The increased hunger seems to be the main reason people find it so difficult to keep weight off. - That seems the perfect segue to talk about GLP-1, glucagon-like peptide one, ozempic, Munjaro, and similar drugs. My understanding of the back history on these is that a biologist obsessed with Gila monsters, a reptile that doesn't need to eat very often discovered a peptide within their bloodstream called Xtendin that allowed them to eat very seldom, curbed appetite in the Gila monster of all things.

And it has a analog homolog, you know, we don't know. I don't know the sequence homology exactly, but there's a similar peptide made in mice and in humans that suppresses appetite. If you would, could you tell us what is known about how GLP-1 works to suppress appetite? Where in the body and/or brain, and your sort of read of these drugs and what's happening there, good, bad, exciting, ugly.

- Sure, I'd be happy to. - Anything else? - So the story of GLP-1, so the Gila monster is an important turn, and I'll talk about that. It actually goes back before that quite a ways. So I should take a step back and say, you know, these were developed as drugs for diabetes, right?

And so, and diabetes is a condition where basically you have elevated blood glucose, either because you don't produce enough insulin or because your insulin is not effective. And so back in sort of the 1920s, right around the time insulin was discovered, there was this phenomenon discovered known as the increten effect.

And what it was- - Increten? - Increten, yeah. - Not the creten effect. - Not the creten effect. - You can observe the creten effect in numerous places in daily life and online. Just kidding. - So it's called the increten effect. You can think of it as increase insulin, 'cause that's what the effect is.

And the idea was that if you take glucose by mouth, if you consume glucose orally, versus if you have the same amount of glucose injected intravenously, more insulin is produced when you take the glucose orally versus if it's delivered intravenously. Suggesting something about the process of ingesting the glucose causes more insulin to be released and causes you to lower your body sugar more accurately and more strongly.

- Interesting. - Which is a little bit counterintuitive because in the pancreas, right? So insulin is released from the pancreas, from the beta cell. The pancreas senses the glucose concentration in the blood directly. And so it suggests that insulin is being released not just in response to changes in blood glucose, but in response to a second factor.

And so they call that an incretin. And through various experiments, it was shown that this incretin effect comes from the intestine. That there's some substance being produced by the intestine that when you eat a meal, sugar goes through your intestine that boosts this insulin response to glucose in the blood.

And people immediately realized this could potentially be very valuable. And the reason is that you can treat diabetes with insulin injections, but insulin is dangerous, right? 'Cause if you inject too much insulin, you can kill yourself by making yourself hypoglycemic, right? So you have to be very careful. But the thing about the incretin effect is it's not causing insulin release directly, but it's rather boosting the natural insulin release that comes when your glucose is higher in your blood.

So it's sort of an amplifier on the natural insulin release. So basically in the years that followed, whenever someone would find a new hormone, they would test it. Is it this incretin? And there's lots of failures. They weren't the incretin. But then, so there's this other hormone that comes from the pancreas called glucagon, right?

And so glucagon, it was also discovered in the 1920s. Glucagon is kind of the anti-insulin. So when blood sugar goes low, glucagon is released in order to cause your liver to release glucose into the blood. So glucagon and insulin are these two opposing hormones. Glucagon was known for a long time, but people discovered in sort of the 1980s that the glucagon gene is expressed in other tissues other than the pancreas.

And it's differentially processed. The protein is differentially processed to produce different hormones, hormones other than glucagon. And they discovered there was one in the intestine. And so they called it glucagon-like peptide because it comes from the same gene, but it's just slightly different. It's cut up slightly differently. And this hormone wasn't incretin.

So basically if you put it on beta cells, you get this increased response of insulin in response to glucose. And so there was the idea, okay, this could be a great diabetes drug, right? And I should say there was one other incretin that's been found. It's called GIP, G-I-P.

And that will be important in talking about some of these other drugs. Also a hormone that comes from the intestine. And so the challenge with making GLP-1 into a drug is that it has an extremely short half-life. So it has a half-life of about two minutes in the blood.

And so even if you inject people with GLP-1, it won't really be useful for anything. You don't decrease appetite, you don't affect blood sugar 'cause it's just degraded too fast. And the reason it's degraded is because there's an enzyme, DPP-4 is what it's called, that degrades GLP-1. So the first thing people tried was let's make inhibitors of that enzyme so we can boost this natural GLP-1 signal.

And those are approved diabetes drugs. They're called gliptins. You've probably heard about them. Genuvia is the most common one. And those boost the level of GLP-1, the natural GLP-1 produced from the intestine by about threefold. And they're effective in treating diabetes. - Do people lose weight? - People do not lose weight.

- Interesting. - And that's one of the key reasons that we know the natural function of GLP-1 is not really to control body weight because you can boost the level threefold with these DPP-4 drugs. Millions of people have taken them. They do not lose weight. That's a great question.

So, but a threefold is great, but you'd like to increase it even more, right? And to do that, you can't block this enzyme. You have to actually produce a GLP-1 that is more stable in the blood. And that's where this lizard that you mentioned comes into play. It produces a stabilized form of GLP-1 and it's a venom.

No one knows why. One hypothesis is that it's something to do with the lizard, as you said, basically having this long time period between meals and it needs to regulate its blood glucose. Who knows if that is true, but it turned out to be fortuitous because then this GLP-1 from this lizard, it has a half-life of like two hours.

And so the first GLP-1 drug that was approved was just this molecule from this lizard, basically. And it's called Xenotide and it was approved in 2005. Works well for diabetes, has a half-life of two hours. You inject it and it doesn't cause a ton of weight loss. But two hours is good, but it's not so great.

So then the pharmaceutical industry tried to say, can we basically improve this even further? And so they start engineering this hormone, making mutations, attaching lipid tails to make it bind to proteins in the blood that would stabilize it. - Chemistry jockey stuff. - Yeah, exactly. And I think the next big advance was this compound liraglutide.

And liraglutide was approved for diabetes in 2010 and then for weight loss in 2014. And so liraglutide has a half-life of about 13 hours in the blood. Now you're getting up to something serious. We've gone from two minutes, two hours, 13 hours. And you get better effects on aspects of blood glucose and diabetes control.

And they started to see that some people were losing weight. Very variable responses. Not everyone loses weight on liraglutide. And one of the things they noticed that I think is just as fascinating just sort of example of how drug discovery works in the real world. You know, a lot of these people would take liraglutide.

Now it has this longer half-life. They'll start to get nauseous. And that would limit how much of the liraglutide they could take. And it's a known side effect of these GLP-1 drugs. It causes nausea and sort of this gastrointestinal distress. But they noticed that over time, the nausea would just sort of go away.

And so they would start dose escalating, sort of raising the dose that the person would take. So you would go, you know, a month at this dose, and then a month at a slightly higher dose, and then a month at a slightly higher dose. And you could work your way up.

And these side effects would reappear, but then they'd go away. And then once you got up to the highest doses, then people really started losing weight. And so there's a couple of things that our pharmaceutical industry realized, wow, these are potentially really effective weight loss drugs. And also this nausea, which we thought was a killer, people are able to just get used to it, and then it just goes away.

It undergoes, the word is tachyphylaxis. So the idea is that the receptor that's affecting, in the gut that's causing these effects, it undergoes some sort of down regulation with chronic exposure. So liraglutide, you know, it's been around, you know, it's been on the market for 14 years now, was used, but still you're only getting sort of like seven to 10% weight loss, which is good, but not like, you know, amazing, impressive.

But then semaglutide came along. And that was approved for diabetes in 2017. And semaglutide is ozempic, or also marketed as Wigovi for weight loss. And semaglutide now has a half-life of seven days. So now we've gone from two minutes, two hours, 13 hours, seven days. And you can really jack up the concentration with a seven-day half-life.

And then they saw people start really losing weight. And so in some of those trials, people lost, you know, 16% of their body weight, which previously had been unattainable. - In what timeframe? - Typically takes about a year. - Okay, and most of the loss in body weight is from body fat or from other compartments?

- The typical number is that if you lose weight, either through dieting or through taking one of these drugs, and you don't do anything like eat a high-protein diet or do resistance training, somewhere between 25 and 33% of what you lose is gonna be muscle. The rest is gonna be fat.

- But as you said, some of that could be offset by resistance training and/or consuming a higher-protein diet. - Yeah, you can almost completely eliminate that if you eat enough protein and do serious weightlifting. Obviously, not the whole population is interested in doing that. And there's been a lot of discussion of how serious a side effect this is.

You know, among elderly people, you don't wanna be losing muscle mass because you're already losing so much muscle mass. On the other hand, the counterargument that has been made, which I think is also kind of convincing, is that, true, you're losing some muscle, but you're also losing all this fat, and you no longer need as much muscle when you're not carrying around as much body fat.

So people who are heavier naturally have more muscle because they need to to move their body, right? And so- - Yeah, the calves on very obese people are often enormous. - Exactly. - And then they lose weight. - Exactly. - And I mentioned the calves in particular because they're carrying a lot of the body load.

- Exactly, exactly. So it's still an open question as to how serious a problem this lean muscle mass loss is, although the pharmaceutical industry is all in now on making drugs that basically are gonna prevent that. So that's something that will be happening probably in the future. - Is it a, sorry to interrupt, but is the weight loss on these drugs the consequence of reduced appetite or some other aspect of metabolism?

And if it's the consequence of reduced appetite, is that occurring at the level of the brain and gut or a combination? - So it's almost entirely reduced appetite, and it's almost entirely occurring at the level of the brain. - Which neurons? - It's thought that the key targets of these drugs are neurons in these two regions.

One's called the nucleus of the solitary tract, and the other one's called the area post-trauma. - So we're back in the brainstem. - Back in the brainstem. So these are actually the neurons in that decerebrate rat story I was telling earlier. These are the brain regions that are preserved in the decerebrate rat.

The decerebrate rat still has these very caudal brainstem structures. They're two very special brain regions because they get direct input from the vagus nerve. So the vagus nerve is the nerve that innervates your stomach and intestines and heart and lungs, and it's sort of the major pathway from gut to brain.

It provides most of the neural input from gut to brain, telling you about things like your stomach distention, how many nutrients are in your intestine, breathing, all that stuff. And almost all of those vagal nerves terminate on these two structures in the brainstem. - When I hear post-trauma, I think about nausea because I was taught that post-trauma contains neurons that can stimulate vomiting.

And this seems to link up well, at least in the logical sense, with the idea that stimulating, activating receptors in these neurons within post-trauma might explain part of the transient nausea side effect of ozempic and related drugs. - Yeah, so the current thought is that a lot of the nausea is coming from activating the neurons in the area of post-trauma, and that a lot of the sort of physiologic satiety is coming from activating the neurons in the nucleus of the solitary tract.

Now, the whole brain is connected to each other, and so if you really turn on these neurons in the NTS and the AP, they're gonna talk to the hypothalamus and all these other brain regions, it's gonna change the whole brain. So it's not just those regions, but these drugs don't have great access to the brain.

They can penetrate a little bit into the brain, but they don't penetrate into the whole brain. And it's thought that if you take fluorescently labeled versions of these drugs and see where do they, so you can visualize where do they actually go, they're enriched in these structures in the brainstem.

So that's why people think that this is probably where they're acting. - And is that because there's an abundance of the receptors for these compounds in post-trauma and NTS, or is it because the blood-brain barrier is somehow weaker at that location? - It's because the blood-brain barrier is weaker.

So basically, it's a region, what's known as a circumventricular organ, meaning it's one of these rare places in the brain where the blood-brain barrier is weakened, and so substances can come from the outside into the brain. And that's important for these big peptides, 'cause these are not small molecules.

These are big peptides with lipid chains on them and other things. And so they can really only get into areas of the brain where the blood-brain barrier is weakened. - Thank you for tuning in to the Huberman Lab Clips channel. If you enjoyed the clip that you just viewed, please check out the full-length episode by clicking here.