#131: GLP-1 Isn’t Enough - Why Glucagon is the Key to Lasting Weight Loss with Dr. Ben Bikman

We talk a lot about insulin when it comes to fat loss, but there's another hormone that works in the opposite direction, and it may be just as important. That hormone is glucagon. Insulin tells your body to store energy. Glucagon tells your body to release it. And the balance between those two, the insulin to glucagon ratio largely determines whether you're storing fat or burning it. Here's an important clarification. In humans, glucose glucagon does not burn fat by pulling it directly out of fat cells. The idea mostly comes from rodent studies. Glucagon does its real work in the liver. It shuts down new fat creation and turns up fat oxidation. That's also what allows ketone production when insulin is low. So fat loss isn't about insulin or glucagon alone. It's about the balance between them. Lower insulin Let glucagon do its job. This is lecture 131 of the Metabolic Classroom. Looking to improve your own metabolic health? Visit insuliniq.com for courses, coaching, consultations and a 10 day free community membership trial to dive deep into the science behind metabolic health. Become an insider@Benbickman.com where you'll enjoy my exclusive content ad, free podcasts, live stream Q and A access and and more welcome to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. For today's mini lecture, we're discussing a rather unappreciated or underappreciated hormone in metabolism, and that is glucagon. Although it is certainly getting more famous almost in real time, as I'll show you at the end. If you've listened to me previously, you know I spend a lot of time talking about insulin, and for good reason. Insulin is the master metabolic hormone. It is the primary driver of fat storage. It's the primary driver of glucose uptake. It basically wants to make sure that cells are taking in and storing energy. But of course, you can't have that happen all the time. Insulin, it's no surprise, has a partner, or you could say a counterpart that works in perfect opposition to it. That partner is glucagon. But here is where you find a little interesting irony when it comes to cell biology. In the human body, glucagon and insulin are produced in the exact same tissue, albeit different cells. But the tissue is the islets of Langerhans within the pancreas, the big gland tucked beneath your stomach. But insulin and glucagon are neighbors, or at least their cells are neighbors. That they come from. The beta cells pump out insulin, while the inside immediate next door neighbor, the alpha cell sitting again right next door, produces glucagon. These two hormones are as close as any two hormones can be anatomically. Yet they do completely opposite things functionally. It's as if nature designed the ultimate checks and balances system right there in this tiny little cluster of cells. While insulin is calling out for storage, pushing glucose into cells, converting any excess into fat, and more, glucagon is calling out for a release. It wants to liberate glucose from glycogen stores. It wants to promote fat oxidation and even stimulates the production of ketones. These two hormones exist in a beautiful and constant tug of war in the balance between them. What we call the insulin to glucagon ratio is arguably one of the most important determinants of whether your body is storing fat or burning it. Today, I want to give glucagon its due. We're going to explore how glucagon promotes fat burning, clarify a major misconception about where this happens, and explain why the latest metabolic drugs are leveraging glucagon in ways that significantly enhance weight loss beyond what we've seen before. Let's get into it. Before we can appreciate what glucagon does for fat burning, we need to understand the context in which it operates. And that context is always defined by insulin. Back in 1971, one of my research heroes, Roger Unger, proposed what he called the bihormonal hypothesis. He argued that it's not just the absolute level of insulin or glucagon that matters, it's the ratio between them. When you eat a carbohydrate rich meal, insulin spikes and glucagon is suppressed. Your insulin to glucagon ratio goes up, shifting your metabolism toward storage. Your body takes up glucose, converts excess to glycogen or fat, and puts the brakes on any fat burning processes. But when you fast, even just overnight, the opposite happens. Insulin drops, glucagon rises, and the ratio shifts the other way. The same thing happens with a low carbohydrate diet. In this case, your body gets the signal we need to access stored and energy. Glycogen breaks down, fat starts mobilizing, and eventually ketone bodies appear if the fast continues long enough. This ratio varies inversely with the need for endogenous glucose production. It's lowest during total starvation, when you need maximal fuel, liberation, if you will. And it's highest after a carbohydrate heavy meal, when glucose is flooding into the blood from the gut. And there is clinical relevance to this. Lest you think it's just a scientific or abstract idea. In type 2 diabetes, the elegant system starts to break down. These patients often have both elevated insulin and elevated glucagon, what we call hyperglucagonmia. And of course, the counter there is hyperinsulinemia. The liver keeps seeing a glucagon signal pushing glucose production, even while peripheral tissues are drowning in insulin and becoming resistant to it. It is a metabolic chaos. Understanding the ratio is key to everything that follows. It's the metabolic fulcrum that determines whether you are in storage mode or release mode. Now, before I tell you where glucagon actually promotes fat burning, I need to address a widespread misconception, one that even shows up in textbooks and medical education. For decades, the story went like this. Glucagon stimulates lipolysis in adipose tissue, releasing fatty acids into the bloodstream to be burned elsewhere. This would make glucagon a direct fat liberating hormone, pulling triglycerides apart in your fat cells, just like a withdrawal from a bank account. And in rodents, this is absolutely true. The early Studies from the 60s and 70s were remarkably consistent. Glucagon activated hormone sensitive lip in rat fat tissue, which, in other words, is stimulating lipolysis or breakdown from adipose tissue. So if you were a rat, glucagon would be a powerful fat mobilizing signal acting directly on your adipose tissue. But here's the problem. Humans are not rodents. And this is one of those cases where the species difference really matters. It doesn't always. I say that in part in a way to defend even my own basic research, where we've used animal models. In many instances, they are a good corollary to what you'd see in humans. But when it comes to glucagon signaling, it starts to fall apart. When researchers looked carefully at white adipose tissue in humans, they found something surprising. Glucagon receptor expression is very low in human fat cells. In some studies, it's essentially undetectable. In these mature adipocytes, the receptors for glucagon simply aren't there in any meaningful number. And if there aren't glucagon receptors, that means there's no glucagon response. The functional studies confirm this. A 2001 study used microdialysis, a technique where you insert a tiny probe directly into abdominal fat tissue and measure what's being released locally. Even when they raised glucagon levels three to four fold above normal. Fasting values, There was no change in glycerol release. And glycerol, of course, is the backbone of triglycerides. So if fat is being broken down, you will expect to see glycerol show up in the blood. It didn't. A 2020 study also looked at this, and it did so systematically in human adipocytes. They found that glucagon receptor gene expression was very low, and it was also highly variable between individuals and not different between people with and without type 2 diabetes. Functionally, glucagon only increased lipolysis at supraphysiological levels, so levels far beyond what your body could ever produce naturally. At physiological concentrations, the effect was negligible. And just recently, just a few Years ago, a 2022 paper using an adipocyte specific glucagon receptor knockout mouse, in other words, they got rid of the glucagon receptor from fat cells and they found that it did not affect fasting induced lipolysis or body composition. So even in rodents, it doesn't appear to be a necessary signal. Glucagon can be a signal. So let me be clear. The idea that glucagon directly mobilizes fat from your adipose tissue is largely a rodent phenomenon that does not translate to humans. So if you've heard that glucagon releases fat from fat cells, that is an oversimplification. And in fact, it's wrong if you're trying to apply that statement to humans. But that does raise an obvious question. If glucagon isn't pulling fat out of adipose tissue, how does it promote fat burning? The answer lies in the liver, and that's where things get pretty interesting. So it's the liver that where glucagon actually does its fat burning work. The liver is absolutely loaded with glucagon receptors. It is the primary target tissue. When glucagon binds to its receptor on a hepatocyte or a liver cell, it triggers a cascade of events that shifts the liver from toward fat oxidation and away from fat synthesis. Here is the molecular mechanism. Very briefly, glucagon binds to an adenylate cyclase or binds to its receptor. And then it activates an enzyme called adenylate cyclase, which in turn increases a molecule called cyclic amp, which in turn activates protein kinase A or pka. And then PKA does a lot of things. One, it will inactivate acetyl Coa carboxylase. This is the enzyme that normally starts pushing the liver towards fat synthesis. But it also results in the inhibition of CPT1, the molecule that it's blocking. So, in a way, with the glucagon activation, we are removing the disinhibition of CPT1. And that matters because CPT1 is the enzyme that shuttles fat into the mitochondria for burning. So by blocking acetyl Coa carboxylase, glucagon is accomplishing two things. It's stopping new fat from being made, and it removes the brake on fat oxidation. Second, glucagon signaling will increase the transcription of CPT1 itself through what's called the CREB or CREB transcription factor. More CPT1 means greater capacity to move fats into the mitochondria, where they can be burned. A recent paper was published in Nature from a lab at Heart at Yale. They found that glucagon stimulates intrahepatic lipolysis, or the breaking down of stored fat within the liver itself through a receptor called INSP3R1, or INSPIRE1. This receptor coordinates calcium release. That in turn activates an enzyme called atgl, which is a rate limiting enzyme for breaking down fat. But critically, this mechanism was confirmed in humans. Remember, so much of the conflict with glucagon is bridging the gap between rodents and humans. A 2024 study in Cell metabolism from the same group showed that glucagon infusion in people with fatty liver disease increased hepatic mitochondrial oxidation, so burning fuel by about 50%. So these are not just effects in rodents. This is human data now. So glucagon doesn't need to pull fat from adipose tissue to promote fat burning. It creates a fat burning metabolic environment in the liver, where fatty acids arriving from the bloodstream, mobilized by other mechanisms like hormones like catecholamines or low insulin, then can get efficiently oxidized rather than stored or exported. So, in other words, glucagon is helping the liver burn whatever fat it has access to. Now, once fatty acids are being oxidized in the liver's mitochondria, what happens next depends on the metabolic state. If there's plenty of oxaloacetate around, this is, and that would be a molecule that would be at higher levels in the cell that would be there in a fed state with a bunch of glucose, then the acetyl COA from fat oxidation will enter the citrate cycle, and then it'll get fully oxidized or burned. But in a fasted state, when glucagon is dominant, the liver's metabolic machinery shifts. Now, oxaloacetate gets diverted toward gluconeogenesis to make new glucose. This leaves the acetyl COA without a dance partner. Molecularly speaking, if you will, what's the result? It is ketogenesis. So in other words, if acetyl COA can't be burned and it can't be turned into fat, which it can't, if insulin is low, then the acetyl COA molecule, the molecules will start to condense together in twos and it will form acetoacetate and beta hydroxybutyrate. The ketone bodies that can, well, ultimately it'll turn into those ketones and these will be the ones that BHB especially. It will fuel the brain, it'll fuel the heart, it'll fuel muscles, it'll induce mitochondrial uncoupling in fat tissue. All these other things that we've discussed previously. Studies in cell cultures of liver cells consistently show that glucagon stimulates both fatty acid oxidation and ketogenesis. The hormone essentially pushes the liver into a fat burning ketone producing mode. However, and this is important for accuracy, recent studies have questioned how essential glucagon is for fasting ketogenesis. A 2020 paper by Miller and Birnbaum showed that mice lacking glucagon signaling still produce ketones during fasting. What this tells us is that the drop in insulin during fasting may be more important than the rise in glucagon for ketone production. But it's important to note this might once again just be a rodent phenomenon. I'm unaware of any study that's been published that would be able to confirm the same phenomenon in humans, because you can't just take away glucagon. Now, what's the practical takeaway? The insulin to glucagon ratio matters more than glucagon alone. You can have all the glucagon in the world, but if insulin is still elevated, you won't see the full fat burning ketone producing benefits. Indeed, in a head to head, insulin will win that battle. This brings us to one of the most exciting developments in metabolic medicine. Drugs that combine GLP1 receptor activation with glucagon receptor agonism or activation. And here's where we see direct evidence of why glucagon may matter. Clinically. You have Certainly heard of GLP1 drugs like semaglutide, sold as Ozempic and Wegovy. Depending on the dose, these drugs do suppress appetite, they slow gastric emptying. And as a result of all of these, changes in diet improve blood glucose control and induce weight loss. At their highest doses, semaglutide can produce about 15% weight loss over a little over a year. That is impressive, but there is a limitation. One of the challenges with weight loss is metabolic adaptation. As you lose weight, your body reduces energy expenditure. To defend against the further weight loss, your metabolism slows down. This is one reason why weight loss plateaus are so common and why maintaining weight loss is so difficult. GLP1 drugs help you eat less, but they don't do much to maintain or increase your metabolic rate. Well, enter the dual agonists. Cervudutide was developed by Boehringer Ingelheim and it activates both GLP1 receptor and the glucagon receptor. The GLP1 component provides the appetite suppression and the glucose control, which we're familiar with. But the glucagon component adds something that you might say is critical. It increases energy expenditure and enhances fat burning in the liver. And here are the data. In a 46 week phase two trial, cervedutide at the 4.8mg dose produced approximately 14.7% weight loss. Now, that might not sound dramatically different from semaglutide at first glance, but remember, this is at a lower dose and a shorter duration than the semaglutide trials. And more importantly, we should look at what happens in the liver. Just last year, in a New England Journal of Medicine study, the same drug was tested in patients with metabolic dysfunction associated steatohepatitis. In other words, fatty liver disease, but a severe form that involves some inflammation and scarring. It used to be called non alcoholic steatohepatitis. So Nash, the results were remarkable. 83% of cerutide treated patients showed resolution of their steatohepatitis or their fatty and inflamed liver based on biopsy, compared to just 18% of people on placebo in the liver fibrosis or the scarring scores improved significantly as well. This is the glucagon component at work, driving fat oxidation in the liver in a way that GLP1 alone does not appear to achieve. Then there is retatrutide, which goes even further. It's a triple agonist, hitting GLP1 and GIP or gypsy and glucagon receptors simultaneously. In a 2023 New England Journal of Medicine trial, retatrutide produced weight loss approaching approaching 24% at 48 weeks at the highest dose. That's approaching what you see with bariatric surgery, albeit with just an injection. The glucagon component is contributing to this by maintaining energy expenditure and fat oxidation in the liver even as the body weight starts to drop. Now, why might this matter? It might matter because it addresses a problem when it comes to metabolic adaptation. With these drugs, you're not just suppressing appetite, you want to try to maintain metabolic machinery or momentum and continue to help your body burn fuel well. Moreover, glucagon keeps CPT1 active, so that's the critical handler of fats, pushing them into the mitochondria. So it keeps fat burning happening in the liver and that can help prevent the accumulation of liver fat that may happen with weight loss if it's very rapid. And this is one of the reasons why pharmaceutical companies are racing to find ways to leverage glucagon's fat burning advantages. Now, I've stated my concerns with these drugs in the past and they stand none of what I just said is meant to be an advocacy at all for these drugs. I have very substantial concerns and I'll just briefly reiterate my points that I've made previously. I think the main utility in these drugs is to help people learn to control their cravings for carbohydrates, rather than just be used for weight loss per se. Of course, an effect of learning to control your constant carbohydrate cravings will be weight loss. It will be improved blood glucose control. So my view is they should be used at low doses with the explicit purpose of helping people learn to control their carbs. And thus it should be coupled with a smart, low carbohydrate diet. Now, let me bring all this together. Glucagon is the great liberator. Energetically, the hormone that signals your body to mobilize and burn stored energy. While insulin builds and stores, glucagon mobilizes and oxidizes the balance between these two pancreatic neighbors, one from the beta cell, one from the alpha cell, determines whether your metabolism is in storage mode or release mode. When it comes to fat burning, the critical insight is glucagon's primary action in humans is in the liver, not in adipose tissue. This is where we see the clearest species differences between rodents and humans. Glucagon drives hepatic fat oxidation, suppresses fat synthesis and creates the metabolic condition for ketone production. These effects are critical for preventing fatty liver disease and maintaining overall optimal metabolic health. The new dual and triple agonist drugs with glp, one seeks to leverage some of this biology and you can't argue with the results. It does appear to be better than GLP1 alone. But again, I have my reservations and they stand. But for those of you looking to optimize your own glucagon signaling, the prescription is quite simple. Reduce your carbohydrate intake and practice some form of fasting. That's going to be the key to helping glucagon work in your favor. These strategies will naturally shift your insulin to glucagon ratio toward the fat burning end of the spectrum and create the metabolic environment where glucagon can do its work. For too long glucagon has lived in insulin's shadow. I think it is time that we give this fat burning hormone its due. Thanks for joining me on the Metabolic Classroom. Until next time, stay curious and stay healthy. Looking to improve your own metabolic health? Visit insuliniq.com for courses, coaching, consultations and a 10 day free community membership trial to dive deep into the science behind metabolic health. Become an insider@Ben Bickman.com where you'll enjoy my exclusive content ad, free podcasts, livestream Q and A access and more.