Make your Fat Flexible: This Can Do what Ozempic Never Could

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. Specificity about the physiology because I think it's freaking cool. So with that, let's dig into it. Welcome to my channel, stay curious. 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 about 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 agonists— so you have these compounds binding to the surface of cells as seen in red, and then you have EX, which is basically the equivalent of semaglutide, GLP-1 receptor agonist. And what is very clear is you see red where there are compounds triseptid or pure GIP receptor agonists that would bind to the GIP receptors. 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. So 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 tirzepatide, 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 tirzepatide 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 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 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 trizeptide 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, trizeptide 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, 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 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. I have fun with it. Bye!