68: How Hormones Control Obesity - The Fuel Partitioning Theory with Dr. Ben Bikman

Welcome to the metabolic classroom. I'm Professor Ben Bickman, biomedical scientist and professor of cell biology. Thanks for joining me for this discussion, this lecture today, the topic is a bit of a long title, but the idea is in fact equally complicated. So the topic for today is just a deeper understanding of insulin and its relevance in obesity in particular, through the lens of this idea, this theory that energy gets trapped and that this then promotes overeating. So it's just a different view that might not make too much sense at the moment, but it's going to by the time we get done with the lecture. So insulin, obesity, and then it's the fuel partitioning theory, this idea that we're moving energy in a way in the body that is promoting weight gain and in turn promoting overeating. Okay, now, why is there so much focus on obesity in the first place? Pardon me for just a moment while we do a little bit of economics and even history here. Globally, There are about 700 million individuals worldwide that are obese. Now this is just obese. Of course, the number that are overweight is multiples of that number. Within the United States, it's already estimated that about 40% of adults are obese and about 20% of children. And this, of course, is going, is continuing to climb. In fact, with regards to childhood obesity, that number skyrocketed with the recent lockdowns. So childhood obesity in particular took a hit. Now, so what, what is it about this weight gain that is problematic? Is it just we don't like the way we feel in our clothes as they get a little tighter? No. There are consequences that go beyond not looking the way we want to look or not moving the way we want to move or wearing the clothes we want to wear. Obesity or any degree of excess fat tissue is linked to myriad chronic diseases like the big ones. Certain cancers go up with obesity. Heart disease, of course, skyrockets. Type 2 diabetes skyrockets. All of these problems and more are intimately linked to how much fat we're storing on our bodies. Even beyond the health impact is the economic burden, the lost work days, the, the loss of productivity, the, the health care costs. This gets into the realm of hundreds of billions of dollars just within the US Alone. So it is incumbent on us to understand obesity. What is it about our current environment that is resulting in such troubling statistics that we are very overweight as a, as a culture globally, and it's just continuing. Current view of obesity isn't working. Our current view of why we get fat and what to do about it is not resulting in any meaningful benefit. We continue to get fatter and sicker. So clearly what, what we, how we view the problem isn't working. And that's an important thing to acknowledge because as much as we are, and we're going to get into this, as much as the ardent claims focus on, it's just purely thermodynamics, it's purely calories. Well then why is it not working? All right, now a lot of what we're going to talk about is come. It comes from a manuscript that was published this year and the title of that manuscript is Trapped Fat Obese Obesity Pathogenesis as an Intrinsic Disorder in Metabolic Fuel Partitioning. And this was an article that was published in Obesity Reviews. Again, this is Obesity reviews 2024. This include some really great authors like Gary Tobs, David Ludwig, Mark Friedman. So there are some really heavy hitters that contributed to this. And it's evident it's a big ish article, lots of good citations. So through the course of this lecture, if you are thinking you want a little more information, you want more of the details, you want to look at these specific studies that have been published on some of the topics we'll cover, please go to look at and look at that article. It's open access. Trapped fat, obesity, Pathogenesis as an Intrinsic Disorder, et cetera, et cetera. That's, that's the title. So you just go do a search for that and you'll find it. Okay, let's get into the first part of the lecture today, which is to revisit something I just said, which is the caloric view of obesity. The basic concept, of course, with this, this traditional view. Now, traditional view wasn't always the traditional view. About 100 years ago, this view would have been a peripher, peripheral view. The simple view is that obesity results in a caloric imbalance that is simply a matter of counting the calories, that more calories are coming in than are going out. And it's that simple. Of course, the supporting evidence for this is that when we see people eating a lot and doing very little, they are the same people who are gaining weight. Now, some of what we're going to touch on today challenges the order or the causality of all of that. Namely, is it the overeating that's causing the obesity? One alternate paradigm, indeed one posited in this article, is that the obesity is resulting in overeating and that's because of the trapped fat. This, this fuel partitioning theory of obesity, which is just another version of the kind of endocrine or hormone view of obesity. Now, however, as as much as the caloric view of obesity has become the global view, it certainly wasn't always the case. And this article outlines that. And I'm One of the things that Gary Taubes, the science author, has highlighted over the years is the focus on history. If you look at the history of obesity research up until about 100 years ago, it really was viewed as a hormone problem. And then it was only within the last hundred years, in fact, particularly after War ii, where the caloric theory of obesity really became the dominant view. And just as I, if I may add in a non scientific comment, look how well that's worked out for us now. The problem with one of the problems with the chloric view is that it, it doesn't account for the exceptions that as outlined in the article, the article ends up giving a pretty good critique that the prevailing focus is oversimplified, that it oversimplifies the complexity of obesity, that there's more, it is a multifactorial issue and that there are some intrinsic metabolic factors such as hormones and even genetic predispositions that can drive fat storage even with perfectly controlled caloric intake. So the one dimensional perspective of the caloric view really ignores the role of fuel partitioning which itself which skews the body's ability or the body's balance of burning versus storing energy. And then of course that including the relevance of hormones, as will become abundantly obvious in this discussion as we talk about rodent models of obesity and then the human analogs of that as well. Also another problem with the caloric view of obesity is that it ignores metabolic efficiency. This is something that I've published on as a scientist, so, so some of my or firsthand work touches on this. But that's another limitation with the caloric view is that it doesn't adequately address the differences in metabolic efficiency. Some people may have a more efficient capacity to store fat that's more favorable to fat storage rather than energy expenditure. And that of course is going to mean that for every calorie consumed the person's more likely to store it. But also the caloric theory of obesity totally, as I've alluded to a couple times, totally ignores the role of hormones, which you cannot ignore, as I'm going to, I hope make perfectly clear. Now, as much as someone tuning in now and who is familiar with me already may believe that I come to this discussion with some preconceived ideas, it may be only it may seem that way only because I feel very strongly that the other view of obesity needs to be discussed. What you will not hear me say now or ever is the calories don't matter. Energy matters. Energy must be accounted for. However, before we move on to the next segment here, I think that it's important for us to appreciate that the laws of thermodynamics that are so affectionately at best, or obsessively invoked when it comes to obesity research at worst, don't apply to the human or were never meant to apply to any biological organism. The laws of thermodynamics were intended to be applied to, I mean, at least originally intending to be applied to creating a better steam engine. It was essentially, how can we harness the heat better to get a more efficient motor? The human body is not a motor. As much as even I like to use the analogy of comparing human metabolism to as if it is like an engine or something. It's not. Of course, all biological organisms are what's referred to as open systems. In other words, we have energy exchanging in ways that can't really be quantified, unlike a closed system, which is where the laws of thermodynamics were intended to be applied, where every aspect of energy can be accounted for, if that makes sense. So in the closed system, everything stays within that system. The human body is not a closed system. We are an open system. Thus, the laws of thermodynamics, while perhaps being true at a universal scale, don't apply to human biology or any, any biology. Now, if I may bring up my own credentials, just to help impress upon the skeptic who's tuning in that I really do mean what I'm saying. I really do mean to say that I appreciate energy and how it needs to be accounted for. My entire graduate career was in bioenergetics. So it was, if I may say so, a fairly deep, extensive dive into this. This combination of thermodynamics and biology, physiology. That has what. That is what has informed my view, including my own work on the matter, so my education on calories and endocrinology and then actually applying and testing some of these ideas out. All right, so there's some of my concerns with the caloric view, in addition to just some general concerns, as noted in this manuscript. Now, let's move on to the next idea here, which is the alternative perspective, which again used to be the primary perspective, namely the hormone influence on fuel partitioning. So the core concept here is the fuel partitioning theory posits that obesity results from a fundamental Defect in how the body is allocating energy, specifically shifting that energy away from being burned into being stored. And then as you are shifting the energy, quite literally these, these energetic molecules, these calorie rich molecules, as you are shifting them from the blood into storage, it results in less energy being available for energy for actually being burned to give the cell the energy that it needs. Now every time I'm saying the word energy, I'm, I'm, I'm grimacing a little bit because energy even is a very misunderstood concept. The human body doesn't store energy. Please pardon another tangent, as I sometimes get a little frustrated that we even talk about calories at all. If we were talking about a steam engine, it did make sense to talk about calories because it is heat itself that we needed in that instance, in the human body, we don't store energy, we don't eat energy, we eat carbons, we eat carbon molecule, carbon atoms and carbon bonds, we store carbon atoms bound to other carbon atoms. So these carbon bonds, that's what we store. Now that can be broken apart or oxidized or burned, thereby giving. But even then, it's not the heat that we need. We're not bubbling water to have the steam engine of human metabolism do work for us. We're breaking those bonds. We get a little bit of heat which creates the body temperature that we have, but we get a chemical energy. So even as I'm using the word energy, there are so many ways this can be misunderstood that again makes me grimace a little bit. But back to the topic. I know you're clamoring for me to stay on topic here. The fuel partitioning theory again is the idea that the body is put into this metabolic scenario where it's storing energy and that is lowering it's storing calories, it's storing these carbon molecules, that, that means there's less in the blood to be available for the body to burn. So the muscle isn't getting as much fuel from the blood, the brain isn't getting as much fuel from the blood. And particularly for the brain, as the brain is sensing this general reduction, the total amount of caloric molecules in the blood, it says, well, we need to eat then, but little knowing that the fat cells are full, for example. So the idea again is that rather than diverting energy calories in the body, these calorie rich molecules, or the potential energy in these molecules, rather than diverting them to being burned, we're diverting them for storage. And while we are excessively diverting the energy into storage, there's less energy to use and that promotes hunger. So that starts to touch on the idea that a person's overeating because they're storing fat. All right, now that's the mechanism, that's the overall mechanism of the fuel partitioning theory, that the decreased fuel availability is, is a consequence of storing more energy than we're burning. And then there's a compensatory response. It's essentially the body's way of saying, well, then there's. There's not enough energy for me to burn to let the body live and work. So we need to eat more, we need to bring more in. A little more on this theory is this idea of energy homeostasis. The theory emphasizes particularly that maintaining a continuous supply of energy is essential for survival. Under normal conditions. The body can balance energy storage with energy usage through this fairly complex system involving hormones and neural signals and various cellular events, cellular mechanisms. However, in individuals that are. That have obesity and are predisposed to it, as some people are, there is absolutely a familial component to obesity. No one can say that there isn't, or I hope that they aren't saying that there are. You can look at a person who is born to obese parents, and that child is absolutely going to be more likely to become obese compared to the child who is born to lean parents. Now, of course, there's an environmental component, but there's also very much a genetic component. So those individuals who are predisposed to obesity who, for example, have a parent who's obese, the balance does in fact get a little disrupted, if you will, and I'm going to touch on that later, where it shows that these are individuals who are more inclined, that their energy is being more selectively diverted to storage, less burning, thereby promoting this compensatory hunger. And of course, throughout all of this is the vital role of the adipose tissue. Not only, of course, is adipose or fat tissue the focus of any discussion of obesity, but that's not necessarily just the out the end result. It's. We shouldn't just say the fat tissue is obesity. We should wonder what is the role of the fat tissue in leading to hunger. And that's this idea that I just mentioned. Again, I'm being a little redundant. This compensatory hunger, because the fat tissue is being told to store the energy, thereby growing, leading the individual to obesity at the same time. That's initiating this almost vicious cycle of stimulating hunger, which, depending on what the person's eating as we'll get into is is further promoting a greater leaning in to the storage rather than the burning. All right, now I've mentioned hormones a couple times and we're going to get into the rodent models that this manuscript uses to support this. And I'm going to make a very strong point of highlighting the human analogs as well. But among the midst of hormones, there's of course going to become a theme and it's going to be very obvious very quickly because I'm a very effective teacher. Insulin is absolutely unavoidably critical in any discussion of fat tissue. You simply cannot understand obesity, why we get fat and what to do about it without appreciating insulin. Now, as we go through this, these experimental models, however, you'll notice I'm not actually going to describe a model that is directly involved with insulin. We're going to talk about leptin in particular, and then we're going to talk about a particular part of the brain in the hypothalamus. So other influences, other signaling influences that play a role here. All right, now let's move on to the next segment then of the lecture and talk about the rodent models of obesity. You know, a somewhat deeper dive. And then I'm, every time I'm going to mention the human parallel here. So firstly, as within basic science, we very commonly will use rodent models or, or rodents, mice and rats, as the experimental model. That is partly for convenience but also partly for necessity, which is if I want to do a brain analysis, which my lab has done for an. For example, it's difficult to find humans who are willing to give you a biopsy of their brain. So I hope just with that obvious example, you're able to appreciate how rodents are involved and useful. Also, as, as I'm going to make apparent, every instance I'm about to cover there is a human version of it. So as much as we are very different from rodents, we humans, it doesn't mean we can't use that biological model to have better insight into human physiology as well. Okay, so the first one is what's called the VMH lesion model, the ventromedial hypothalamic lesion model. I'm going to say that one more time. Ventromedial hypothalamic lesion model. So in this experimental model, they take rats and they will, they will basically burn out. It's a survival surgery. So the animals survive this and go on to live long, mostly healthy lives with the complication that with the loss of that particular part of the brain, they have a loss. We often will say they have the loss of the sight that controls hunger. And so that makes you think, well, then they're just eating more all the time, and that's why they become obese. So we just still come right back all the way to calories. It's not that obvious, however, because with the loss of the vmh, the animals do become fantastically obese. However, even if you pair feed them, and this is an important caveat that applies to every single animal model we're going to go through and the human comparisons as we talk about the human version of it every time in this one, if you pair feed them. So you VMH lesion the animals, you sort of burn out that little part of the brain, or you disrupt it, you snip it out. They live, they, they survive the surgery, and they eat a lot. But if you only allow them to eat as much as the healthy animals who had a sham operation, so they didn't, they kind of underwent the whole same process, except nothing actually was changed in the brain, they will. For every calorie the VMH lesioned animals eat, they gain six times more fat. This was work by last name Brooks at the University of Massachusetts in the 1960s. Again, his observation was that for every calorie consumed the vma, the VMH lesioned animals gained six times more fat. Now, in humans, this happens too. So there is human evidence, in fact, an abundance of evidence. This is often referred to as hypothalamic obesity. So if you wanted to learn more about this topic, you could look for hypothalamic obesity in humans. We have instances where the hypothalamus has been damaged, whether it's due to a pituitary or a hypothalamic tumor, whether it's due to surgery in that area, Maybe they're removing a tumor and accidentally clip the VMH part of the hypothalamus, the ventromedial hypothalamus, whether it's trauma, whether it's radiation to the hypothalamus, perhaps again to address a tumor, but ends up damaging the vmh. We have human analogs of this. If the VMH has been damaged in humans, these people will become very, very overweight and obese very, very quickly. Now, what is it about the vmh? What is it that can account for this? Yes, it does regulate hunger. So these instances, and there's one case study of a young girl who had her VMH damaged through a Surgery. It talks about her absolute insatiable appetite. So again, people would then just say, well, it's all just because they're eating too much. But I just told you that in the well controlled animal studies, if you clamp their calories or match them, you pair feed them to the healthy animals, they, they have six times more fat gain. So clearly, clearly, this is not just a matter of overeating. It comes in fact down to one humble hormone who can never be circumvented, and that is insulin. Now you're thinking, you're wondering, Professor Bickman, how does the VMH regulate insulin? The VMH regulates a nerve called the vagus and the vagus nerve and its associated vagal activity. And that's often what I'll see. So whether it's vagus as the nerve itself or vagal as an adjective form of that word, the, the VMH regulates vagal activity to the pancreas and the vagus nerve when it's working well, when stimulated, will promote insulin secretion. And so the heightened. So what the, the problem here then is that with the VMH lesion animals, there's no regulation of that anymore. And so the pancreas begins releasing insulin all the time. So the animals become hyperinsulinemic very, very quickly. Now, as I've gone this far into the lecture, I realized that I haven't quite described the biochemistry of insulin at the fat cell. Very, very briefly, insulin regulates both sides of the fat cell as much as people only want to focus on one. So at lower levels, insulin has the ability to inhibit fat breakdown by inhibiting lipolysis. Lipolysis is the word for the breakdown of fat. At even modest increases, insulin turns that off. Now, at slightly higher levels, and depending on the size of the fat cell, it does so more at smaller fat cells. Insulin also regulates the intake of fat into the fat cel stored and the intake of glucose and its subsequent conversion into fats. So insulin both regulates the exit of fat by inhibiting it from the fat cell, but also regulating the intake and the storage of fat, the intake and storage of fat, and the intake of carbohydrates or glucose and its conversion into fats, lipogenesis, although at higher levels and more especially at smaller fat cells. All right, so that was another tangent, and we've already had several. Okay, for the sake of time, rather than talk about the specific mouse and rat versions of the next problem, we're just going to lump them all into one, which is leptin. There are various Leptin models of obesity. Leptin based models of obesity. We've talked about leptin in a previous metabolic classroom. So please go watch the leptin resistance lecture topic if you want to learn more about that. Specifically, I, I do a much deeper dive in that lecture than I want to do right now. But in these animals you can either take the animal that has stopped making leptin, which is often referred to as the obobi mouse. Obob, referring to the inheritance, the genetics from, so leptin mutation from mom, leptin mutation from dad, that gives them the obi Obi mouse. So just again referring to the coming homozygosity or the genetics of the animal. So either the animal isn't making leptin or the animal isn't sensing leptin. But in this case that's referred to as the db, DB mouse. And there's also a rat version of this called the fa, fa rat fa fa. Once again, it's a leptin mutation, in this case receptor. Now all of these animals of course become fantastically and even if I may say so, adorably obese, having worked with all of them. And they eat a lot. They are so. They have such a voracious appetite that they will eat their own feces if, if it's, if they don't have anything else to be snacking on, they just eat a lot. Now once again, the, the caloric obsessed perspective would say, well that's just it then, it's just purely a matter of calories. Once again, that is not the case. If you pair feed these animals, which has been done in every instance, they still gain multiples 4 to 5 to 6 times more fat than the other animals do. So once again it absolutely challenges and dare I say even refutes the caloric theory of obesity. Now you're thinking to yourself, Professor Bickman, you earlier just said that it all comes back to insulin and yet now we have multiple instances that it's leptin, including human evidence, when there are humans that are born with honest to goodness, leptin mutations. And this is mostly a problem that has been seen in South Asia, so in Indian, South Asian populations. That's where most of the case studies have been identified for reasons that I don't know. Nevertheless, when you, when you block leptin from working, you block one of its many actions. People often just want to refer to leptin as being a hunger hormone. That is wildly unfair. Again, go re watch my leptin resistance lecture for more. But one of Leptin's most important metabolic effects is to inhibit insulin secretion. So leptin is one of the many signals that generally provides this kind of antagonistic signal to the beta cells, telling the beta cells of the pancreas to produce less insulin. However, if you've removed that signal because there's no leptin being produced, or there are no leptin receptors to sense the leptin that's being produced, or in the case of many humans, the person's become leptin resistant, you aren't able to provide that downward signal on the lep, on the insulin production, thereby enabling insulin secretion to be even higher. So once again, just like with the VMH lesioned instances of obesity or the hypothalamic obesity, where it goes, it ultimately comes to a matter of elevated insulin. Once again, with leptin not working well, we, we once again come back to elevated insulin. Now, there's one final instance here, and this one's almost the most obscure. It is probably the most uncommon in humans. And this is in the animal model. It's called the agouti yellow mouse. It's interesting here because in addition to the altered receptors in the brain and their function that also manifests with a particular pigmentation. So, and there is a human version to this as well, which I'll mention. So in the agouti animals that become very, very obese, they have this inhibition or this blocking of what's called the melanocortin receptors. Specifically, it's the melanocortin 4 receptors of the hypothalamus, sometimes just abbreviated as MC4. So MC4R is expressed in the hypothalamus, that small, little, it's a small, little part of the brain and plays a critical role in regulating energy homeostasis when, when the melanocortin 4 receptor is activated, it will suppress vagal activity. So once again, we're coming back to that general same part of the brain that we started with, namely the ventromedial hypothalamus, that. But if MC4R isn't working well, the vagus isn't able to regulate insulin production very well. And by reducing vagal stimulation, normally the Mc4R is able to reduce insulin release. However, if the Mc4R or that pathway is, is broken or disrupted, now you don't have that ability to regulate insulin production, and insulin production just starts going through the roof. Now, one interesting quirk of this in the animals, this results in an, in an excessive, in a different kind of melanin expression. So that makes for the animals to be a very sort of yellowish appearance. That's why they're referred to as agouti yellow animals. In humans, this actually manifests with a very pale and very gingery complexion, which I'm sympathetic to as a former redhead myself. The people are born not only becoming obese very, very quickly, but with this shockingly bright red hair that again is a result of this disrupted melanin pathway, or the melanocortin pathway, to be a little more precise. So in every instance that is highlighted in the manuscript, whether it is the VMH lesion instance, whether it is the agouti Instant, the, the MC4R mutation, whether it is the leptin mutation, not only are there human analogs to this or instances where humans have the exact same problem, which gives us confidence in the rodent model, but every single model has one thing in common, namely they will result in a hyper secretion of insulin. Insulin cannot in any way be bypassed. Now, there are other points in human physiology that become relevant as we near the end of the lecture. The first point is the differential sensitivity of tissues to insulin. And this touches on a fat versus glucose metabolism. So insulin sensitivity can vary significantly between different tissues and even within various metabolic processes. For instance, as I mentioned earlier, insulin inhibits lipolysis or the breakdown of fat from fat cells. And it does so at much lower concentrations than is required for myriad other instances other effects, but especially for glucose uptake. So if you want glucose uptake, or if you're focusing on glucose uptake as your primary outcome of interest, that requires a higher insulin bump than there is for insulin inhibiting lipolysis. This means that even in states of insulin resistance where glucose metabolism is affected, insulin may still be effectively suppressing fat breakdown or inhibiting lipolysis, thereby generally promoting fat storage. Also number point number two, that we do see a selective insulin resistance in obesity, that individuals with obesity and type 2 diabetes will exhibit insulin resistance again related to glucose handling, but the ability of the insulin to suppress lipolysis in response to insulin remains intact. So, so this is further evidence that in but this is not everyone notices this. So let me mention another instance here that the manuscript in this publication, they note that after consuming a high fat but a mixed macronutrient meal, so fat and carbs a normal weight person who has an immediate family relative who's obese, so we would say that they have a predisposition to obesity, they will have reduced fat burning compared to the person who weighs just the same as them, has the same fat mass as they do, but they don't have a first degree family relative who's obese. I'm going to say that one more time. So if you have an individual, let's say imagine you have two individuals, one person has parents that are obese, the other person who weighs the same, same body shape and size and fat as the other individual who does not have a first degree relative who's obese, and you give them a mixed macronutrient meal. Then you measure, you just, you look at who's burning more fat after that meal, the individual who has a first degree relative or this predisposition to obesity, they burn less fat. That of course could mean that with the reduced fat oxidation following the meal, it could predispose the individual to storing more fat because they're burning less of it. Also individual women in particular, a study done highlighted in this manuscript, women who have lost weight and who are no longer obese, if you compare them to women who weigh the same as they do now, they will display even with normal insulin sensitivity, they will have normal insulin dependent glucose regulation, but they will have a heightened sensitivity to insulin's anti lipolytic effects. In other words, in these women who had been obese but lost the weight and now they were the same as their never obese counterparts. So at the moment they're just the same body type. You'd look at them and not know there's anything different. They have a heightened sensitivity of insulin's ability to, to promote fat storage. Now one other follow up on this, another point that the manuscript makes, which I very much appreciate, is the effects of looking at the meal. So kind of related to the topic I just got done discussing, but in studies that have compared dietary interventions, once again these people who have lost weight, so weight reduced individuals on a high carbohydrate diet, if you give them a high carbohydrate meal, they will exhibit lower circulating energy availability aft in this postprandial state. So after eating than if you give them a low carb diet. Now what's the difference between a low carb diet and a and a high carb diet but but matched for calorie number. So one is high carb low fat, the other one is low carb high fat in these individuals who had lost weight. Then you give them these two different meals and then you look at the sum of all calorie potential molecules in the blood. Free fatty acids, glucose, ketones, lactate, all of these molecules that can be burned for energy. If you look at them in the blood after the person eats the high carb meal, all of those are much lower. The sum of all of them them, the total energy available from the blood is significantly down compared to when they eat a low carb meal. And of course, the difference between those two, which one spikes insulin the most? And of course, it's the high carb, low fat version. If you eat a high carb, low fat meal, your insulin spike will result in this selective storage of energy. And the brain, who's generally not relying on any reservoir of energy, not like fat cells or even muscle, muscle even can store a lot of energy as f. Glycogen. The liver can store a lot of energy as fats and glycogen. The brain doesn't really have that potential. Thereby its reliance on what is readily available from the blood is much greater than those tissues. And then it's no surprise that the same metabolic milieu, which is resulting in reduced energy availability because of a greater insulin spike, comparing these two meals in these two studies, again is the same intervention that promotes hunger more sooner. That was a separate study. But if you do the same experimental breakdown of two isocaloric meals, high carb versus low carb, but matched in total calories, then the higher carb meal, which again elicits a greater insulin spike and less energy availability in the blood, promotes a faster hunger than the other version, even if it's the same number of calories. And so you can imagine the relevance here if you were able to track people for long enough, which most studies don't do, and, and allow them to be free living, the individual who is hungrier more often is of course going to be eating more. Now, again, why are they eating more? It's because, as this theory suggests, it's because their elevated insulin is always pushing the energy into storage, thereby allowing less to be actually used for the energy demands of living. Now, all of this so far has been as, as I start to wrap up how all of this has been looking at these interventions that are promoting weight gain for the most part, certainly all the animal models and the human analogs, it is instances of excessive weight gain. What about instances of excessive weight loss where you have a pathology? Is there a disease where a person cannot store fat on their body? There is in fact a problem called lipodystrophy, but that's not when I want to focus on, that's a primary deficit of the fat tissue itself. I want to look at someone whose fat tissue is fine. There's no genetic problem in the fat tissue. And yet because of another problem, they cannot store any fat. Can you read my mind? Can you think of a scenario? Is there a human disease which is surprisingly common, which if left unattended, they cannot store any. In fact, they can't keep any energy in their body, and it's just most obvious that they can't keep fat. That would be a little problem called type 1 diabetes. We don't think of type 1 diabetes as a fat problem. We think of it as a glucose problem. Now, if you'll allow once again, another little tangent here. There was once a very compelling article where the title of it was something like, what if Minkowski had been a gusic? Basically, if the original one of the earlier diabetes scientists had been unable to sense any difference in taste of urine, might these early scientists and clinicians have noticed a difference in the smell? And they would have noticed the ketones, the acetone, and then they would have said, well, ketones are a product of fat burning. So diabetes is a problem of fat burning rather than glucose. It's a pretty compelling idea just to think of how differently our view of this disease could have unfolded. Nevertheless, be that as it may, if you. If. If a type 1 diabetic is deprived of insulin, which in the natural course of the disease, they are, they cannot store any energy on their body. They are wasting away, even if they are eating thousands of calories. Indeed, they are eating a lot of extra calories, and they cannot keep a single scrap of fat on their body. This topic first became of interest to me when I stumbled on the work of two legendary scientists, legendary in the realm of cell biology, which means no one knows who they are. And this is Elliot P. Joslin, who is the godfather of modern endocrinology, indeed. Diabetes center named after him. The Joslin Diabetes center, truly one of the leading authorities on endocrinology, literally wrote one of the first textbooks on the topic. And his work that he did with Francis G. Benedict, which is one of the legends of metabolic rate, his Benedict equation is still used to this day. His. His insight was so remarkable. About 100 years ago, Joslin and Benedict came together to create the perfect kind of rock band of. Of metabolic science, where they. They vigorously quantified the degree to which metabolism is disrupted in type 1 diabetes, which they didn't call it that at the time, they called it severe diabetes, which was a death sentence. The person would literally waste away and then die, even though they were eating an abundance of calories. Later on, years later, groups would see that when you treat a type 1 diabetic with insulin, two things happen. They begin eating less and they begin getting fatter. How can we say that human obesity is purely a matter of calories in, calories out. Because if I just eliminate one single variable, namely the insulin, no amount of eating or drinking calories can keep a scrap of fat on that body. All right, so how do we wrap all of this up? How do we reconcile these two ideas, the caloric view of obesity and the endocrine view of obesity? And I think we ought to reconcile them because calories matter. They must be accounted for, even if we can't really account for them in all of the ways in which they're the energies kind of moving around. As I've said before, hormones, especially insulin, tells the body what to do with the calories that it has available. Or as this manuscript would say, hormones as drivers, calories as substrate. So if you have a fat cell, insulin tells the cell to store fat, but then the cell must have the building blocks for that fat or the calories, as we would say, or to say it a little more precisely, it must have the carbons to actually store. So that's where the calories come into play. You can't have one without the other. You cannot. There is no human obesity in the absence of even either of those signals. Let's just tease out in the final minutes here, because I continue, I continue to kick this longer than I intend to. If you had a scenario where only insulin was elevated, which is promoting the storage of energy, but it wasn't matched with a commensurate or a compensatory consumption of calories, the person would die. So that would be a person who just is, is spiking insulin and not eating. Then they become very, very hypoglycemic. Ketogenesis stops. So profoundly low glucose, profoundly low ketones, the brain must have one of those two fuels, and the brain shuts off. So if you had a scenario where you're trying to promote fat gain with just elevated insulin but no compensatory increase in calories, death is the result. Now, so that's the elevated insulin in the absence of energy. What if you flipped it? What if you have an abundance of energy but no insulin? Well, that's type 1 diabetes that we were just talking about. So you have an abundance of energy and yet you can't store any of it. It's all accumulating in your blood. The person's massively hyperglycemic. They're massively hyper ketonemic, or the ketoacidosis ultimately they're dead, they die. They can't use and store the energy. It's always just dumping into the blood. You need insulin to tell the body what to do with the energy that it has. Thus, in order to understand human obesity, we have to appreciate that you need a signal to stimulate the fat storage insulin, and you need sufficient calories to, to, to provide, to match that stimulus. You need the building blocks, so you need stimulus and you need, you need the stuff, the substance, the substrate, in order to actually fuel that growth signal. So the stimulus and the fuel both are necessary. You cannot have human obesity with just one. You have to have both. And, and as this study highlights, the order would be important that if you're chronically stimulating your insulin, you're directing energy to be stored, which in turn is resulting in a compensatory hunger, causing the person to eat, even though they're storing hundreds of thousands of calories already on their blood. I had a little more to talk about, but we've gone too long. Some of the practical implications here. I think I've made them all abundantly clear. I hope this helps when you understand. I'd like to think that as we understand the two part both essential aspects of obesity and the order elevated insulin resulting in the hyp, the excessive calorie consumption because of the partitioning. I believe that should also be the strategy for reversing obesity. That if our efforts to reverse obesity just start with low calorie without addressing the high insulin, that creates a scenario where we start to get hungry. The total energy availability in the blood goes down. The brain senses this and panics and says, we have to eat. And then the person will. Hunger wins. This is not just a matter of gritting your teeth and getting through it. Hunger wins and then they go right back to where they were before. So don't have the first step of weight loss be cutting calories. Let the calories be what they will. Let the first step be dropping insulin. Drop insulin and that will increase metabolic rate. It will increase ketone production. And ketones have a calorie that gets excreted from the body. Every, every ketone has a calorie load roughly comparable to glucose. We're dumping that into the breath and into the atmosphere. We're dumping it into the urine. So we have these, we, this outlet of wasting energy. So let the first step be controlling insulin, helping the body learn to burn its own energy for fuel. And then the calories will take care of themselves for the most part. All right, I hope this has helped. Until next time. More knowledge, better health.