological process that ramps up your hunger that makes you more focused on food cues, greater cravings, it down regulates your energy expenditure, and does everything it can to try to bring the fat back. So that is a key reason and possibly the primary reason why weight loss is so difficult and so temporary. There was no regulation happening. Weight loss would probably be pretty easy, and weight maintenance certainly would be very easy.

But it's not, you see that people tend to regain back to their former level, unless they're being really well supported in that weight loss. And even then, there's usually some amount of weight gain. Weight regain, I should say. Let's go back to leptin for a moment. So leptin is a hormone, is it made in the adipocyte? It's made in the adipocyte and secreted in proportion

to body fat mass. So the more adipose tissue you have, the more leptin you have. Is it generally pretty static? Does it change with meals or exercise or anything like that? Yes, it does. So over the long run, the amount of leptin in the blood stream is strongly correlated with fat mass.

However, it's also strongly impacted by short-term energy balance. So if you, let's say, cut your calories by 25% for a couple of days, you're going to see a drop in leptin that is disproportionate to your amount of fat mass. So where is the leptin receptor? Is there a leptin receptor in the periphery or are they central? There are leptin receptors in many parts of the body, but the ones that are relevant for body weight regulation are in the brain. Are they in the hypothalamus? There is a high concentration of leptin receptors in the hypothalamus, yes.

There are leptin receptors in other parts of the brain too. However, it's not 100% clear where the important ones are for body weight regulation. Probably somewhere in the hypothalamus, but there are a lot of different papers where they take mouse models, and they knock the leptin receptor out of different cells in the brain. If you knock the amount of GABA urgic cells,

basically you recapitulate animals that don't have the leptin receptor at all in terms of their body weight. GABA urgic, that's a major, one of the two big neurotransmitters that's the main inhibitory neurotransmitter in the brain. And then you can knock it out of certain cell subtypes in the hypothalamus and get big effects.

There was a paper suggesting you can just knock it out of AGRP neurons and recapitulate the obesity phenotype of animals that have no left and receptor. However, that is controversial. Not every paper has shown that. I'm not sure what people who are on the cutting edge of this field would say about where that evidence is, but certainly there are cell populations, and probably the most important ones are in hypothalamus. There are cells in the brain, probably mostly in the hypothalamus, that are receiving that

signal and conveying it to the key cell types that are kind of at the center of this lipostat, which are agRP neurons. I refer them in my book as MPY neurons just for storylines and simplicity, but more commonly they're called agRP neurons and POMC neurons. So the AGRP those are the hunger neurons the POMC are the satiety neurons or you could think of them as hunger slash body fat increasing neurons the POMC or the opposite essentially What is leptin resistance and how does it manifest, why does it manifest, and how frequent is it? When leptin was discovered first in 1994 by a team led by Jeff Reedman and Rudy Leibal,

they found that this was the gene that was missing in an obese mouse model called the OB-O-B mouse. Animal was extremely obese as a result of lacking a defect in the production of this protein. One single base pair that destroyed this protein and caused the loss of function in this massive obesity. And when this was discovered and also discovered that humans have leptin, then it was like this scientific bananzo. It was like, well, maybe we've discovered the cause of obesity.

Maybe people with obesity don't have enough left in. And so their brains think they don't have enough body fat when really they do. The failure to perceive the body fat, that's what causes obesity in these OB-OB mice. So they started measuring leptin levels and people with obesity and it turns out they were actually elevated because it's correlated. We now know it's correlated with fat mass. What's the deal? If this is a hormone that regulates body fatness, why is it that people with obesity have so

much of it and it's not suppressing their excess body fat mass. The concept that has been invoked to explain this is leptin resistance. So in the same way that people can develop insulin resistance where it takes more insulin to do the physiological jobs in the body, people with obesity require more leptin for the hypothalamus to be satisfied. Another way to say that, they require more leptin to avert the starvation response that the brain has where alarm bells start going off because it thinks you don't have enough body fat.

So they require more leptin to achieve that state. So we call that leptin resistance, but we don't really know how it works yet. That's just a general term for requiring more leptin to avert the starvation response, but we don't know whether that is something where there's fewer leptin receptors on certain kind of cell, whether there's a downstream signaling impairment in serosellular signaling cascades, whether there is a change in cell-to-cell communication. Maybe the cell that's receiving a leptin is getting the message just fine, but there's some kind of downstream change in neural processing where the signal gets clouded or modified. We don't know

the answer to that question. It seems like the only thing we know is it's not too low an amount of circulating leptin, as evidenced by two things. not too low an amount of circulating leptin, as evidenced by two things, one, the high circulating levels of leptin. And the fact, I think more importantly, that when you give exogenous leptin, it doesn't improve the condition, suggesting that that's not the defect. Yes, you can give high levels of leptin, and it will cause weight loss, but it doesn't do much. If you look at leptin signaling,

there were some early studies done in animal models suggesting that if you mash up the hypothalamus and you look at what's going on in it broadly on average, you find that the amount of leptin response, the intracellular signaling cascade that's activated by leptin is not really impaired in animals with obesity. It's like they're getting the same leptin signal from a much higher level of leptin. I looked at some twin concordant and discordant studies, identical twin, and I was

surprised to see, maybe I shouldn't have been surprised, but I was surprised at how heritable obesity was. It was about 0.7. When you see heritability of 0.7, that tells you something is very, very genetically predetermined. So even though 100 years ago, virtually none of us were obese, and today, let's just call it your lifetime incidence of obesity is 50%. Our genes haven't changed in 100 years. So clearly, our susceptibility for obesity has been with us for a great period of time, and it is highly, highly preserved. It's just that in the last, whatever, 40, 50 years, we now have matched or mirrored our

genes to an environment that is allowing that trait to flourish. What do we know about the genes that regulate obesity? Or fatness? Let's just talk about it through that lens, I suppose. The meta-analysis of twin studies that I like to cite these days suggests an average heredibility of 75%. Wow, that's even stronger. It's massive.

And there's some debate about that. But, directionally, this is a really big deal. It's very heritable, and a lot of things are very heritable. I think that's one thing we're learning. So, you have this very high heritability of body mass index, variation between individuals and body mass index, about 75% of those differences between people is explained by their genetics.

That's what that implies. If we look at other methods that I've tried to figure out, what are the genes that underlie this? What are the genetic differences? These are the genome-wide association studies that I think are particularly informative in this regard. They simply ask the question, if we look at the entire genome and we look at these

representative genetic markers where different people have different genetic code called SNPs, single nucleotide polymorphisms, where in the genome what markers correlate with differences in body mass index. Fortunately, body mass index is really easy to measure, so you can get really big sample sizes in these studies, which you need to get statistically significant results. Because you're looking at, I think, millions, I don't remember exactly how many, but you're looking at a lot of genomic markers, so you need tremendous statistical power to detect anything with the high level of confidence. So you have these studies, I think the latest is like 800,000 people. The leader of the pack is the height genome-wide association study.

I think they have like 3 million. And now they've saturated the hair ability, they've gotten all the information they can with that sample size out of what the common genetic variants are that correlate with differences in height. I think with body mass index, we may, in the near future, we may saturate it as well. We may know what are all the common genetic differences that correlate with differences in body mass index. So far, these studies have identified 900 variants that differ. What this suggests is that differences in body mass index between individuals are very complex, that genetically very complex are determined by a lot of different genes with very small effect sizes. So you get this sorting of all these different genes

and whatever combination you get, lucky or unlucky, determines whether you're to a large degree, determines whether you are susceptible or not susceptible to obesity in a fattening environment is the way I would put it. So they have various ways of looking at what these genes are doing because that's one way you can use these genome-wide association studies. That's particularly informative. You could say what's the underlying biology that makes some people fatter and some people slimmer. And I want to talk a little bit about why this is such an important approach.

One is that you're looking at people in their regular everyday context. This is not an artificial lab scenario. You're just looking at people living their lives and experiencing higher or lower weight, and you're saying what genes correlate with that. So it's very naturalistic. Second, it's very replicable. These studies are highly replicable. In other words, if you do three studies of this nature, you're going to tend to get similar

results. So the methodology, it's one of the most rigorous, I would say, in the biological sciences that we have. And the third one is that it's unusually objective as well. It has a higher level of built-in objectivity, resistance to bias, compared to other types of investigation, because it's not hypothesis-driven. You're just looking across the whole genome

and seeing what pops up. You're not saying, I'm going to focus on the connection between x biological process and y outcome. You're just saying, I'm interested in y outcome, what correlates with it, and let's see what biology pops up could be anything. We're just going to see. That really gives you a chance to, I think, check your thinking on what the underlying biology is in various traits and diseases. Part of that comes from the strength of what ultimately makes genetic analyses like Mendelian randomization, so powerful, is the genes are randomly distributed. That's what cleans out some of those biases is when you are looking at a million people for who the genes are randomly spread across them and you take an unbiased view of the sample

and then you get those results over and over and over again I think it becomes very powerful and look if people are listening to us saying God What are these guys talking about? I mean, I think it's just important to understand the big picture here The big picture here is a thousand years ago, two all intents and purposes, none of us were obese. But that still means, directionally, 50% of us, at least had the genes that would allow us to become obese in an obese adgenic environment.

That's really what we're explaining here, is that there are a highly, highly heritable set of genes that will allow a subset of the population. And actually, one of the things I'm just curious about your thoughts artilologically, why is it 50 percent? Why isn't it 100 percent? Was this just a fluke of evolution? You would almost think that evolution would have wanted everybody to have those genes.

Since you want to step back a little bit, I just want to also add. What we're talking about is why some people can effortlessly stay thin and other people have to really struggle to maintain their weight and maybe are not able to. That's kind of like the everyday thing that we're trying to explain here, that many people recognize intuitively, that is a thing that different people have different propensities for becoming obese, for developing obesity or not. So we can look at the underlying biology and that's been done, and there are a couple different ways you can do it.

One is you can say, what are the genes that seem to be associated with these genomic differences and where are those expressed, What tissues are those expressed in? There was a paper where they looked at I think 43 different traits of all kinds, diseases, personality traits, other stuff, and they asked what does the tissue enrichment look like? And if you look at body mass index, it looks like psychiatric diseases and educational attainment. All of those are heavily enriched for brain-related genes to a similar degree. So conditions that we know are related to the brain like educational attainment, how many years of education you have attained, whether you are susceptible to schizophrenia, depression,

Tourette, like all these brain-related conditions, obviously the brain shows up in genome-wide association studies for those conditions, and you put those next to body mass index and you couldn't tell them apart. That's how heavily enriched for brain-related biology body mass indexes. And those diseases, by the way, that you just mentioned are some of the most heritable diseases we see in medicine. I mean, when you look at autism, when you look at schizophrenia, these have heritability indexes of 0.6 to 0.7.

They're highly genetic conditions. So there's two things going on, right, which is you have these parallel things that are highly, highly genetic, and then they're disproportionately concentrated in the brain. That's right. And I don't want to say that it's literally 100% about the brain. I think that's unlikely to be true, but it's certainly the primary signal that emerges across the literature. And so I think that really validates this idea of the brain being important for body

fatness. And if we look a little bit deeper at what is going on, for a lot of it, we don't really know. We don't really know exactly how the brain is doing this, what it is about these genes. But we can see that it correlates with certain types of ways of interacting with food. So people that have obesity promoting genes tend to have greater eating drive, they tend to have lower satiety, but this is an area that hasn't really been very well explored yet. So there's a lot we don't know.

However, if you look at the monogenic obesity syndromes, so where there's one mutation that causes severe obesity, those really revolve around the leptin brain signaling axis. So those mutations tend to be in leptin, the leptin receptor, melanocortin, melanocortin receptor that are downstream of leptin in the brain. And those types of signals also show up in the genome-wide association studies, but they're not dominant. A lot of this stuff is really general. It's like stuff that affects general neuronal development and neurotransmitters that are involved in a lot of stuff. So I think there's a long way to go before we really understand

exactly how those genes are affecting the brain in a way that impacts body fatness. But I do think we can say that differences in body fatness between individuals are primarily determined by differences in how the brain is constructed and how it operates. So, Stefan, let's now go back and try to put all of this in the context we were just ready to get to a moment ago, which is, it's 250,000 years ago. For all intents and purposes, we're the same creatures we are now,

obviously, minus the environment that we live in. But food and energy are one of our top priorities. I'm not an anthropologist, but you know, it have to seem to me that security from other tribes and animals and the environment, right, whether acquisition of energy and reproduction were kind of the only things that would have mattered. There probably wasn't a lot of other stuff that mattered at the time. And acquisition of energy was

essential in that it could kill you very quickly if you failed to do that. So acquiring energy, storing energy was the struggle that defined us, probably in the short-term much more so than reproduction, which obviously is a huge other contributor here. So we evolved over millions of years and everything you said about leptin now starts to make sense in that environment. Leptin is a signal that says there's not enough energy, and that's what should really trigger the response. So in that sense, it's not surprising that leptin isn't doing the opposite. It's not surprising that high leptin doesn't make you want to stop eating.

It's who cares? Nature wouldn't have cared about that. But it certainly would care if leptin gets too low. That should be a screaming signal to go and eat. Resist that sign. What do we know about the efficiency with which we store energy? I mean, we haven't really talked about that, but the ability that we have to get fat is kind of a remarkable thing. We don't really store carbohydrates, can't really store protein, and we don't want to be breaking down muscle to get amino acids. So we do really have to rely on this ability to store fatty acids and excess carbohydrates as fatty acids in a relatively inert structure of white adipose tissue, yeah?

I think Herman Ponser would be a great person to talk to about this. His book is on my list to read and I definitely plan to have him on to get into this. Yeah, he has some good thoughts. John Speakman has some good thoughts on this as well. Another person I should probably have on the podcast. There are good reasons to have a certain amount of body fat. The basic idea is pretty obvious. You want to have a way to cover your energy needs between eating opportunities.

We have other energy reserves, we have glycogen, but they're just far more limited. The thing that's awesome about fat is, first of all, it's a very concentrated source of energy. Dietary fat is nine calories per gram, carbohydrate is four, protein is four. It's anhydrous, there's no water. Exactly. Literally just pure energy. That was the second thing I was going to say

is that it's hydrophobic. And so you can store it without having to hydrate it like you do with glycogen. Glycogen, the weight of glycogen, I think, is mostly water. Three or four to one water. OK, there we go. And then the weight of adipose tissue, even if you include all the interstitial stuff and all that,

I think it's like 85, 90% here or fat. So the energy density is just off the charts relative to any other storage method that the body has. And so it makes sense that that's kind of our long-term energy buffer. By the way, just for people who think about EVs and stuff, there's no battery that can come close to the energy density of our fat, just to put that in perspective, or any hydrocarbon for that matter. Yeah, that's right. So I think the importance of that is obvious to have a way to cover times when you don't have as much energy coming in as you would like. And in the evolutionary context, the thing that comes to mind from our modern perspective

is whether they find food or not, but there's also the question of illness. And I think that's a really important one. So if we look at the primary causes of mortality in children under five in low income settings. What we see is that it's strongly related to their weight for height, which is kind of a different way of measuring BMI. And it's also strongly related to disease pressure, especially diseases like diarrhea that interfere with nutrition. If you look at the correlation between weight for height and mortality, there's a massive correlation. So kids who have malnutrition, moderate or severe

malnutrition, that's what we call being underweight to a certain degree. They have massively increased mortality because basically if you don't have those energy stores, you can't defend yourself against infections. It's not just about energy. There are other nutrients that are important, vitamin A and some other things, but energy is huge. And so because it's such a huge source of mortality, especially in kids, there's this massive selective pressure to maintain a certain amount of energy storage in the body.

So that would be an example of a selective pressure that would select for a certain amount of body fat. And it is interesting in this regard that humans have a lot more fat than our closest primate relatives. So chimps are like mid-single digits fat and they don't develop obesity. They cannot physiologically develop human like obesity is my understanding. We're kind of special physiologically in our capacity for fat storage. Has anyone ever looked at different ancestral populations? This might be just irrelevant to do because we don't have enough data where there were different amounts of food scarcity

and seeing if there's an inverse relationship between the food scarcity that that population emanated from, whether it's this part of Africa versus that part of Europe, and how that translates into the genetic predisposition to obesity in their modern kin today. I don't know the answer to that. But you understand the question I'm asking? Yeah, it does a history with starvation select for more obesity type genes. For even greater obesity today, exactly. I know that John Spieckman has argued against this idea. He has pointed out that apparently people with obesity do not survive famines better than lean people, which is

kind of counterintuitive. I'm not sure why that would be. I know that's a point that he's made. So anyway, that's about all I know about it. I don't really know the answer to that question. So let's start to talk about the hedonic aspect of food. We have five tastes. We can taste sweet, sour, bitter, salty, and umami. Those are the things, the five things we taste. What's the best way to describe umami to somebody? It's a meaty flavor that is present in cooked meat, bone broth, soy sauce. Okay, so I think people kind of get it. It's distinct from salt, I think, is an important point here. Yes.

Although they often go together. And now different parts of our tongues have different, we sense, for example, sweet on the very front of our tongue, I recall, but that's about the extent of my knowledge and recollection of where our tongue resides in that. But what does the taste that we experience today, you and I, if we go out to a restaurant, how does that compare to the range of taste that our ancestors experienced? This brings up the topic that I like to talk about because if you look at what hunter-gatherers actually eat, let's say we're looking at contemporary and historical hunter-gatherers where data have been collected and using that as a proxy for types of food that our ancestors would have eaten.

It is radically different than what we eat today. In many ways, but one of them is the hedonic properties of it. If you look at what the hodza eat, they go out and kill an antelope. They just like cut off pieces of meat and throw it in the fire or put it next to the fire in coals. They don't have sauces, they're not putting salt on it. And then they just like cut off the charred parts and eat. And sometimes it's like half raw on the inside.

They eat rotten meat that we would consider literally rotten. They will eat. I was just thinking about that the other day, by the way, because I eat so much wild game that I've killed, but I realize like I'm still a baby because, hey, I cook it, because I eat so much wild game that I've killed, but I realize like, I'm still a baby because, hey, I cook it. I don't need it raw. But more importantly, to your point, I season it, right? Like I use salt. I use pepper. I put lemon on it.

I'm sure it would taste fine without those things. It would certainly be edible. I just don't do it. That's right. And if a person, a typical person were to try to eat at a hodza camp for like a week, I think it would be really challenging for them. Even meat, as you said, cooked unseasoned, doesn't taste bad, wouldn't taste as good. But now imagine like the outside is charred, inside is half raw, you're brushing sand off of it. That's kind of the context. That's the meat.

That's like one of the most palatable things they eat. And then we have probably the most palatable thing. And certainly the thing that they really like is honey. But they're not putting it on toast with butter on it. They're literally drinking it. It's great. They're just taking the honeycomb, eating it, and like drinking the honey. So it's a bit of a

different scenario even there. They eat a lot of beobob. That is a very fibrous fruit that has sweetness to it, but it also has some off-lavors. It's not a very sweet fruit. It's not like an apple. It's got a lot of fiber. And then there's the tubers, which is another major article of diet. And to be fair, this is their least preferred type of food. Oh, it is. They would rather eat things other than tubers. But they roast these things in the fire. They dig them up.

They're these like long stringy things that look like long sweet potatoes. There are multiple species, but that's one of the common ones. And they're so fibrous that they actually have to spit out a wad of fiber after they're done chewing it. So it's like a sugar cane or something where you suck out the nutrient, but you're spitting out the pure, unsolvable fiber. Yeah. And so they're not sitting there or sauteing onions on the stove.

They're not putting sauces. They're not spicing. They're just taking food out of nature and cooking it and eating it. It's just a radically different type of diet than we're accustomed to. I think in this regard, it's interesting to consider how rewards circuits adapt to that. Basically our brains are set up to not be satisfied with ordinary stuff once we have gotten good stuff. It's a simple way to put it. Michael Crashes did a really interesting neuroscience study on this in mice. Mice normally they eat these unrefined food pellets that would be like the default diet, but they much prefer these calorie

dense refined high fat pellets. If you give that to them, they will very much preferentially eat that over the healthier, unrefined pellets. What happens is they actually neurobiologically devalue, if you look at the circuits, activity of their reward circuits, once they've been exposed to the preferred food, they devalue the less preferred food. So it no longer satisfies them, no longer motivates them in the same way that it did

before they were exposed to the highly preferred food. To bring this back to our context, if you have somebody like you or I who's been raised in a context where we have tasty, calorie dense, easy to eat food, and that's how we were raised, then going back to eat food more like how our ancestors would eat is really difficult. Why you've mentioned the calorie density. So let's now talk about that because that's kind of different from taste.

The taste thing is interesting to me. This is something you and I actually remember speaking about probably one of the first times we met, which was, I actually think table sugar is disgusting. Like I truly do. Like if you put a bowl of that white crap in front of me and said, dip your finger in and eat it, like it maybe do it once. But that's about it. If you said just mix it into water and drink it, it's gross.

Taste fine and coffee and tea, but just by itself, it's really disgusting. And similarly, if you just have me eat lard, it's really disgusting. Despite the fact that I was on a ketogenic diet for three years, I never developed a taste for putting coffee and butter and things like that. But I freaking love ice cream. I think ice cream is about one of the most beautiful tastes in the world, everything about it. And it really isn't that much more than sugar and fat. I mean, yes, there's some flavors to it, and if you make it a coffee, ice cream, I like it even more. But so I guess my question is, can you walk me through

what my brain is doing when it's tasting sugar, when it's tasting butter, neither of which by itself, I find remotely enjoyable. But then when I'm tasting ice cream, because the ice cream is not that much more caloric than the butter, there's something I'm trying to understand here, which is taste and energy density and how are those figuring out because I believe they are instantly rewarding. So I'll give you one other analogy here. I remember when my daughter, who's now 13, turned six months old. And my wife and I were really fistidious about not feeding her any junk. Fortunately, my wife was able to breastfeed so she didn't have all that formula. And we were like your typical idiot

first parents. We spent way too much time thinking about what she was eating I'm sure. But on her six month birthday we got a ice cream. So this is kind of an interesting experiment right like she's never experienced anything like this. So I take a little ice cream cone and I put it up to her face and I still remember where we were sitting in Delmar when I did this. Stefan, we're talking in milliseconds response from her. Milliseconds, her eyes opened wider than they've ever opened and she couldn't get into that thing fast enough. So to suggest that that isn't her brain responding is crazy.

There's nothing in her periphery in the moment that governs that response. So whatever ice cream loving jeans I have, she got them. So I'm in a hard degree on ice cream. It's really for me, like, almost drug-like the effect it has on my brain. This brings up a couple of interesting questions. So you're alluding to the fact that sugar and pure fat are very calorie dense. So if our brains are wired for calories, why are those not very motivating, which is a great question. So I'll start with that.

And the reason is that this starts to get into the complexity of it. There is an optimal concentration of these nutrients that is not 100%. A great way to illustrate this would be with salt. Eating straight up salt is not something that most people would enjoy, like eating spoonfuls of salt, it's horrible. But at the right concentration, it's excellent. It really enhances food. And so that's actually generally true about all of these nutrients.

It's true also about carbohydrate and fat. A term that's been used for that is the bliss point. So there is an optimal concentration for enjoyment and presumably also for reinforcement, which is that dopamine release that sets your motivational drive and helps you learn and form habits. Ice cream, if you take out the sugar, probably wouldn't taste bad without the sugar, but not nearly as good, right? If you take out the fat, fat-free ice cream is not flying off the shelves, even though it does exist. It's really that combination of the two that really puts it over the top and that's generally true. When you look at the types of foods that are most commonly associated with strong cravings

and loss of control over eating, so like addictive like behavior, you see that generally the foods that are cited are combinations of carbohydrate and fat. Usually there's other stuff involved, there's flavorings, there's salt in the savory items like pizza or french fries. So sweet or savory generally they're combinations of carbohydrate and fat. Again, it just relates to the fact that there is an optimal concentration of these nutrients in terms of stimulating our reward centers. What you see in modern foods that have been crafted to maximally stimulate enjoyment and motivation, either they've been crafted by food industry or by grandma,

passed down through the generations of recipes, what you see is that generally these items are hitting multiple bliss points at the same time. That's just not really a combination you see in nature. You don't see foods that are as reinforcing. The closest we would come is like maybe certain types of nuts would have some carbohydrate and some fat together, but we really don't see anything that really hits the high points as much as the foods that surround us today. Let's go back to our ancestors for a moment. What apparatus was at their disposal subconsciously or consciously to help them understand and prioritize colorically dense food. Because I got to believe that the three things

that mattered most, correct me if I'm wrong, would be total calories, protein, and sodium. It can't be an accident that sodium is the only mineral we can taste. That is how I think about it as well. And to break down the energy piece, that would come for an animal with a digestive tract like a human, that would come primarily from carbohydrate and fat.

So we have carbohydrates that protein, salt, and then sometimes I add glutamate, umami, to that list as well. And this is subconscious. Is this, again, just part of that stuff that was now so wired into us that we didn't want to eat grass? We knew that even though you could get the gastric distention for meeting a lot of grass, like a cow could, it was doing nothing for us. Both it didn't taste good.

So, in the short term, it wasn't pleasing, and in the long term, obviously it didn't say, Shatus. Yeah, that's right. There's a couple of angles on this. One, obviously, humans have cultures, so we figured out what foods are good over long periods of time. But a key aspect of this is dopamine-mediated reinforcement. Essentially, our bodies are set up to respond to certain types of nutrients, like the ones you mentioned, and create a motivation and learning response that prioritizes and sets the motivational level on the seeking of those types of foods. Presumably,

these are the kinds of nutrients that our ancestors would have needed to prioritize to maximize the reproductive success, the currency of natural selection. So essentially, we have these motivational systems that were selected to seek certain types of nutrients in the environment. And if you look at the modeling that's been done on foraging behavior in a wide variety of animals and in humans, you see that it revolves around maximizing the energy return rate of foraging. It doesn't describe every species, but it does describe many species.

It's amazing to watch it in big cats, for example, where they'll be chasing an analope. And it's literally almost like they have a sensor inside that says, I'm going to stop chasing now because my energy cost is not going to be met by my consumption over this period of time. Absolutely. And these animals, they don't know how to do math. They don't know that they're actually implementing a mathematical equation in their head, but they are.

It's just wired into their brains. The same way it's wired into us. You can predict hunter-gatherer foraging behavior to a surprising degree just by knowing the calorie return rate of different foraging options. So our brains are very much wired, not just our brains, but our bodies are very much wired around energy acquisition in terms of how our motivation and learning is set up on a non-conscious level. This is very much hard wired. So we have dedicated sensors in the digestive tract. This is all pretty recent research since 2018. They discovered these cells that they named

neuropod cells in the small intestine primarily that have receptors for specific nutrients that are directly, these cells are directly hooked up to vagal neurons. So when they detect glucose or amino acids, fatty acids, so that would be carbohydrate, fat, protein, they get the concentration and they start sending signals up your vagus nerve, up to your brain stem. And from there it gets distributed to many parts of your brain, but particularly relevant part is the parts of your brain that have to do with dopamine release onto your reward centers.

If the food that you're eating contains a high concentration of these valuable nutrients, particularly in combination with one another, you're going to get a higher level of dopamine release. The more dopamine release you get, the more of a motivation you will develop toward that food. Is it there, and maybe this is just me, I don't know what the literature would say, so this could be incorrect, but in me, like a ribeye is not something I seem to be able to eat into excess, and I feel like I should. Shouldn't I be wired to eat ribeye until I can't stand? Shouldn't I be wired to eat ribeye until the point of vomiting, given how high

it is in sodium, fat, and protein, and total calories? Like the only thing it's missing is sugar and fiber and carbohydrates and things like that. But it's easier for me to overeat baked potatoes than it is to overeat a rib eye. And I'm not sure I understand why. Let me just clarify, with a potato, is that with or without toppings? Let's say with, let's put on butter, sour cream, and salt. So I'm clearly making it much more than the carb, of course.

And it has to be crispy skin too, like if I're gonna do it right, you know, I can't be like some lame-ass buffet baked potato. It's gotta be my style. I don't know why like a fatty piece of meat is not something I have an amazing... Is my experience typical? Would most people be able to just eat rib eyes until they puke? Oh, that's a good question. I really don't know. I will say that when you look at the foods that people cite as the most typically associated

with strong cravings and loss of control over eating behavior, meat does not usually come up high on that list. Which seems like it should. I can understand where you're coming from. I don't know whether that's a kind of generalizable phenomenon. I can only speculate about why that might be. So there are a couple of things that come to mind for me. The first is that meat is about 75% water.

So the calorie density of is actually... It's not low, but it's not especially high unless you're eating a really fatty piece of meat. So that's one thing. If we're comparing it to something like brownie or something like pizza, which is more calorie dense than the steak. The second thing is it doesn't have any carbohydrates, so it doesn't have that fat carbohydrate combination that is most closely associated with foods that people lose control around.

The third thing I would cite is the high protein level. So even though we have the strong protein-specific appetite that's been demonstrated in many different species, protein doesn't work the same as carbohydrate and fat. We recognize that that's the case. Protein seems to, it's something that our body really want to get enough of, but don't want to get too much of. So there's really not only there's a drive to acquire it, but there's a drive to keep it within a certain range and not eat too much. And we see that, you know, if people go on high protein diets,

their overall calorie intake will drop. I wanted to talk about the carnivore diet with you a little bit because I know you guys did a review on a book. It's not a diet I've spent any time really thinking about, so I've basically spoken to, I don't know, a dozen people who have gone on it. And without exception, they all lose weight, which I think for some of them is their motivation for doing it. And it must simply be that they just get tired of eating. They just can't take in the number of calories if they're doing it in that format. We don't have any good data on the impact of carnivore diet on weight.

There's no randomized control trials, but we have these anecdotes of people saying they lose a lot of weight. I certainly don't dispute that. But I think if you came to me with this diet on paper and you asked me would this cause weight, I would say absolutely, because it has multiple properties

that I would expect to, because it has multiple properties that I would expect to make it a particularly effective weight loss diet. One, this is something we could talk about more if you want, but it has zero carbohydrate. If you're on the extreme of the fat to carbohydrate ratio, any other direction that's more slimming than being in the middle, so the most fattening diets are rich in both carbohydrate and fat. So there's zero carbohydrate. You're on the extreme, or I shouldn't say zero, very, very little. Right, outside of the glycogen in the meat, that's about it. Yeah, there's a little glycogen. So you're on the very extreme end of the macronutrient distribution.

It's high in protein, that's also known to contribute to weight loss. You're eliminating almost every type of food. The variety of your diet goes very low. I mean you can prepare your meat in different ways. You can eat chicken or fish or beef or whatever, but your variety is greatly greatly reduced. So that's I think part of it. And you're cutting out all of these highly processed calorie dense foods that are the foods that I think part of it. And you're cutting out all of these highly processed calorie dense foods that are the foods that I think we could debate about but why but I think everyone agrees that those are foods that drive excess intake and elevated body fatteness. So I think all these things together, it's just even on paper, it's a diet that I would very much expect to cause weight loss

to greater degree than your average diet. And while we're on the topic, tell me a little bit about your review of this, because I know you've put some time into this. I don't really plan to do a podcast on the carnivore diet. It doesn't seem to make a lot of sense to me, although I don't dispute that there are people who I think have had very successful outcomes on it with respect to dealing with some of their physical ailments. So maybe it has a role in overcoming some acute illness. And maybe I'm just biased towards thinking plants are valuable. It seems to me that one of the core tenets of the diet is that

plants are low-grade toxic. Isn't that sort of part of the thesis? is that plants are low-grade toxic. Isn't that sort of part of the thesis? The thesis is basically everything is toxic except grass, fed, animal foods. Even tap water is considered not optimal. The book spends a lot of time going through the litany of all the potentially harmful compounds in plant foods. And actually, you know what? I sympathize with some of this. I think there is a bias toward thinking if it's in a plant, it's healthy.

And I don't think that's true. I think the book is right that that's not necessarily true. There are some plant compounds that, at least for some people, are not so good. And there are well characterized examples of this. If you eat a lot of spinach, you can get kidney stones from all the oxalate. There are studies suggesting that the glucosinolates in cabbage family plants might contribute to type 2 diabetes. Kidney beans,

if you don't cook them enough, they can be really toxic because the lectin. So it's not like there aren't examples of this. It's definitely true that to some degree, I think it just gets taken far beyond where the evidence is and the way to think about how healthy food is is not to say does it contain toxins, is to say what's the cost benefit analysis on this food, and most importantly, what are the empirical outcomes that we can see when its impacts on health are directly studied? This is something that I've kind of focused on in my evaluation of some of the ideas that are put forth in the public sphere, is that a lot of people who are coming out with, let's say, unusual ideas in this sphere, they take a mechanism and they run with it.

Like X toxin is really bad. Like lectins, for example, gundry, lectins can do XYZ, lectins are in plants, therefore we shouldn't eat these types of plants. And that's really like a bottom-up approach, extrapolating empirical effects on health from mechanism. When really, I think in a complex field like nutrition, it's better to start with the empirical evidence. Oh, we have this study that suggests that there's actually an effect on health.

Let's see if we can understand the mechanism. What are some of the biochemical changes that occur in people on a carnivore diet? I mean, the obvious one must be the dyslipidemia, right? Yes. There's a shift toward a ketogenic metabolism because of the fact that it's very low carbohydrate. That would be an obvious shift that occurs. I don't know if I'd use the term dyslipidemia, but one of the potential downsides I focused on in the review that is downplayed by many carnivore diet advocates, including Paul Saladino, is the change in LDL cholesterol and LDL

particle count. And again, we don't have great evidence here, and this is kind of the crux of our review of the book on Red Pen Reviews is simply that there are a lot of claims made that are not supported by any kind of convincing evidence. But we have some evidence, so there's this survey study that was done on something like 2,000 carnivore dieters. I think David Ledwig was involved in that. And they just reached out to people in social media groups like their Facebook groups and things. And they administered this survey. And one of the questions was what was your various

blood-lippied values before and after this diet. And you see that there are changes in positive and negative directions. Tricholicerides go down as you would expect. I don't remember what HDL did, but it probably went up. Probably went up. Yeah. And then there was a large increase in LDL cholesterol. And that's a concern. As far as I'm concerned, and I think you would agree,

and Paul Saladino himself, I'm not trying to pick on him, I don't wanna make it personal, but he's been public about some of this stuff, so I think it's fair to just repeat what he himself has said, but his LDL cholesterol is 533 makes per deciliter, and his LDL particle count is also absolutely through the roof. Not everyone responds like that. If you look at the survey data, I think there was a mean increase of like 30 mixed per desoliter and LDL,

30 or 40, something like that. So I think it depends on the individual. I think Sean Baker's lipids are fine. He's another kind of or diet guy. Last time I saw his lipids look just fine. So I think it depends on the individual, but some people do experience a large increase in LDL cholesterol. You know more about this than I do, but that certainly raises red flags for me in terms of cardiovascular risk over the long run. Yeah, the thing I've never understood, and this is probably true of not just carnivore, but ketogenic or anything that does produce that hyperbeta, like a protenemia, it almost

seems to be worn by some as a badge of honor, as opposed to saying, well, maybe this diet is doing a lot of really good things for me. It's improving my insulin sensitivity. I feel better. I have fewer energy swings, but this one thing isn't so good, but here's the thing of all the things that could go wrong. That's about the most treatable one out there. It's very easy to treat elevated APOB.

This is what we do clinically, right? This is how we treat patients. We have patients who only get better on very, very carbohydrate-restricted diets. But then if they develop that pattern, that elevated LDL pattern, we have a choice to make, which is we abandon the diet or we treat the elevated APOB. And that's not a failure.

That's simply using modern medicine to help us achieve the best of both worlds. I think I've always struggled to understand why the person will go on that diet, have an ApoB or LDL go from the 50th percentile to north of the 99th percentile, and instead of being curious about what the implication is, dig their heels in and say clearly this is a good thing, and LDL does not cause heart disease. I absolutely agree. It's a dietary ideology. It's an ideology that has emerged to defend a certain type of dietary pattern. These kinds of ideas emerged from the low carb community, essentially, to defend against the idea that there might be some downside to certain types of low carb community, essentially to defend against the idea

that there might be some downside to certain types of low carb diets. And they've been taken to an extreme, I think, in the carnivore community, because that's a particularly potent stimulus for increasing LDL. So people don't want to believe that there's a downside to the thing they're doing.

I kind of get it. Like people go on this diet, they lose weight, they feel better. Some people say their skin cleared up or XYZ condition improved. There's all these tangible things they can see that are getting better. They don't want to believe that there's an intangible thing that's actually putting them at severe risk. I say severe risk. I just mean cardiovascular disease is a big risk generally. As you know, this is the number one killer. Cardiovascular disease is a huge big deal, even if it doesn't kill you. It can do really bad things to you physically and cognitively. So

it's not a risk you want to be ignoring. It's an irrational part of dietary tribal ideology that is holding people back from experiencing their best health. And it's so treatable. I said that in the review too. I was like, you don't even have to stop the diet. You can just get it treated or you could modify the diet. You see the same sort of equally stubborn ideology at the exact opposite end of the spectrum, where we see these patients that will go on these incredibly restrictive plant-based diets,

and it's usually some combination of micronutrient deficiency and-or-protein deficiency that's going to be the death of them, but there's no deviating from it. There's no, like, I'm going to supplement with protein shades, because I'm going to take B vitamins, I'm going to do, and again, it's the same sort of thing. It's like, somehow, if I acknowledge the fact that I need to supplement with these other things to work around a diet that I otherwise like, or that is congruent with a belief system I have around the treatment of animals, which I can respect that. If that's your belief system, then by all means, be true to it. But yes, I find it somewhat self-destructive. Absolutely. I think it's very analogous to what we see in certain corners of the vegan diet community. They want it to be best for everything. It's got to

be best for the environment and for ethics and for health. It's just very hard to swallow that there might be some downsides. And for the carnivore diet too, you see like they try to justify the environmental aspects of it too. In the carnivore code, he talks a lot about regenerative agriculture, which is a concept that I think is interesting and I support it, but it's a certain, I would say, spin on it that makes it seem particularly favorable. And also, there's an underlying assumption that the average carnivore is gonna eat nothing but regenerative agriculture beef,

which I think is not the case. Let's talk about one more big topic, Stefan, which you've written a lot about. I don't know if you're sick of it or you're still enjoying it. But this idea of energy balance, carbohydrates and insulin and unifying theories around adiposity. Very recently I heard you and Kevin Hall on a podcast.

I don't remember what the podcast was called, but it was a wonderful discussion because I know you well, I know Kevin well, and anytime I can listen to a podcast with people who I know a lot about and I know most of what they have to say But yet I still pick something up in the discussion. It's fantastic and that was an example In it you guys did a pretty good job I thought of really Explaining the history of these models which I think you acknowledged are probably not perfectly named So there's a little bit of historical baggage that goes into the nomenclature.

And anybody who's able to pay attention long enough will realize that there's a lot in common with these models, but there are some fundamental differences that are important to understand. Maybe we could talk a little bit about that. Again, I think this is not a time to be overly simplistic, right? I think this is a time for nuance, and it is a time for putting the finer point on the similarities and differences of these models. So maybe just start by explaining, pick the one you want to start with and kind of walk

through them. So the two models are the carbohydrate insulin model and the energy balance model. And the carbohydrate insulin model, I just want to get a little more specific with that because there are different versions of this. So this is the one that has been promoted by David Ludwig and particularly in a recent review paper that he published, along with some other researchers. The energy balance model, in this case, is being represented by Kevin Hall, but I would

say it has very deep roots in similar models that go back decades. Carbohydrate insulin model, and its most recent incarnation is a lot more complex than previous inclination, so I'm going to do my best to summarize it and hit the key points. Essentially, it's the idea that there are things in the diet and in the environment that impact insulin signaling and insulin signaling impacts body fatteness, and then that fattening process of insulin signaling on adiposity, then downstream leads to elevated calorie intake and possibly a decline in metabolic rate. So it proposes a reversal of the relationship, this is

one of the key aspects I want to highlight, proposes a reversal of the relationship, this is one of the key aspects I want to highlight, proposes a reversal of the relationship between energy balance and body fatness. Basically, the energy balance phenotype is downstream of that fattening process instead of being upstream. That really, I think, is a key difference. When we go to the energy balance model, the energy balance is upstream of the fattening process. So basically we have all these things happening in the environment and physiologically in our bodies.

Those signals are impinging primarily on the brain and then energy balance is a result of primarily that brain activity and then that is feeding into adipose tissue. So in that context, adipose is body fatness is kind of receiving the excess energy. It's not really the driver of this process, but when excess energy enters the body, it's what mobs it up. That's kind of the difference between those two models. Let me say that again just to make sure we've got this right.

So in the former model, in the carbohydrate insulin model, the idea is that the primary cause is the adipose tissue increasing in its fatness, right? The adipose tissue wants more energy that's driven by the external factors, both carbohydrate and otherwise. So in a drive to increase the influx of fatty acid into adipose tissue, you see a reduction in circulating metabolic fuels, which drives an increase in appetite. So intake goes up to accommodate the reduction in circulating metabolic fuels, which is being caused by a drive towards fatness. The conventional model basically says that's happening in reverse. It's saying that the input

of fuels into the system leads to an increase in circulating metabolic factors that is now driving energy balance into the fat cell. Is that safe overview? Yes. You said conventional model though. I've heard both terms used. Sorry, I think this is worth a moment to clarify. If you look at David Ludwig's paper, he contrasts the carbohydrate insulin model against what he calls the energy balance model, which is basically calories and calories out. None of this is really regulated. It's just however many calories you happen to passively eat or how much you decide to exercise.

And then your fat tissue is a result of that. The energy balance model in contrast is acknowledging all of this brain regulation of body fat, brain regulation of appetite, and saying actually body fat is a regulated process. However, its body fat, and I should say, is a regulated variable. However, it's regulated by the energy intake and expenditure via the brain. Got it. Okay. The conventional model, I will say, is not a model that really any obesity researchers currently ascribed to, at least the obesity researchers who are actually studying the mechanisms of

body fat regulation. One of the things that Kevin pointed out on this podcast to go further on that, down that thread is the energy balance model does not consider all calories identical. Yeah, it does not presuppose that they're all identical. That's right. In terms of their impact on body fat. So not only do they potentially have different thermogenic effects, they also might have different regulatory effects on compensatory appetite, right? also might have different regulatory effects on compensatory appetite, right? That's right. And I think where we really see this emerging is in animal models, I don't know how relevant this is for humans, but I'm just using it as a general proof of principle

that it can happen. You can see in animal models where you can change their diet composition, David Ludwig has shown this for carbohydrate quality. It's been shown for dietary fat as well. And you can actually produce animals that will gain fat independent of calorie intake. So you can actually clamp them at their former calorie intake and they will nevertheless gain fat. At least in principle, those types of effects are possible.

I believe Rick Johnson described an experiment like that on my recent podcast with him, which was an isocaloric swap to a very high fructose diet, where the animals didn't gain weight, but they fuel partition differently. They got fatter. This was over a long time. This was over nine months, so nine months for a mouse, right? As an eternity. Yeah, absolutely. That has been shown in a number of contexts that that can happen in rodents. I think it's worth pointing out that rodents have their energy expenditure is more plastic than ours. By the way, I want to go back to that. This will tie into what we're about to talk about. But you have a person who weighs 200 pounds, person who weighs 160 pounds of the same height.

The 200 pound person loses 40 pounds, they're now 160 pounds. The other person's always been 160 pounds. On the surface, they look identical. In fact, let's pretend they're siblings, but one was obese and he's now post obese. The other was never obese. Let's pretend that that one that lost the 40 pounds

has really kind of dialed it in and doesn't yo-yo. He manages to stay there. It's three years later. Are they the same person yet? No, probably not. So Rudy Libel has done studies where I think they've had people out to a year, maybe two years, where they have them weight-reduced, and the starvation response, this left independent starvation response, he hasn't seen any sign that it goes away.

Could it maybe be possible under some circumstances, maybe, but the evidence that I've seen suggests that it is at least not typical. So I want to specify that the set point around which the light-pastat regulates can change based on dietary and environmental variables. An example that you'll be familiar with and others probably listening will be familiar with.

If you take someone on a typical diet and put them on a low carb diet, you don't have to tell them to reduce their calorie intake. That will occur spontaneously and they will lose fat and end up in the typical person comfortably being at a lower weight. They're not experiencing the starvation response. And you can see this on other diets as well. So I think there are things we can do to change the set point. However, that doesn't mean that they are cured. If they went back to their other diet, if they just went back to how they used to be eating,

so they're not maintaining this attempt for weight reduction anymore, they generally will go back to where they were. So it's not that there's a durable resetting of the set point to like flipping a switch and resetting, like restarting your computer, it's more like the set point has been modified because it's in a different environment. And as long as you maintain that change, you can maintain the effect. But if the change goes away, then the effect goes away.

Where do we think is the greatest window of vulnerability for someone just going back to these two hypothetical individuals? Let's take the genes out of it. Let's pretend they're identical twins. Born in the same household, they both possess the genetic traits that would allow them in the right environment to become obese. But one of them, let's just say, had an injury in high school that kept him home from playing sports and he ended up playing more video games and kind of eating more. The other one was more active. So that explains why when they're now 40 years old, one's 40 pounds overweight, the other's not. Are there windows in a person's life when they are more susceptible to that resetting

of a set point, a higher and higher set point, which it sounds to me like it never goes down. It's a monotonic crank. I honestly don't know. Certainly there is a substantial potential for most people to gain weight at almost any point in life. So I'm not really sure. And by the way, let me say that I think there are other people who could probably answer this question better than me. There are people who have studied the trajectory of waking over the life span.

So part of the issue here is I'm just not that well first on this literature. One thing I'll point out that is potentially interesting is there may be an influence of the intra-uterine environment. So what's going on as you're developing inside the uterus. So there is evidence, I wouldn't call it strong, but there is evidence that women who undergo bariatric surgery for obesity and lose a lot of weight, their children are at a lower risk of developing obesity than women of similar weight who did not undergo bariatric surgery. And the effect size is large. Wait a second. Meaning two women of the same weight have children. One of them is that weight naturally and the other one is weight reduced at

that weight secondary to gastric bypass. No, no. Think about two women with severe obesity. One of them has gastric bypass. After that surgery, they both have children. But starting from different weights, obviously, because the gastric bypass one is weight reduced. Correct. And the children of the woman who had the surgery and had previously lost weight before getting pregnant have a lower risk of obesity. Again, I wouldn't call the evidence strong. What if she achieved that weight loss without gastric bypass?

So what if you had two women who were overweight and one of them lost weight through diet and nutrition? I don't know. I am not aware of data on that. If you wanted me to guess, I would say it would probably be similar, but gastric bypass, is that really the same physiologically If you wanted me to guess, I would say it would probably be similar. But gastric bypass is that really the same physiologically as the physiological situation that you get from diet and weight loss, diet and lifestyle?

I don't think it is. I think gastric bypass is a unique situation where provided a person doesn't take in liquid calories. It's quite durable. The ruin why. Where provided a person doesn't take in liquid calories It's quite durable the ruin why obviously liquid calories can completely disrupt the feedback mechanism there Kind of similar by the way to a GLP1 agonist this actually kind of gets back to I've seen patients who take Semiclutide who Don't lose weight and the way you can cheat somaglutide is to drink your calories. If you drink massive amounts of calories, again, this is anecdotal.

I don't know that this has been studied. I'm just saying this based on observing a number of patients. But if you continue to drink a lot of alcohol, if you continue to drink juices and things like that, you can sort of bypass some of the GLP1 effect on the brain. It would seem. That's my only explanation for why I see that. And we do see that definitely with gastric bypass. So who knows about what that would look like. What advice or what insight comes from this as it pertains to a person who's listening to this? And by definition, half the people listening to this are probably at a body weight above where they want to be. What's the takeaway?

In terms of pregnancy? No, no, just in terms of overall weight loss. You know, we're sitting here in this environment that is almost deliberately trying to put weight on us. We're not going to get any help from our ancestors because the reality of it is our ancestors didn't care if we gained weight. Quite happy to have us gain weight, actually. They just want to make sure we don't starve.

And so what can they do? And more importantly, how do they keep it off? Because as you said, most people can lose weight. But the keeping it off is really, it poses a challenge. I'm going to take this as a question about on the individual level, which I assume is what you meant. Yeah. There are a couple of different things to think about. For people who have obesity, bottom SNX, 30, 35, I think it's worthwhile to consider medical treatment,

something like some agglotide, for example, the tools that we have now are just way better than what they used to be. That's a separate topic we could talk about. Somagletide, as far as we can tell, it's a very safe drug. It causes something like 18% weight loss, which is much better than the typical effect you're gonna see in diet and lifestyle

strategies, but like diet and lifestyle is something you have to maintain. So I think at this point now that the tools are getting better, particularly now that the tools are getting better, I would recommend seeing you know, obesity medicine specialist for people who are experiencing substantially impaired quality of life or really concerned about the health impacts. You know, if we switch the focus to people who might just want to lose a few pounds or who are overweight, whether or not in a serious situation, your appetite and your body fatness are very much regulated by your brain based on inputs that your brain is receiving.

And a lot of that is non-conscious. The approach that I like to take is to try to give the non-conscious brain signals that are going to be more consistent with your goals, signals that are going to tell your brain to regulate things in a more slimming direction. And that way you're not relying on heavy exercise of willpower all the time, which I don't think is really sustainable or effective for most people. You are instead of setting up a scenario where you have these non-conscious urges that you're having to fight with your conscious

brain, you're addressing the non-conscious urges directly so there is no fight. That's what I prefer. Controlling these signals that your brain is receiving is really important and there are different ways to do that. One of them is to control your food environment. So, the sensory cues in your environment that your brain is exposed to, whether there is food in your immediate vicinity, how tempting that food is, how hard you have to work for it. If you can just grab it and put it in your mouth, that's not as good as if you have to,

you know, walk into a room and then peel an orange before you can eat it, just little effort barriers like that. And then with the types of food we're eating, there's a wide variation in the number of calories that it takes to feel satisfied at a meal depending on what foods you're eating. A typical person sits down and eats food until they feel satisfied and then they stop eating. That is the intuitive, typical, natural, easy way of interacting with food.

But depending on what's on your plate, that point can be reached with vastly different numbers of calories. Is the proximate sign of satiation more a gastric distention function in that immediate cessation mode? I can say that it's important. But if I were to like assign what percentage of the effect is attributable to that, I don't know what percentage I would put on it, like is that more than 50%.

It's a very complex system. The brain is receiving a lot of signals. Some of them are stomach distension. Some of them are signals from the small intestine about what the nutrient composition is. Some of them are simply or a sensory detection of food properties and stimulating your brain nose based on the sensory properties, what the nutritional composition of the food is based on prior experience that it has stored. So there's a lot of stuff going on that contributes to ultimately that

sensation of satiation would be the proper term for it and satisfaction that causes us to end the meal. Certainly stomach distension is a biggie. So that relates to calorie density which is an important determinant of the satiating and satiety promoting properties of food. So in other words, how many calories are there per gram or per volume of this food? If you have a food that has more volume per calories, fills up your stomach more,

it stimulates those stretch receptors more that goes up to your brainstem and that's a signal that opposes further food intake. Protein, some more protein is more satiating per calorie, palatability, the better something tastes, the less it fills you up per calorie. And I'm actually not sure how to disentangle that from calorie density. Like, what's the independent variable there and what's the dependent variable or is it some of both? I don't know the answer to that, but they're both strongly correlated

with lower satiety. I've also seen these experiments where people are drinking from a bowl or a cup and it's being refilled constantly versus one where it just kind of runs out. I mean, what are the differences in how much people consume based on, I noticed this in myself. I put a little too much in the bowl, but I eat it anyway, because it's like, oh, I gotta finish this thing.

And if I had finished it 10 bites earlier, I would have been totally happy. Does that type of behavior factor in the long tail here, or is that just an acute thing that is sort of irrelevant in terms of optimal weight maintenance? I think it's very plausible, but the problem is that stuff comes from Brian Wonsink,

and so it pretty much got blown up. He was the guy at Cornell that he falsified a bunch of data or something. I don't think there is clear evidence that he falsified. But he p hacked a lot of it pretty badly, I think. Oh yeah, really badly. And there are some data where it's not clear where they came from and they're very implausible.

I don't know how strong the evidence is that there was actual fabrication. I think there may have been some evidence of that. I don't know where that landed, but basically there were a bunch of problems and yeah, he got blown up. I would say that anything that has his name on it at this point is pretty suspect.

The refilling suit bowls was one of his classic experiments. I'm just going to disclose that I did cite one of his studies in my book, so I wasn't immune from getting taken in by some of this stuff. Going back to this energy balance model versus the carbohydrate insulin model. One of the arguments in favor of the carbohydrate insulin model is other examples of growth that are regulated from the hormones out to the intake of energy. And I was thinking about this the other day because I measure my kids. I have three kids and every three months, each of them gets a little tick on their closet door. Anybody listening to this who measures their kids at regular intervals, I don't know why I pick three months,

but four times a year. The non-linearity of this is unbelievable. They'll go little, little, jump, jump, slow down, jump. It's pretty intense. And that growth correlates with how much they seem to eat during that interval period. Like right now, my youngest, who's not yet five, I think he eats more than the other two combined.

And I'm probably not being facetious. He goes to a preschool or a pre-k where they give them breakfast there. He eats two breakfasts at home, then he goes there and still eats more than all the other kids. I mean, the kid's just an eating machine. And he's growing, commensurate with that. I think most people would agree he's not growing because of how much he's eating. He's eating that much because of how much he's growing.

So he's responding to growth hormone and all these other things. And I think that's basically the central thrust of this carbohydrate insulin model, right, which is whether it be sleep disturbances that increase or decrease insulin signaling or foods that stimulate insulin, they're driving that hormonal environment that is driving the increase in food intake. But I think experimentally, what can we say about the differences in these models? Experimentally, you have to think about this in terms of animals and humans. It seems to me that the balance of experimental data would suggest the energy balance model is easier to explain. Would you agree with that?

I think so. Although I do want to acknowledge the fact that they're not mutually exclusive, so it has not been ruled out that there could be a contribution from that type of a model. Why is this so important? Is it so important? Is it important to understand this? I suppose the implications have to come down to how we treat the condition. It is important in the sense that if you understand the mechanism of something, it makes it easier

to address. If you look at the history of obesity drugs, weight loss drugs, I should say. Most of them were discovered in entirely haphazard ways. Dynitrophenol was a high explosive that was used in World War I and somebody figured out if you take it, it makes you lose weight and it does so by increasing your energy expenditure. So some people managed to cook themselves literally from the inside out. And then you look at other drugs and most of them are psychiatric drugs. They are just repurposed psychiatric drugs that just happen to cause weight loss.

Some psychiatric drugs cause weight gain, some cause weight loss, and the ones that cause weight loss, we just said, hey, can we repurpose these? Can we combine them to accentuate the effect? That was kind of most of the history of weight loss drugs. And now, for the first time, we have drugs that are safe and effective, FDA-approved, I should say we have A-drug, Wig of the AK, some acyl-tide, that is safe and effective,

and was developed for this purpose based on mechanism from the bottom up. So it wasn't just a haphazard discovery. So we are in a new era now where we are actually designing weight loss drugs based on mechanism, based on an understanding of the biological mechanisms of regulation. Because we're out of the haphazard era and into a more targeted refined era, we're in a place where it becomes really important to understand mechanism. And, you know, in cardiovascular medicine, I'm sure you recognize this, there are incredible

insights that have been coming out of the genetics that have resulted in therapies, like the... PCS canine inhibitors. Thank you. I always mix the letters up. That's a great example of it, where we first understood the biology and then we came out with a therapy and it works awesome. I think that's the era we are getting into now with obesity.

So I think it actually is really important to understand the mechanism. My prediction is over time these models will have more and more in common. One of the arguments against at least the way the carbohydrate insulin model is typically played out is actually given by somaglutide, which raises insulin in the short run. One of the things we always see when we put patients on this drug is they're going to lose a ton of weight and their insulin levels go up slightly. Now, this tends to resolve over time. So we're long enough period of time we tend to see insulin come down, but in the short run, for about three months, we see elevations in insulin. And we also know that it's increasing insulin sensitivity. So they're getting really the double effect, but it's hard to reconcile that

with a model that would state insulin must go down for weight to go down, for fat to go down. I think that model is just not even plausible at this point. If you want to say, is it a factor, I think that's still in play, but to say like, this is the determinant, I just don't even think that's plausible at this point. This class of drugs was identified based on its ability to increase glucose-stimulated insulin secretion. That is what GLP1 does. It's an increase in hormone. So that was the original purpose and why it was used in type 2 diabetes management because it gives people more insulin around meals when they really need it. Because if you just inject insulin, that's a really kind of crude way to manage your blood glucose.

It's not time specific. So GLP1 gave it that much needed time specificity and also had some other beneficial effects. And it was only after that that they figured out that it has this big impact on food intake and body weight. Absolutely, I agree with that. There's just a lot of other literature. I want to throw the hypothesis of bone though. So if you look at genome-wide association studies on body mass index, they're all about

the brain, largely about the brain. If you look at genome-wide association studies on body fat distribution, you're controlling for BMI and you're saying where is that fat on the body, those have more of an insulin signal. So insulin pops up pretty prominently in those. In other words, the distribution of fat on the body where it is seems more related to insulin signaling. Correct. The total amount of fat on the body seems more related to energy intake if I remember what we talked about really at the beginning, whether it's not just regulated by the brain,

it's more on the intake side of the equation. Even to add a little bit of extra nuance on top of that is we're really talking about body mass index. If you consider this idea of energy partitioning, which the carbohydrate insulin model is all about, there could be some of that flying under the radar of body mass index. I don't think the door is closed to that, and the fact that it's showing up in body fat distribution, and now, you know, David Ludwig is publishing studies suggesting that there could be correlations between baseline insulin secretion and how much what proportion of fat loss is lost as fat versus lean tissue. There's a

world in which there could be some energy partitioning effect. I just don't think it explains obesity because obesity is not just energy partitioning. You have a bigger body, you're eating more energy, you're burning more energy, you have more lean mass, more fat. That phenotype is not explained by energy partitioning. What? Could there be some subtle energy partitioning phenotype that is operating also, maybe. So that's kind of like my view of how there could be a way that this has validity. And you said something earlier about the more u-restrict carbohydrate or the more u-restrict fat, typically the more weight you're going to lose, the sweet spot, if you want to gain

weight, is to have lots of both of them. How much of that do you think comes lose, the sweet spot, if you wanna gain weight, is to have lots of both of them. How much of that do you think comes down to the hedonic component of how good ice cream tastes? The ubiquity of food choices, or do you think there's something very unique physiologically going on? You've probably heard of the potato diet. All these diets just sound so stupid.

But if you talk to somebody who just mainlines potatoes all day, they lose weight like crazy. This has been shown really clearly in animal models, which have the advantage of you can get really tight control for a large proportion of the animal's lifespan. John Speakman published a study that is the best one that's been done in animals where 29 different diets, I believe, in five different strains of mice. They systematically varied the carbohydrate to fat ratio in the diet and they said, how does that interact with body fatness? And what they saw was, if you start with animals

that are on a low fat, high carbohydrate diet and you start replacing that carbothat, they get fatter and fatter and fatter and fatter and fatter and fatter until you hit about 60%. And then you keep increasing the fat and decreasing carbohydrate, they get slimmer again. And there are studies published mice lose weight on a ketogenic diet, just like humans do. You can put mice on the diet, you can put rats on the diet,

they lose weight. So it's really in the middle that the problem is. Which is ironic, because that's where the standard American diet is. If you just walk into the grocery store and just eat without any filtering, you will eat that wrong combination of fat and carbohydrate.

Exactly. And if you look anywhere in the world where people are rich enough and industrialized enough to eat whatever they want, that's generally what you're going to see. At least after a couple decades of cultural adaptation, you're going to see pretty equal proportions of fat and carbohydrate. That's what you see in most parts of the world. So why is that? Well, I think there are some hypotheses that can be considered. And let me just be clear here that this is speculative. So I don't want to present this as the answer.

Because I don't think we really know. I think this is primarily a empiric observation that we're trying to explain. But some explanations, you could say, maybe it's a physiological effect. So if you're not eating much carbohydrate, your body has to work a little bit harder to synthesize glucose, for example. So there are some physiological ways in which you're

increasing the demands a little bit, metabolic demands. Same with very low fat diets, you're slightly increasing metabolic demand. You're going to synthesize more fatty acids. slightly increasing metabolic demand. You're going to synthesize more fatty acids. But I don't know. I don't think that's great explanation because those metabolic demands are very small. In speakments experiments, these were al ad libid at my assume, where they also significantly eating less

at the extremes in terms of total energy intake, and were they controlled for protein? I think the answer is yes to both of those if I'm recalling correctly. I do want to put a little asterisk on that that sometimes there is not a perfectly tight correlation in rodent studies between energy and take and fat gain. So you can get some results where it's not fully explained by that, or in some cases not explained at all.

Yeah, where was I? What was I saying? Well, I think we're still trying to reconcile why at the extremes is it all being driven by less intake or is there some increased metabolic cost of living at the extremes? So the physiology would be one and then the other would be just the neurobiology and the food intake. And I think that's the most satisfying explanation we have right now, is that it is simply more appealing to eat food, more motivating to eat food,

that has both carbohydrate and fat. I'm not saying I have strong evidence that that's the explanation, but that's kind of the only thing I can think of that explains it. I mean, why else the metabolic cost of being at the extremes should be pretty modest. It can't explain effects of hundreds of calories a day, which is what's observed when you put people on a very low fat or a very low carb diet. Their energy intake declines by hundreds of calories a day right away automatically. That's the only thing I can think of is that essentially a food has less implicit value

to reward regions of the brain because of how our motivation is determined for certain types of food properties. The food is intrinsically less motivating, and so we eat less of it. That's my best guess as to the main reason. It's not very difficult to take your carbohydrate intake down to five to seven percent. Like a ketogenic diet will do that, and it's a pretty easy diet to adhere to,

especially today, harder 10 years ago when there were fewer food choices geared towards it. But I'm not necessarily saying it's an overly pleasant diet, but it's not difficult. You don't have to put a huge amount of effort to eat 5% of your calories in carbohydrates today. I don't even know how one would go about getting only 5% of their calories from fat. That is a much harder thing to do, is it not? Yeah, I think it would be very difficult to get that low. When you look at studies that

test low fat diets, some of the lowest fat diets I've seen were in the kind of 10% fat range. I mean, even foods like whole wheat and corn have a fair amount of fat, and not a lot of fat, but I don't remember exactly what it is, but not far off from 10% just from those foods that we would call starch foods. So I think it is quite challenging to get that low in fat. You can do it with more refined diets, like semi-purified diets. It's not so hard to do that in rodent studies, but to design a diet that someone will actually eat as a human in a randomized control trial or something at that level of fat intake I think is pretty challenging.

Even 15% is not easy. You're really working hard to do it. And I'm not convinced that there are great health benefits to that either, probably better than being in the messy middle, but it's pretty hard to do. Last thing I wanted to ask you about was Red Pen Reviews. So tell folks a little bit about how long you've been doing that and what's the frequency with which you guys put these reviews out. Red Pen Reviews is a 501C3 nonprofit

that publishes the most informative, consistent, and unbiased reviews of popular nutrition books available. And the thing that really makes us unique is that we have developed this semi-quantative review method, structured review method, that we apply to each book that yields numerical scores for scientific accuracy, reference accuracy, and healthfulness. What this does is it allows us to apply the same rigorous method to all books such that you know where the numbers are coming from and you can compare in an apples to apples way between different books.

So you could say, I want to know the best book on Topic X and you can literally compare the scores of two books, apples to apples, and choose the one that has the highest, let's say, scientific accuracy. This is a pretty labor-intensive process. So how many do you bang out in a year? It takes us about 4,200 hours per book. We've been operating since 2019 and we have 14 reviews. I will say that our pace was quite slow last year due to COVID-related time challenges. We're on target to have probably six to eight reviews published this year.

We have some things going on behind the scenes that could potentially greatly accelerate that pace we're seeking funding. How many folks do you have that review the books? We have a total of, I believe, eight reviewers right now. So each reviewer might do one a year on average? On average, yeah, but the way it turns out is that some people do the majority of reviews and then other people only rarely do a review. And how do you guys select books for review?

We are trying to maximize our impact on public health knowledge and public health. So we really try to pick the books that are most impactful right now. So we're looking for books that are selling the most. We're looking for books that are having the most social media engagement. We're looking for books from authors that are particularly influential. We're really trying to give people information about the things that they are already interested in. So what are some of the recent ones that you guys have published, which books?

Obviously, we talked about the Carnivore Code as one of them. That's one of the recent ones. The most recent one we did was the Volumetric Diet, Ultimate Volumetric Diet by Barbara Rolls. Before that, we did the Carnivore Code. I was the primary reviewer on that. We have a primary reviewer and a peer reviewer. Before that eat, drinkin' be healthy by a Walter Willett.

Before that eat fat gets in by Mark Heimann. So that's a taste of some of the ones that we've been doing. Given that you've been doing this for three years now, anything surprised you so far, were there any that you went in thinking, yeah, this seems like it's gonna be a pretty good book and you came away thinking, no, they really didn't get this right.

And vice versa, where you went into it thinking, this is gonna be nonsense and you came out thinking, actually, they've changed my view on something. One of the things that has really come into focus through the course of this process is that credentials are not a reliable correlate of information quality. So there are people that have MDs like David Pearlmutter, he is a board-certified neurologist

and his book, Graeme Brain, got the lowest scientific accuracy score of any book we've reviewed. I'm not trying to pick on anybody in particular, but that's just an example of the credentials not lining up with the scientific accuracy. And we've seen that in many cases. Probably there is some correlation there. So I think credentials, they're not completely meaningless, but once you get into people who are highly credentialed,

it's just highly variable. Some of their books do really well, some of their books do really poorly. That's been somewhat of a surprise to me. I think most people who are educated in the sphere know that there's a lot of low-quality information in the sphere, right? But you can't help but be shocked sometimes at just how bad the situation is. We know in science there's a replicability crisis. So scientists are not infallible.

There's problems like this, even in this peer-reviewed literature. But once you get outside of the sphere where there's accountability, and you're in the public sphere where there's very little accountability, it's like a free-for-all. And many people, even those who are well credentialed, share information, that is very low quality. Most people have very little ability to detect it. And even somebody like me, who I consider myself knowledgeable, at least in some areas, I can get taken in too. I might read a book and it seems compelling. I'll tell you the carnivore code. It did worse than I expected. As I was reading it, there were parts where I was like, interesting. I'm going to look into this. This is kind of make it sense to me. And it wasn't until

I started checking the citations and doing scientific literature searches where I was just, this is not the best interpretation that an unbiased person would come to looking at this body of evidence. There have been many surprises, and most of them were updates in the direction of thinking that the state of popular nutrition books is actually even worse than I thought. I'm in the process of trying to finish my book, and one of the things that is so daunting is the fact-checking process. And I don't know what an author relies on

because I could certainly never rely on my publisher to fact-check my book. It's too technical. They don't have people with the knowledge to do the fact-check. So I have to have analysts who work for me fact-check, but they have to be analysts who had no help in doing the research for the book because you have to get fresh eyes on it.

So I think that means my book will come out more accurate than it probably would otherwise, and yet that's very difficult. I just know there's going to be something we get wrong. We're going to either incorrectly cite something or we're going to have misinterpreted it or something like that. And I feel like we're in as good a position as almost anybody can be given the size of our team. And yet it's still very daunting. There's something about a book that is daunting in the sense that you know this, you've written a book from the time you put your last last last edit into a book until it hits the shelves is about eight months.

Something's going to change in those eight months. So even if it was perfect, the day you finished it, which I think is impossible, eight months later, it's not, let alone two years later. Every book's gonna have mistakes, but the process that you described is I guarantee far more rigorous than most books that are being published in the sphere. And as you said, publishers

do not impose a filter on the contents of these books, very little of one. They just simply do not view it as their job to police the claims of authors. So if somebody comes in with an MD, for example, their position is, and this is literally what my publisher told me. They're like, you're the expert, we're not experts, we are not here to check your work. So for me, my process was I sent each chapter out to experts in the field and had them look at it. Does that mean my book has no mistakes?

Absolutely not. I've been catalog mean my book has no mistakes? Absolutely not. I've been cataloging my mistakes on my mistakes page on my website, the ones that I know about. I think that's inevitable. And I've sort of accepted the fact that that's going to be the only way I'll sleep at night. It's just acknowledging 5% of this stuff is gonna be wrong.

Let's collectively figure out what it is and let's create a repository where we can put the updates. I think that's absolutely the best attitude because not only is that a truth seeking attitude, but you are putting yourself in a position where you're not presenting yourself as someone who has to be right to be rational. You're presenting yourself as someone who's trying to get towards the truth and your audience can help you and Help all together to get closer to the truth and that's kind of the attitude that I like to cultivate as well

One thing I want to mention in this context is that the method that we developed for red pen reviews is available on our website for authors to see and Part of the reason why we do that is because we're trying to help authors write better books. We do random citation checks, that's one aspect of it. We have certain criteria for healthfulness, we have certain criteria for scientific accuracy, and it can't be gained.

I don't think our method can be gained. If you look at our criteria and you write a book that you think would score well, that's going to be a good book from an evidence standpoint. I don't think it can be gameed. When I think about me and my book, which came prior to the Red Pen Reviews, I would have loved to have this resource. If I had had it, I would have written a book with higher evidence quality, just like knowing that there's accountability and having a method that helps you turn that into something concrete to improve what you're doing, I like to view our organization as not just being finger wagging at people who make mistakes,

also providing a resource to help the information quality be good from the beginning. Are the reviews available to everyone or only to donors? They are freely available to anyone. We love receiving donations, but access to our resources does not depend on that. Well, Stefan, this has been super interesting. I always enjoy interacting with you and talking about all of these things. It is kind of amazing how much we still don't know about something that is so ubiquitous and so important.

But I also get the sense we're kind of converging. And I do think that these good faith debates that exist between people like you, Kevin, David Ludwig, I think they're really good for the field because I think it's forcing people to be sharper in their thinking. And ultimately, I think getting as closer to theories that are aligning better with experimental evidence. I know my thinking on this has changed quite a bit. And I certainly find now the balance of the evidence more on the energy balance side of the equation, but I constantly enjoy just Trying to understand both sides of this. It's very complicated. Again, suggesting that there's more overlap than we probably appreciate I appreciate you having me on. It was fun to discuss all this stuff. Thanks, Stefan. Thank you

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