The Science Behind Ozempic & Other GLP-1 Medications

GLP-1 receptor agonist medications, drugs like Ozempic and Wegovy, are changing the obesity medicine world, that's for sure. But there are a lot of really strong opinions out there. Should you take them or shouldn't you? Well, this video is going to be something entirely different in a couple of ways. First, it's a compilation of shorter past videos packaged so you can listen to complimentary collections in one place, like a movie or a podcast. Second, my goal here is not to tell you should or shouldn't like so many others do. Rather, I just want to share science with you without judgment and speak about data that are fundamentally intriguing. We're going to explain how mechanistically GLP-1 medications do really quiet food noise and liberate people to make better choices, how they are more than just weight loss drugs, how they affect inflammation, why some are better than others, and how they can be used for more than obesity. What's to come is too filled with interesting data and curiosities to have any room left for judgment. So let's dig in. I hope you enjoy and learn something. Take a moment to imagine your culinary kryptonite, that food when it's placed out in front of you, you just can't resist. You need to have it. For me as a kid, that was Walnut Dream Bars from Rosie's Bakery in Boston. If they were anywhere around, if we drove by Rosie's or if I got a whiff, I would hunt them down like a Walnut Dream Bar assassin. Now, I want you to imagine your culinary kryptonite. Imagine it was in front of you. Imagine that feeling of desire you would have. Now, I want you to imagine what if you could snap your fingers and you had the power to just kill that desire entirely, modulate your brain activity at will so your culinary kryptonite was entirely defused. Well, I can't grant you that superpower, but what I can do is tell you about brand new science in the journal Science about a neural mechanism behind the pre-ingestive desire and how a hormone can shut it off. This paper, again published in the journal Science, one of the top journals in the world, is entitled, "GLP-1 increases pre-ingestive satiation via hypothalamic circuits in mice and humans." Now, I don't know, I'm still holding that J-Ball. Now, what the researchers behind this study wanted to do was decode some of the neural mechanisms by which GLP-1 receptor agonists, this new class of drugs that's all the rage for weight loss, like Ozempic and Wegovy, by which they affect the brain to promote satiation and thereby promote weight loss. And what they found was really interesting, that humans given GLP-1 receptor agonists had greater satiation in particular during the pre-ingestion phase when provided with a food cue. So that's like me going by the Rosie's Bakery as a kid, and rather than needing that walnut dream, I'm like, eh, whatever. So humans provided with GLP-1 receptor agonists in general as a population have greater pre-ingestion satiation, and this effect is actually much larger than during ingestion satiation. So it's more about seeing the food and not really wanting it than starting to eat the food and getting full quickly, which is the common messaging. Now, that doesn't mean that isn't an effect. But based on these data, there was a larger group difference in the pre-ingestion phase, which is quite novel and very fascinating. They then went on to show that this phenomenon was conserved in mice, that if you gave mice GLP-1 receptor agonists, they also had higher pre-ingestion satiation. Now, you might be asking, well, why would you even go to the lowly mouse? You already know that there's an effect in humans. So what's the point of going back to mice if we care about humans? Well, what you really wanna do is figure out what is the neural circuitry that is mediating the effect. And in order to do that, you need to manipulate the circuitry, which you can do more easily and ethically in mice than in humans. So what they did is they identified both in mice and humans, there's an area of the brain called the dorsal medial hypothalamus, which expresses GLP-1 receptor-containing neurons. So the neurons have GLP-1 receptors, therefore they might be mediating the effect of the GLP-1 receptor agonist. But in order to prove that, they needed to go into mice and change activity in these neural circuits, which you can do with different techniques. One of my favorite and an increasingly common one is called optogenetics, where basically you express different channels on these cell surfaces that you can hit with light. And when you hit them with light, you literally kind of drill through the mouse's skull, and then you can like, you know, shine a light on these neurons. You can turn on and off the neural circuits. To show is it sufficient to promote or inhibit an effect. Now, I have a whole different video breaking down optogenetics, so go to this time point on this video if you want to learn more about that. But moving on, they were indeed able to show that the dorsal medial hypothalamic neurons expressing GLP-1 receptors were sufficient to promote satiation when turned on. And when they were turned off, there was that effect of 'Oh dang, I need that walnut dream' when it's present. So you can think of these as the pre-ingestion satiation neurons, at least a subpopulation of them. Now I say a subset of neurons because what I want to transition to talking about next is broadly heterogeneity. So take a look at this graph. Now the emotion I want to be evoked by saying 'take a look at this graph' and show you this intimidating graph is an intimidation factor. What you see here is what looks like a lot of messiness. —but basically what it's saying is there is heterogeneity in the neurons in the brain. So there are some neurons that are active during pre-ingestion, there are some neurons that are activated during ingestion, and then there are different populations of neurons that are all kind of jumbled together, some expressing leptin receptors, other GLP-1 receptors, some expressing both. It's all very messy. We like to imagine mapping out neural circuitry as like, you know, breaking up the subcomponents of a rainbow. Where they are very clearly delineated. But it's really more like looking at a bowl of soggy Froot Loops with a bunch of different colored Froot Loops in some sort of like liquidy mess. Hopefully your cerebral spinal fluid isn't milky, that would be bad. But point being, things are quite messy appearing. And there's a lot of heterogeneity geographically in the brain. But that is within a brain. More interesting perhaps, and more relevant, is heterogeneity between brains. Among brains, between minds, between people. And so a really, really interesting graph, going back to the human data, is this one. Because what it's showing you is the effect of the GLP-1 receptor agonist treatment on pre-ingestion satiation. And I mentioned before, in the population— I did emphasize population— there is greater pre-ingestion satiation when given the GLP-1 receptor agonist. That was the main effect. However, what this graph is showing is the effect broken down person by person, and greater pre-ingestion satiation in the GLP-1 group would be represented by an upward slope, so going from the bottom left to the upward right. And you see that in most people. However, you'll note there are certainly people who have the opposite effect. Some people who in the control group have a larger pre-ingestion satiation signal relative to the GLP-1 group. And this is really important because we like to use these, you know, randomized trials that we use to validate different drugs and just assume that the effects will generalize across populations. But the thing that's really important to acknowledge is there is enormous amount of heterogeneity among humans, in part due to the fact that we have different brains. And so you're going to get different responses. You're going to get people like that patient who, rather than having a positive response to the GLP-1 receptor agonist with a massive increase in pre-ingestion satiation might have no response or even a negative response, which when you're talking about real human beings, n=1 lives, is really important to acknowledge. Now I want to zoom back to this other graph, and I realize I'm jumping around, that's intentional, I'll explain why in a moment. But I want you to narrow in, I want us to narrow in on panel S, and what you see in panel S is a graph of neuron activities in these different subpopulations of neurons. You have the pre-ingestion neurons active during the pre-ingestion phase, and then the ingestion-active neurons active during the ingestion phase, with activity being on the y-axis labeled z-score. And so you'll see in the pre-ingestion phase, shaded in green, the pre-ingestion neurons spike. And in the ingestion phase, shaded in purple, the ingestion neurons spike. Makes sense, right? But you see something else that's quite conspicuous. The pre-ingestion neurons spike after ingestion. So they're not just pre-ingestion neurons, they're actually post-ingestion neurons too. So what do we make of this? The authors were actually surprised by this finding, but here's how I would frame it. To be clear, the authors didn't say this, this is my interpretation. Basically what's happening is, now that you've eaten, these pre-ingestion neurons are thinking, okay, these are satiation neurons, right? They're more active. When they're more active, there's more satiation. And so it's kind of anticipating the next food bolus. You just ate, right? So the neurons that will be engaged in seeking out food and driving you to grab that walnut dream are gonna be like, "Well, we just ate, so we might as well promote satiation because we just ate. We don't need more food." But food's on the mind because you just ate and food is presumably around, so you're thinking about it. That is a high-level overview. But what I really want to get to now is let's contrast that to something I think a lot of us experience, which is the inverse of the so-called sensory-specific satiety effect. You could call that inverse the "there's always room for ice cream" effect. Because what we're looking at here is again another generalization. Oh, you just ate, so these satiation-promoting neurons then become active. However, that doesn't necessarily account or necessarily correlate with behavior we see every day, where even if you're stuffed full of, say, turkey or steak, you might still have room for ice cream. So these neurons, these activities in the brain, become much more complex when you fold in different levels of heterogeneity, different geographies in the brain, different humans, different brains, different minds, different psychologies, different environments, different foodstuffs. The emphasis here is on the complexity, on the messiness. But really, I don't think of it as messiness. It's more elegant complexity, which I wanna highlight because I think people get frustrated with the nutrition world. They want the simple answers, things like calories in, calories out. We gravitate towards that. But we always need to appreciate that is incomplete and does not do justice to the incredible beauty, complexity, which sometimes look like messiness, that is inherent in our biology. And I think the moment you can accept that messiness, or what is really elegance, you can start to appreciate how cool your body is and embark on understanding it as a forever learning journey. I hope I'm getting you to appreciate some of that awe that I have for physiology, metabolism, biology. That's why I'm here talking to you. So I hope you have it, and I hope it's growing. It's something that I think you really should cultivate. But with that, let's get to less pie in the sky abstract ideas, some more actionable takeaways. What are my prescriptions for you? Well, as always, my number one prescription is please administer, please self-administer deep thought at least Q4 hours plus PRN. Just kidding. No, but in all seriousness, I hope what these data and me sharing these data do for you is inspire you to reflect and think about things like pre-ingestion signals in your environment that are specific to you and might hit your specific dorsal medial hypothalamus. So observe your brain activity. Now it's true you can't actually observe your brain activity, but you can observe the manifestations of your brain activity. Hold them in your awareness and then curiously explore how you might manipulate them to achieve the ends you want. And that could include developing the superpower to resist your culinary kryptonite. Hope you found this video fun. About a year ago, I thought if I said GLP-1 or GLP-1 receptor agonist, your average non-medical person would have no idea what I'm talking about. Oh, how that's changed. This family of weight loss drugs has taken the obesity and metabolism world by storm. With mixed opinions. Some people think they're God's gift to modern medicine. A secular scientific miracle. Others are skeptical. Given the history of weight loss drugs in medicine is, well, not so great and riddled with missteps. But what if GLP-1 receptor agonists, these weight loss drugs, are different? What if they're not weight loss drugs, or at least not only weight loss drugs? In this video, I'll prove this to you, and by the end, we'll come full circle to acknowledge a shocking truth that's deeper than muffin tops and love handles. And I'll end by telling you what's even better than GLP-1. It may surprise you, or it may not. But first, a big caveat. I am not here to place judgment on the clinical use of these medications. That is not my place. That place is the doctor's office. I'm here to talk science. But because my opinion is probably relevant to my audience, I'll just say my opinion on these medications is that they're powerful tools that should be used in the right patients, like many medications. However, at a societal level, I am personally concerned about adopting a widespread cultural position that injections and drugs are the answer to the obesity epidemic, to the point that we lose sight of this fact, and that the obesity epidemic— obesity is a disease of lifestyle, it's a disease of environment, and that these are also things we must change if we are truly to succeed in forcing obesity towards extinction. Anyway, on to the science. A recent review article published in the journal Science discussed many of the applications of GLP-1 medications. Including beyond obesity in cardiovascular disease, liver disease, mental health and neurological disorders, and so on. It makes the point that the benefits of GLP-1s are not just related to weight loss, but also that, and now I'm quoting, "A potentially unifying mechanism of action for GLP-1 receptor agonism is the reduction of inflammation." And this led me to another paper published in Cell Metabolism earlier this year, where they showed that the actions of GLP-1 on the brain caused a decrease in inflammation in the body. I'll repeat that: GLP-1 actions on the brain caused a decrease in inflammation in the body. And in this study, what they did is they treated mice with a substance that causes inflammation, lipopolysaccharide, or LPS. Which can be measured— inflammation can be measured by an increase in inflammatory signaling molecules like TNF-alpha. And then they also treated some mice with a GLP-1 receptor agonist and observed reduced inflammation in the GLP-1-treated mice. But then they did something else very important. They did the same experiment, treating mice with the inflammatory substance to induce inflammation and trying to dampen that inflammation with a GLP-1 receptor agonist, but they applied it in mice missing the receptor for GLP-1, the GLP-1 receptor, in various tissues and organs. So in one experiment, they deleted the GLP-1 receptor from various blood cells and cells that line blood vessels, endothelial cells. And interestingly, in these mice lacking the GLP-1 receptor in those tissues, GLP-1 could still reduce inflammation. So those receptors were dispensable. They weren't that important for the anti-inflammatory effects of GLP-1. But in another experiment, they deleted the GLP-1 receptor from the brain of the mice exclusively, and in these mice, GLP-1 did not reduce inflammation. And they even verified this with another mouse model lacking GLP-1 in the brain. And all this strongly suggests that it's the action of GLP-1 on the brain that mediates the systemic whole-body anti-inflammatory effects of GLP-1 drugs, at least in animals. But what about humans? Because you can't very well delete GLP-1 receptors from various organs in humans, especially not the brain. However, there are signals that the benefits of GLP-1s in humans can be independent of weight loss, or separable. For example, in the SELECT cardiovascular outcomes trial studying people with obesity, the extent of weight loss did not correlate with the effects of the drug to reduce heart attack, stroke, and cardiovascular death. Also, another prior long-acting GLP-1 therapy was withdrawn from the market owing to its modest effects on reduction of glucose and body weight in people with type 2 diabetes. However, it still reduced the rates of major adverse cardiovascular events by 22%. So again, in humans, we see the signal where GLP-1s can have benefits even independent of or separable from weight loss. So point being, GLP-1s in humans almost certainly have benefits beyond weight loss, and in part this might be due to reduced whole-body inflammation. So now pivoting a little bit and getting more abstract or zooming out, here's the core truth I want to communicate in this video: metabolic health is not simply about weight. Duh, right? But more importantly, good metabolic health causes healthy weight, not the other way around. As applies to obesity, one could reframe this is that eating in a way that promotes high blood sugar, high insulin, and inflammation, and overall throws your body into metabolic disarray, that's what causes obesity. And this is in contrast with the overly simplistic calorie balance, energy surplus mindset that's still plagues society like a mind virus. And this critical contrast is really important to acknowledge since we are living in a world where calories remain king from a mechanistic point of view on obesity, but where we're leaning into drugs to solve the problem and inappropriately attributing their benefits to simply less hunger and fewer calories eaten, when the effects of these GLP-1s are clearly more metabolic and more complex. As I hope I've convinced you in this video. And that brings me to the intervention that's even better than GLP-1s, albeit a little bit harder to implement, which is living a healthier lifestyle. Okay, I'll give you a moment to finish your eye roll or groan or moan, but hear me out. The lifestyle line—live a healthier lifestyle—has taint because it's often seen as victim blaming in the camp of eat less, move more advice. But that is not what I'm suggesting. I'm suggesting that as a society, we have lifestyle and environmental creep, where being more sedentary and eating worse— not more calories, but worse food in terms of food quality— is facilitated by changes of our social norms and physical environment. I could provide many examples, but I know you know what I'm talking about. So the solution, as I see it, needs to be talking about these social norms and changing our environmental structure. I want to see a world where there aren't junk food-filled vending machines in hospitals, where it's not normalized to dump 10 teaspoons of sugar in your coffee, where supermarket aisles aren't themselves obese with colorful sugary breakfast cereals targeting innocent children for profit. And that doesn't mean— it does not mean that GLP-1s aren't a useful tool, that they don't have their place, but they're not enough. Let's not lose sight of the metabolic forest for one very financially fruitful tree. Tirzepatide. It's a big word, but don't be intimidated. And it's a word you're going to be hearing a lot of if you've heard the word Ozempic. Ozempic obviously being one of the brand names for the blockbuster class of weight loss drugs that is taking over obesity medicine and quite honestly has ingrained itself in societal psyche. So basically, tirzepatide is Ozempic Plus. I call it Ozempic Plus because, well, one, it actually has the mechanism of action of Ozempic, plus another that I'll talk about. But more to the point, it outperforms Ozempic for weight loss. So it's better than Ozempic for weight loss, and a big question that remains unanswered is why. What is the particular advantage of tirzepatide over Ozempic? That's the trillion-dollar question, or I guess however much the obesity pharmacotherapy market is worth. I didn't actually do that research, but you can go Google that if you want and tell me in the comments. Anyway, a new paper published in Cell Metabolism just a couple weeks ago starts to unpack the physiological distinctions between tirzepatide and semaglutide, Ozempic, and shows why the advantage of tirzepatide occurs. Now, to be clear, I'm not advocating for or against this drug. That's not my domain. But I think that there are very interesting physiological teachings to be drawn out of the literature. So my purpose here is to stimulate you to think, and I promise at the end of the video I'll also provide you links to access more information about GLP-1 receptor agonists and tirzepatide and this new generation of weight loss pharmacotherapy. Again, not to advocate for or against, but to make you possibly an informed consumer, or just to stimulate your curiosity about the physiology, because I think it's freaking cool. So with that, let's dig into it. So what is the structural distinction between semaglutide, Ozempic, and tirzepatide? Semaglutide and related drugs are called GLP-1 receptor agonists, agonists means you're activating a pathway. So basically semaglutide and other GLP-1 receptor agonists activate the GLP-1 receptor pathway throughout the body. Now, tirzepatide is also a GLP-1 receptor agonist, but in addition to that, it's a GIP receptor agonist. So there are multiple incretin hormones, incretin hormones being released from gut cells, and these medications are effectively mimicking these incretin hormones, but they're dosed at supraphysiological levels, and they stick around in the blood for a long time. So they kind of have a chronic effect rather than an ebbing and flowing that occurs with normal ingestion and endogenous production. So now I'm going on a tangent, but to get back to the point, the fact that tirzepatide activates the GIP receptor in addition to the GLP-1 receptor is unique and an interesting thing. But the GIP receptor versus the GLP-1 receptor is GIP receptors are expressed on adipocytes, fat cells whereas GLP-1 receptors are not so you can see that here what you see here is human fat cells and basically you have a control on the far left and then you see that the second column is tirzepatide or a pure GIP receptor agonist so you have these compounds binding to the surface of cells as seen in red and then you have— eX is basically the equivalent of semaglutide— a GLP-1 receptor agonist. And what is very clear is you see red where there are compounds, tirzepatide, or a pure GIP receptor agonist that would bind to the GIP receptor. So basically this is showing fat cells express GIP receptors but not GLP-1 receptors, which leads to the possibility, hmm, maybe the advantage of tirzepatide, say over Ozempic or semaglutide, has to do with actions on fat cells, which, spoiler alert, is what they discover in this paper. Moving on, think about this. I already told you that these drugs stick around in the bloodstream for a long time. The half-life of trazepatide, which is the amount of time it takes for a drug's levels to cut in half, is about 117 hours, which is about 5 days. So over the course of 5 days, what does the average person, minus snacks, do about 15 times? Now, I said minus snacks because obviously I'm alluding to eating. The point I'm trying to make here is that because trazepatide sticks around so long, you're going to be in postprandial periods after you ate and there's going to be a particular metabolic context there, and fasted periods. So, tirzepatide is going to affect fat cell physiology during both postprandial periods and fasting periods. What it does specifically is interesting. Basically, again, trying to keep this as high level as possible, it enhances metabolic flexibility. It improves disposal of fatty acids and glucose to improve glucose homeostasis in the postprandial period. But then when you're fasted, what it does, and they show that in this paper, it enhances lipolysis, the liberation of fat from fat cells to fuel the body during the fasted state. So tirzepatide acts on fat cells to enhance metabolic flexibility. But let me not just tell you, let me show you. So here are key data from the paper. And what you're looking at here is effectively a measure of lipolysis on the y-axis, whereby a higher level on the y-axis suggests more lipolysis, more liberation of fat from fat tissue. And what you see is that treatment with tirzepatide, which activates GIP receptors on fat cells, or a pure GIP receptor agonist, the blue line, increases lipolysis. Fatty acid and glycerol, that's the backbone of stored fat, triglycerides, increases lipolysis versus insulin, which kind of acts as a lock on fat cells. So it has an opposite effect of insulin on fat cells, in particular during a fasted state versus during the postprandial period. It might actually synergize with insulin. So there are overlapping and distinct actions with insulin whereby it can enhance insulin sensitivity, improve glucose disposal during the postprandial period, but in the fasted period it enhances the liberation of free fatty acids. And just a little bit more data, what you're looking at here, for example, is expression of key enzymes in lipolysis. So HSL is hormone-sensitive lipase, which is really important in releasing stored fat. And what you can see is that tirzepatide, the red bar, massively increases increases hormone-sensitive lipase levels and activity. This is actually the phosphorylation, which is basically putting a tag on the hormone-sensitive lipase to activate it. And bottom line, what you're seeing is trizepidide activates fatty acid liberation and fat burning pathways versus insulin, which kind of inhibits them. So that is again just showing you some of the data to give you a little bit of a taste. I'll link to more information below. But simply put, trizepidide has a benefit beyond GLP-1 receptor agonists. By further enhancing metabolic flexibility. During the postprandial period, it can help take up glucose by enhancing insulin sensitivity. During the fasted period, it can help liberate fatty acids to fuel you. So basically, tirzepatide has the enhanced benefit of improving fuel partitioning—how energy fluxes into and out of fat cells over time, over feeding and fasting cycles. So I really want to impress on you the importance of fuel partitioning. In weight management. Now, sorry to beat a dead horse on the whole fuel partitioning thing, but I did promise I'm not advocating for or against these drugs, but rather wanted to highlight these data to emphasize a broader physiologic teaching. And I think what that is, is that these data are consistent with the idea that tirzepatide's primary anti-obesity advantage over just GLP-1 receptor agonists like semaglutide or Ozempic is that it affects fuel partitioning by altering physiology, metabolism, and the hormonal intricacies at the fat cell.. And that downstream of that, as a consequence of that, there may be things like decreased caloric intake. However, the primary driver, the quote problem, if you want to consider the problem being the etiology or the primary driver, is not as simple as, oh, people just ate less. Rather, fuel partitioning and physiology at fat cells can drive energy balance. As I've said before, calories are like the wheels on the car. They're taking directions from the driver. Fuel partitioning, physiology, metabolism, which are not only way cooler, but they are what give us pathophysiological insights into obesity where calories in, calories out, CICO, never will. That's my lesson for you. You can let me know your thoughts in the comments. Oh, and I will link to a bunch more information on these class of medications below because I'm going to have a bunch of cool fun facts that I dissect based on the current literature, new papers published in Nature Metabolism, Nature Cell, Cell Metabolism. And again, it's just not to advocate for or against these drugs, but because I think that their advent provides a lot of substrate— sorry for the puns— to provide physiologic teachings. And I hope you appreciate that. This video is going to be something different. I'll fully unpack what I mean by that in a moment, but broadly, this video is going to be about GLP-1 receptor agonists, that new class of blockbuster weight loss medications like Ozempic and Wegovy that are taking over the obesity medicine world, and honestly, social psyche as well. Anyway, I'm going to go over 4 papers published in top journals—Nature, Nature Metabolism, Cell Metabolism, and Science—published just within the past couple months. So this isn't information you're going to be getting really from other sources. And also, to be clear, I'm not going to be advocating for or against the clinical use of these drugs. This is going to be about basic science and physiology, what the mechanisms that are being discovered underlying the efficacy of these drugs can teach us about physiology. So this is a physiology lesson, not a clinical lecture. Anyway, with that, I did say this was going to be something a little bit different. What I meant by that is it's going to be a high-level overview of these 4 papers. I'm going to keep it as basic as I can, actually do a 1-1-1 approach where I present a finding, draw a conclusion, and then ask you a question. And it's gonna be a nested intellectual environment. So for each paper, I've also done a separate deep dive, which I'll link below. So we'll keep this one high level, but if you wanna go into the nitty gritty, see the other videos and resources. Anyway, with that, let's dig into it and hopefully learn some really cool things about physiology. Ozempic without nausea. So the first paper I wanna talk about was published in Nature, July 10th, 2024, which is one week ago. At the time I record this. And it talks about this common phenomenon of nausea with taking these GLP-1 receptor agonists. About 60% of patients will experience some degree of nausea. And they kind of ask the question, could you design an Ozempic 2.0 that doesn't carry the risks of nausea? Now, for that to be the case, you'd need separate biological circuits, one exerting a pure satiety effect and weight loss effect, and the other exerting a nausea effect. And what they find in this paper, high level again, is indeed this is the case. That there was an area of the brain, the nucleus of the solitary tract, that you could specifically target and get weight loss and satiety without any nausea. Whereas the area postrema, a different region, exerted a nausea effect. And while targeting the area postrema could cause nausea, food aversion, and weight loss, these two areas, activating these two areas that express GLP-1 receptors in the brain, were not additive. So you didn't get any extra weight loss benefit, at least in the preclinical model, by targeting the area postrema, leaving open the possibility that you could basically target this one center, the nucleus of the solitary tract, and get all the satiety, all the weight loss, without any risk of nausea. So that's really interesting. That's kind of the conclusion, the extrapolation. I guess the question that I would then bring up is, to do this in mice, you can manipulate brain circuitry. You can use optogenetics, reviewed in other videos, to shut off, silence certain brain circuits. How would you do this in humans, though? How would you design a drug to target one region of the brain and not the other? Or, otherwise stated, how could you shield a region of the brain? Could you do this with human pharmacotherapy? Anyway, provocative question. I think it's really fascinating that there are these different neural circuits, and I'm going to leave you with that., and you can go check out the deeper dive if you want to. Now, moving on. GLP-1s and polycystic ovarian syndrome. So now I want to talk about a paper that was published in Nature Metabolism, May 20th, 2024, and it discusses polycystic ovarian syndrome, a very common reproductive disorder in women typified by irregular periods, elevated androgens, so male sex hormones like testosterone, and/or polycystic ovaries. You need at least 2 of those 3 to have polycystic ovarian syndrome. Now, an interesting thing is that polycystic ovarian syndrome is associated with insulin-resistant disorders like diabetes, also cardiovascular disease. And GLP-1 levels are known to be reduced in various insulin-resistant disorders. So GLP-1 levels are reduced in obesity, and GLP-1 levels are reduced in PCOS. What they found in this paper though, the main finding is that giving back GLP-1 was sufficient to basically erase PCOS in a PCOS mouse model, which is really fascinating. You can see that here. Here's the PCOS mouse model. What happens when you give liraglutide, uh, GLP-1 receptor agonists? Boom! Cysts be gone. Now that is the main finding. The conclusion therefore, or the extrapolation, is maybe GLP-1s could treat PCOS in human females. And the question I guess I'd leave you with is, do you think Ozempic or related drugs are going to be approved for PCOS? And if so, give your best guess on the time frame over which that'll occur. Anyway, resisting your culinary kryptonite. I have to admit, I had fun with the title, uh, concept, packaging, and thumbnail on this one. You should definitely go check out that video because I'm particularly proud of it. I thought it was a lot of fun. Anyway, this paper published in Science, June 27th, 2024, talks about broadly food noise. Food noise is a subjective descriptor that patients and physicians might use to describe that chatter that goes on in your head about food. So you're always thinking about food, always thinking about how to access food, and eventually it leads people to falling off the bandwagon. And people say GLP-1 receptor agonists like Ozempic reduce food noise. Now, that's obviously a subjective descriptor, but now there's science published in Science to explain why that's the case. And what they did in this study is they looked at the effects of GLP-1 receptor agonists on satiety, but they bucketed it into ingestion satiety—so when you're eating, you know, how full you get, how quickly—versus pre-ingestion satiety, which relates more to food noise. So when you get cued to food in the environment. Do you have a lot of food noise, or are you able to say, "Nah, I don't need that"? That's pre-ingestion satiety. That's reducing food noise. And what they found actually in humans and in animal models is that indeed the biggest differentiator in the GLP-1 receptor agonist group versus the control group was the pre-ingestion satiation, basically the reduction of food noise. So I find that quite interesting. It basically is a finding that— this is the conclusion— confirms the subjective experience of patients with respect to this descriptor, reducing food noise. So another question, this is the question I'll pose to you if you're not taking this drug, or if you are: what are other ways to reduce food noise, maybe without pharmacotherapy? Are there lifestyle interventions? Are there environmental building exercises maybe just getting certain foods out of your access, out of your awareness, that can help reduce food noise and therefore help be lifestyle interventions that could lead to better success. Better than Ozempic. So in this paper published in Cell Metabolism, June 14th, 2024, they start to dig in to the differentiating physiology between a newer generation of weight loss drugs, the GLP-1 receptor agonist combined with GIP receptor agonist versus Ozempic. So you might have heard of this drug tirzepatide. It's kind of like Ozempic, but it's Ozempic with a bonus. That is, it's a GLP-1 receptor agonist, but it also is an agonist of the GIP receptor, with GIP being another incretin hormone released from the gut. So you have GLP-1 released from L cells, you have GIP released from K cells in the intestine, and they act on different receptors around the body. Now, earlier in this video, we alluded to the fact that there are GLP-1 receptors in the brain, and they're elsewhere in the body as well. But interestingly, where there are not a lot of GLP-1 receptors is fat cells. So GLP-1 doesn't act that directly— it can act indirectly, but not that directly— on fat cells. But GIP is highly expressed on fat cells. And what they find in this paper is GIP receptor agonists, including tirzepatide, can act directly on fat cells, bind to fat cells, as you can see here in red. And what it does is basically enhance metabolic flexibility. That will be the high-level summary. Where tirzepatide, when provided, has a long half-life, about 117 hours, or about 5 days. So it takes about 5 days for the drug's level to be halved. And over that time, it's chronically stimulating signaling in the fat cells as you go through feeding periods and you're in the postprandial period and fasting periods. And in the postprandial period after eating, it helps with glucose disposal, keeping your blood sugar more stable. And in the fasting period, it enhances lipolysis, it enhances fat burning. So basically what it's doing is it's making your fuel partitioning. Your metabolic flexibility more dynamic and adaptive. And so basically the benefit, the margin between the benefit of tirzepatide, which is more powerful than Ozempic, has to do with enhanced metabolic flexibility and fuel partitioning via action on fat cells. And if you want more on that, my conclusions and questions, I'm actually going to tease you to go watch a whole separate video on fuel partitioning. So I have a video on tirzepatide. And why it's better than Ozempic physiologically, and then a separate video on fuel partitioning. You should go watch both of those. With that, I'm going to wrap up this video, but again reinforce what I was trying to do here. Not talk about the pros and the cons clinically of these medications. You can get that elsewhere. You can get fearmongering about the side effects or praying to the altar of GLP-1s elsewhere. What I want to talk about here is, look, we have these medications out in the world. We have interesting physiology via these medications, and we should just study it, and I think be interested in the underlying physiology of how they work, because from that we can gain knowledge that can lead to future innovations. And it's not always clear the benefits we'll get out of just studying basic science. It actually is a nice, you know, full circle coming around, because where do these medications come from? They came from studying the basic science of Gila monster venom. And then when scientists in the '90s were studying Gila monster venom, they didn't know that now in 2024 we'd have multiple drugs and multiple evolutions of drugs that are changing the weight loss game. They just were studying the humble Gila monster. They were staying curious, and look where we are now. Whether that's a better or worse place in your opinion, I think it's a pretty fun and exciting ride. I hope you agree. I don't have ovaries. Surprise! Or maybe not. What I'm trying to say is I'm in the privileged position to not have to worry about polycystic ovarian syndrome, or PCOS, a burdensome condition that is defined by at least two of the following three criteria: irregular periods, elevated androgens like testosterone, and polycystic ovaries. And PCOS is further associated with cardiovascular disease, high blood pressure, and insulin resistance-related disorders like diabetes. But as you learn in medical school, the etiology, the cause, the pathophysiological cause of PCOS is pretty poorly understood. It's something to do with insulin resistance, but the specific causes are still being worked out. And a paper recently published in Nature Metabolisms, quickly becoming one of my favorite journals, entitled "The microbial metabolite Aggmantine Acts as an FXR Agonist to to promote polycystic ovarian syndrome in female mice, although they have a lot of human data which we'll get to, provides new answers and highlights avenues for further solutions. So let's dig into some of the data and hopefully learn something valuable. First, for a bit of background, it's known that patients with PCOS tend to have insulin resistance and microbiome dysbiosis, an altered gut microbiome. Now, these are rather nonspecific signs associated with metabolic diseases, so what we really need is mechanistic links between PCOS the microbiome, and insulin resistance. It's like taking a biological puzzle box, flipping out the pieces, and then you have to flip the pieces over and puzzle them together to get a better pathophysiological picture, a clearer picture of the puzzle. So that's what we're doing here in this paper. So let's start to puzzle some of the pieces together, starting with data from human subjects. In this paper, they looked at patients with PCOS and healthy controls. The patients with PCOS had much lower levels of the hormone GLP-1. You might have heard of this hormone name before because it's the hormone that blockbuster weight loss drugs like Ozempic and Wegovy try to mimic, which is why they're called GLP-1 receptor agonists. They bind to and activate the GLP-1 receptor. This is also why you can call GLP-1 nature's Ozempic because it's the natural form of the hormone that these drugs try to mimic. So they looked at patients with PCOS and saw they had much lower levels of GLP-1, as you can see in this graph, and also that lower levels of GLP-1 associated with higher androgens, as you can see in this graph, and more insulin resistance. So what you're really seeing here is that GLP-1 levels are lower in PCOS, and that, that associates with the profile, the metabolic profile of PCOS— higher androgens, more insulin resistance. Now let's change to talk about a little bit of mouse data. Okay, now let's turn to a little bit of the mouse data. From prior research, the researchers knew that mice with PCOS tended to have higher levels of a particular gut bug, B. B. vulgatus, and that they thought this may have roles in PCOS. So they looked at these mice and found they had a very, very similar profile to humans with PCOS, including lower GLP-1 levels and of course ovarian cysts. And you can see that here. Look here, this is the control and this is the B. vulgatus, BV, PCOS mice. And you can see these large cysts represented by the clear cysts and the hashtag over them in the PCOS mice. But here's the interesting thing. What if you take these mice with the B. vulgatus and you treat them with the GLP-1 receptor agonist. If GLP-1 deficiency is driving PCOS, that should improve the PCOS and the cysts should go away. Do we see that? Indeed we do. So these are the PCOS mice now treated with the GLP-1 receptor agonist liraglutide, and you can see the cysts go away, which is really cool. Okay, now pause and see what I've done here. I've intentionally filled in some of the puzzle, started to put the corners together, but left out conspicuous pieces. We have the observation that a particular bacteria B. volgatus, might be elevated in PCOS, and the GLP-1 levels are reduced. But let's link these together. What is the metabolite produced by the bacteria, and to what receptor does it bind to potentially decrease GLP-1 production? What we really want is a microbe-metabolite-receptor-hormone axis to help explain PCOS. So let's work backward along this pathway, starting by talking about the receptor. If there's a receptor activation of which depletes GLP-1 levels, drives PCOS, then if you break that receptor so you can't activate it, you should restore GLP-1 levels and improve PCOS. So that's what they did in one experiment. Because you can genetically manipulate mice, they broke a receptor they identified as key in depleting GLP-1 levels, the FXR receptor. So the FXR is activated, and when it's activated, it depletes GLP-1. When they took mice and broke FXR, what you can clearly see is that GLP-1 levels are restored. So the orange bar is the the PCOS mice, and the pink bar is the PCOS mice but they broke the receptor. So the BV bacteria couldn't produce some mystical metabolite that activated the receptor because there was no functional receptor to activate. And you see when the receptor is broken, GLP-1 levels are restored. Now what happens to PCOS? Well, let's look at the ovaries. You can see here very clearly PCOS cysts, PCOS mice, but when you break the FXR receptor, the cysts go away. So you have here a restoration of GLP-1 levels and a recovery from PCOS, showing this FXR receptor is critical in the pathway. And there's reason to believe this is relevant in humans as well. Now, you can't genetically manipulate humans, at least not yet, but you can look at markers, say, of FXR activity, one of which is FGF19. And if in humans FXR activity was elevated, driving down GLP-1 and driving PCOS, you'd expect FGF19 levels to be elevated with FXR activity. Activity. So do we see that? Yes, patients— human patients with PCOS have elevated FGF19 levels, the marker of FXR activity, and there's an inverse association between FGF19 and GLP-1. So really what this is saying again is in PCOS there's this BV bug that's somehow activating FXR to drop GLP-1 levels, driving PCOS. And the next question again is what is the metabolite the BV bug is making that is the mediator of this axis. So again, microbe-metabolite-receptor-hormone axis. We have B. vulgatus as the bug, FXR as the receptor, GLP-1 as the hormone, and what is the metabolite? So how do you find a metabolite, or where do you look for a metabolite that's produced by gut microbes? You look in the poop. So they look in the feces of human patients with PCOS and the BV-PCOS mice, and what they found in both cases, seen here in the orange bar FRS is higher levels of a metabolite called agmatine, which is a byproduct of arginine and amino acid metabolism. And again, in both cases, human and mice, agmatine levels were elevated, and they found that agmatine can bind to and activate FXR. So we complete the puzzle: B. vulgatus produces agmatine that activates FXR, drives down GLP-1 levels, and that drives PCOS. So now the obvious next question using this better physiological understanding, can we intervene on this axis to treat PCOS? In this study, they show that you can indeed intervene at multiple points along the axis to treat PCOS. For example, you can inhibit agmatine production with an enzyme blocker called difluoromethylarginine, or you can block the FXR receptor, or you can just boost GLP-1 levels downstream with a GLP-1 agonist. That's all summarized nicely here in this little diagram. And in humans, this should work too, in theory. The issue is, well, what's really available? There are quite a lot of options, potentially a few family of compounds that could, say, boost GLP-1 levels, including TGR5 agonist, FXR inhibitors, DFMA, and of course GLP-1 receptor agonists. But as far as I'm aware, you can't go pick up any of these classes of compounds at your average drugstore over the counter. Now, obviously I can't prescribe you a GLP-1 receptor agonist over YouTube, nor would I, or should I. But, um, I can offer you one potential idea, which is related to the sugar allulose, the rare natural sugar allulose, which I've covered in deep dives in prior videos. Now, the interesting thing about allulose, potential metabolic advantage, is that it boosts GLP-1 levels. It's been shown, at least in animal studies, it can boost GLP-1 levels up to fourfold in the portal vein going to the liver, which is really, really interesting and provides biological plausibility for how allulose could actually treat PCOS. Now, there are no human studies on this. I'd love to see that study. It hasn't been done. But in theory, by boosting GLP-1 levels, it could ameliorate PCOS. So allulose is something that you could try if you want to.

You said something about how, how they should be used and, uh, what your thoughts were on that. So yeah, I, I, I'd like to start there. Just kind of, um, what is your current understanding of what, what exactly the science is behind them, how they're working, and, uh, yeah, what is your thought on how they should be used, if you have any.

Yeah. When I say should, I'm talking about population level, not individual level. That is not my place. I am not yet a clinician. I think they are really incredible tools that are scientifically fascinating. When I cover them, it's because it's like, well, that's interesting. Like, this is how it quiets food noise. You know, you hear those things in the clinic like, you know, quiets food noise.

What the heck does it mean?

You read a paper And it's like, oh, that makes a lot of sense. It's acting on the dorsal medial hypothalamus to do X, Y, and Z. And this manifests in what's called pre-ingestion satiety. And people basically, when they're cued by their trigger food, don't have as visceral a response. And so you can kind of like match up the human experience with what's going on physiologically. And I think my opinion is their best use case is to use them as a catalyst for lifestyle change because the fact of the matter is We live in a really problematic food environment that is just littered with dietary booby traps, and people are going to be tempted. It's not just a matter of willpower. It's more complicated than that, socially, environmentally. I think some people really do suffer from this phenomenon of, "Let's just focus on the food noise." So imagine you can give them something that creates that mental space and mental freedom, so when they're at that dinner party and there's the cupcake. Or whatever their Achilles heel food was. For me as a teenager, I'll tell you, there's a bakery in the Boston area called Rosie's and they had these Walnut Dreams. And like, I was like a heat-seeking missile if there was any possibility of getting them. Like, that was my like food noise food. I could not stop. Now, I didn't have a weight problem, but imagine if I did. Like, if I could take something, including an injection, to give me the peace of mind so that like I don't just reach out for it impulsively but have the pause, and be like, oh, you know, maybe I can make a smarter choice. That's an incredible tool. So I think that GLP-1s can be used as a catalyst for lifestyle change, and that is the best use case they could have rather than using it as like, you know, the pill mill approach, or I guess, you know, most are injections obviously, but where, you know, diet and lifestyle isn't really part of the conversation and people just think, oh, this is going to make you eat less. Because I don't think that is a sustainable solution either on an individual level, probably more for economic reasons, or definitely not on a population level. So my main concern with them is not their metabolic effects, not the side effects, um, not even the economic effects, but this idea that they become the safety net and then we stop talking about what the root cause of obesity is, which continues to be lifestyle. So we need to talk at a broader level about How do we restructure the food environment? How do we change grossly dysfunctional food norms? And what role does like, you know, government or just like social discussions have in this? So with the success of this pharmacotherapy, I think comes the danger of losing sight of what the real cause is and seeing the tree and missing the forest. So it is more that sociologic perspective that I find the concern. Metabolically speaking, I think that they are a great tool for certain patients. And on an individual level, I'll just say like, you know, if I have a family member who struggled with obesity, and I do, like, I will advocate for them to have access to this tool because I know the world they're living in, I know what they've struggled with. Um, so I just think we need to have these parallel conversations. I am not pro or anti, I'm interested in the science. I think they're a useful tool in the right patients. But I think it would be a gross shame to lose sight of the fact that really it's lifestyle that we still need to focus on.

Holly, I absolutely want to hear your thought on this too as well. I'm just going to add that it's unfortunate that it's already beyond the point of what you're saying. I mean, Dr. Fatima, I think, or Fatima was her name, came out on Yeah, yeah, she came out on, um, 60 Minutes, uh, January 1st, 2024, and said it's a brain disease, it's a brain disease. And this— oh my, that really, it really upset me.

I'm about like a block from her right now, actually. I mean, she's at MGH, and I love next to MGH. We've talked a few times. She seems lovely in person, honestly. Um, I didn't— yeah, you see that whole 60-minute clip? Oh yeah. Was she really, she really like, that was a legitimate representation of her overall point and wasn't taken out of context.

All right. 100%. Uh, it's a brain disease and, and that's why I was like, hey, we're beyond the point of it being already used incorrectly or thought of removing all responsibility from our ability to take responsibility and it's lifestyle. Like now that she's mentioned it and how it's being used is exactly like that. And of course people Oh, right, as soon as they hear that, oh, I could— it's not me, you know. And that's the problem. That's the problems right there. And I don't know how we're going to— how we're going to beat that. Holly, what's your thoughts?

Yeah, I mean, that's definitely the Band-Aid solution, right? I— look, I think, um, I liked what Nick said before, that, you know, it allows people to pause before making a decision around whether they need to eat something else. And I think this is kind of relevant to me because a lot of the people that I'm working with have come to me with a background of disordered eating or eating disorders. Um, for those that don't know, I openly shared my story on the Peter Attia podcast about, you know, a lifelong struggle with, with an eating disorder. So I, I think that for many individuals there is definitely a huge psychological component to this. So, you know, this, this drug, I mean, it is so effective at suppressing your appetite. So, you know, if there are reasons other than physiological hunger or environmental stimulus or social implications, you know, that are making when somebody chooses to eat more food, it really does give an individual the opportunity to pause for a second and actually think about that. You know, am I actually hungry? Do I have a physiological need to eat right now? Or is this something that's related to an emotional circumstance? Is this a feeling of anger or frustration or sadness? You know, it just allows for that pause. So I have several clients that are utilizing the drugs at the moment, and, you know, I think when you're using this in conjunction with diet and lifestyle medical intervention. I think it can be very effective. I wouldn't say that I'm pro it. I'm not against it. I think it can have its benefits, absolutely. But I don't think that it should be treated as a disease, or obesity should be treated as a disease of the brain, which completely bypasses, you know, personal responsibility and accountability for your choices when there are decisions to be made that could help you and improve your health. So I think that was the first thing that I kind of wanted to comment about. I have other thoughts. Thoughts about the potential risks that are maybe being overlooked at the moment. I don't know if you want to go there right now, but I'll throw it back to you guys.

I, I guess one thing I'd add to kind of like shift it away from the brain is think about all the peripheral diseases we're looking at using GLP-1s for. Polycystic ovarian syndrome, take one. Now, right now this is in preclinical settings, but like what we do know is there's a GLP-1 deficit peripherally in a lot of insulin resistance-related disorders. Including diabetes, including obesity, including PCOS. Um, so I mean, like, for— from a clinical perspective, you can almost think about treating, you know, it as a primary endocrinopathy. So like, what happens if you have Hashimoto's and hypothyroid? You give back thyroid. What happens if you have adrenal insufficiency, Addison's disease? You give back cortisol so you don't have cardiovascular collapse. You replace the missing hormone. And we know in these insulin resistance disorders, a lot of them, GLP-1 levels are low. So are we just replacing it? Not really. It's a super physiologic dose. But the idea that there's actually a peripheral metabolic dysfunction, maybe having to do with inflammation in the gut— there are cells there that like sop up GLP-1, decreases bioavailability, won't go into L cells, yada yada yada. Point being, there are lots of use cases beyond obesity. Yeah. Um, and beyond the brain, which GLP-1 is being explored for. Which suggests this isn't— this is— no, it's not just brain disease. And it's also not just as simple as weight loss. There's literature showing that GLP-1s reduce inflammation even independent of weight loss. So there's more going on here, and it's a tool that could be used and is being used outside of just obesity medicine. So it's a cool tool with multiple applications, kind of a Swiss Army knife of sorts. I love understanding how it works, how these different drugs work, because it's just physiologically interesting. Like, take tirzepatide— sorry to go on a tangent for a sec— but like, you know, what is the difference between tirzepatide and Ozempic and Wegovy? Tirzepatide is the one that's a GLP-1 and the GIP. What is the advantage of that? Well, it turns out fat cells don't really have much GLP-1 receptor. They do have the GIP receptor, and the chronic activation of the GIP receptor on fat cells increases uptake of glucose in the postprandial periods, you have more stable blood sugar, increases lipolysis in the fasting period. So what is it doing that semaglutide isn't or the GLP-1s aren't? Sorry, I'm throwing around the generic and then the other names at the same time. But basically like what is the advantage of this other medication? It's making your fat cells more flexible. Recompetition is paralleling what we see with different lifestyle interventions. So there's actually like a Venn diagram and an overlap here again where you can see it as the catalyst. Could this drug enhance your quote metabolic flexibility and help you achieve better lifestyle interventions? Absolutely. So, one of the things I also like is like looking at the parallels between these medications and lifestyle changes. Another example, because we talked about carbs and insulin, GLP-1s. Most people think they increase insulin, they don't. They actually decrease insulin area under the curve in a mixed macronutrient setting. So, it aligns with things like the carbohydrate insulin model. Sometimes in science, we are handed natural experiments of sorts or large population scale experiments when you have implementation of intervention on a population and we just get to study the physiology and you get to learn a lot from it. I like taking that approach to this, but interesting tool, a lot of use cases, not just a brain disease.

100%. There's so many and Just a couple things I wanted to respond to what you said, Nick. My gosh, where do I start? Probably metabolic flexibility, because we, we use peptides too. And my— our favorite peptide where we get the best results is AOD-9604. And I've always looked at AOD as a peptide that improves metabolic flexibility, mobilization of body fat, because I look at— and from my understanding, and correct me if I'm wrong, Nick, but hyperinsulinemia, elevated insulin levels create a scenario where for an individual, their, their body is gonna struggle when you put it into a caloric deficit. It's, it's, and that's the, the issue with its inability to mobilize fat. So we've noticed, and I noticed clinically so much more success even on a GLP-1 when we stack the AOD because it like compensates for that lower metabolic flexibility that I'd like to think is going on because their insulin levels are elevated. And you mentioned tirzepatide, that's our preference too. We get much better results with tirzepatide over semaglutide. And again, I, I saw your video too on that and I, I also think it's because, and this is educated guesses here, but because of that metabolic flexibility part of it and the AOD kind of confirms that, I think. But I'm really curious on just what is your definition of metabolic flexibility?

Oh, I would say, I mean, technically it's being able to like shift metabolic states and use fuel substrates, you know, as needed. So like, you know, shifting into, you know, fat burning mode when you're not eating, I consider that metabolic flexibility. Being able to liberate, you know, free fatty acids from your fat cells, I would consider a mark of good metabolic health and metabolic flexibility.