How Do Ozempic, Mounjaro & Other GPL-1 Agonists Work? | Dr. Zachary Knight & Dr. Andrew Huberman

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 glp1 glucagon like peptide 1 OIC monjaro and similar drugs um my understanding of the back history on these is that a biologist obsessed with heila Monsters uh a a reptile that doesn't need to eat very often discovered a peptide within their bloodstream called extendin yeah that um allowed them to eat very seldom a curbed appetite in the hila monster of all things and it has a analog homologue you know we

don't know uh I don't know the sequence homology exactly but a there's a similar peptide made in mice and in humans that suppresses appetite um if you would could you tell us uh what is known about how glp1 Works to suppress appetite where in the body Andor brain sure and uh your sort read of um these drugs and what's happening there um good bad exciting sure ugly sure be happy to anything else so um the story of glp1 so the heal monster is an important turn and I'll talk about that it actually goes back before

that quite a ways so so I should take a step back and say you know these were developed as drugs for diabetes right and so and know diabetes is a condition where basically I've elevated blood glucose either because you you don't produce enough insulin or because your insulin is is not effective and so back in in sort of the 1920s right around the time insulin was discovered um there is this phenomenon Discovery known as the incretin effect um and uh what it was in intin not the effect not the ctin you can observe the effect

in numerous places in daily life and online just kidding so it's it's called the incretin effect you can think of it as increase insulin because that's what the effect is um and the IDE was that if you take glucose by mouth if you consume glucose orally um 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 uh the glucose causes more insulin to be released and causes you to to lower your body sugar

more accurately more more more strongly interesting um 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 that insulin is being released not just in response to changes in blood glucose but in response to a second factor and so they called that an incretin and through various experiments it was it was uh 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 uh sugar goes through your intestine that boosts this insulin response to glucose in the blood and people immediately realize this could be potentially be very valuable and the reason is that you know you can treat diabetes with insulin injections but insulin is dangerous right because if you inject too much insulin you can kill yourself by making yourself hypoglycemic right so this 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 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 um but then so there's this other hormone that comes from from the the um pancreas called glucagon right and so glucagon which also discovered in the 1920s glucagon is kind of the anti-insulin so um when blood sugar goes low glucagon is released in order to cause your liver

to release glucose into the blood so glucose glucagon and insulins are these two opposing hormones glucagon was known for a long time but but people discovered in s 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 CES from the same gene but it's just slightly different it's cut up slightly differently and this hormone was

an in Creon so basically if you uh put it on beta cells um you get this increased response of insulin in response to glucose and so there was the idea okay this could be a great diabetes drunk right and there I should say there was one other incre and that's that's been found it's it's called Gip Gip and that will be important talking about some of these other drugs also a hormone that comes from the intestine and so um the challenge with making gp1 into a drug is that has an extremely short half life so

it has a half life about 2 minutes in the blood um and so even if you inject people with glp1 it won't really be useful for anything you don't decrease appetite you don't affect blood sugar because it's just degraded too fast and the reason it's degraded is because there's an enzyme dpp4 is what it's called that degrades gp1 so the first thing people tried was let's make Inhibitors of that enzyme so we can boost this natural G1 signal and those are approved uh uh uh diabetes drugs they're called gpin you've probably heard about them Genovia

is the most common one and those boost the level of glp1 the natural glp1 in the in the produced from the intestine by about three-fold and they're effective in treating diabetes people lose weight people do not lose weight and that's one of the key reasons that we know the natural function of glp1 is not really to control body weight because you can boost the level three-fold with these dpp4 drugs millions of people have taken them they do not lose weight that's a great question so but you know a three-fold is great but like 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 glp1 that uh uh is more stable in the blood and that's where this this lizard that you're talk you mentioned comes into play it produces a stabilized form of gp1 and it's Venom no one knows why one hypothesis is that it's something to do with the lizard uh 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 gp1 from this lizard it has a half lifee of like two hours and so the first glp1 drug that was approved was just this molecule from this lizard basically and it um it's called exenatide and it's approved in 2005 for works well for diabetes um has a half life of two hours you inject it and um doesn't cause a ton of weight loss but two hours is good but it's not so great so then pharmaceutical industry Tres said can we you know basically improve this even further and so they

start engineering this hormone making mutations attaching lipid tails to make it binds as proteins in the blood that would stabilize it chemistry jockey stuff yeah exactly and I think the next big Advance was this compound liraglutide um and liraglutide was a proof for diabetes in 2010 and for and then for weight loss in 2014 and so L glutide has a half life of about 13 hours in the blood not so now you're getting up to something serious we've gone from 2 minutes 2 hours 13 hours and you get better effects on on 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 L glutide and one of the things they noticed that I think is just is fascinating just sort of example of how drug Discovery works in the real world um you know a lot of these people who take log glutide now it has this longer halflife they start to get nauseous and that would limit how much of the log glutide they could take and it's a known side effect of these gp1 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 go away and then once you got up to the highest doses then people really started

losing weight and so there's a couple things that our pharmaceutical industry realized W these are potentially really effective weight loss drugs and also this nausea which we thought was was you know a killer people are able to just get used to it and then it just goes away it under goes the word is Tac aaxis so the idea is that the receptor that's affecting the in the gut that's causing this these effects undergo some sort of down regulation with with chronic chronic exposure so L glutide you know was it's been around it's been on the

market for 14 years now um was used but still you're only getting sort of like 7 to 10% weight loss which is good but not like you know amazing impressive um but then semaglutide came along um and that that was a proof for diabetes in 2017 and semaglutide is OIC or also Al also uh marketed as uh wig oie for weight loss and semaglutide now has a half life of seven days so now we've gone from two 2 minutes 2 hours 13 hours 7 days and you can really jack up the concentration with a 7-Day

uh uh halflife and then they saw people started really losing weight and so and some of those trials people lost you know 16% of their body weight which previously had been unattainable in what time frame uh typically takes about a year okay and most of the loss and body weight is from body fat or from other other compartments the typical number is that if you um if you lose weight either through dieting or through taking one of the 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 going to be muscle the rest is going to be fat but as you said some of that could be offset by resistance training Andor consuming a higher protein diet yeah you can almost completely eliminate that if you eat enough protein and do serious weightlifting um 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 um among elderly people you don't want to 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 the calves on very um obese people are often enormous exactly and then they lose weight and exactly the and I mentioned the Cavs in particular because um they're

carrying a lot of the body load exactly exactly so it's still an open question as to whether as to how serious a problem this this musan muscle mass loss is although the pharmaceutical industry is all in now on making drugs that basically are going to prevent that so that's that's something that will be will be happening probably in the future is it a sorry to interrupt but is the um weight loss on these drugs the consequence of reduced appetite um or some other aspect of metabolism and if it's the consequence of reduced appetite um is

that occurring at the level of the brain and gut um or cination so it's almost entirely reduced appetite and it's almost entirely incurring at the level of the brain which neurons it's thought that the key targets of of uh 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 Posta so we back in the brain stem back in the brain stem so these are actually the neurons in that desate rat story I was telling earlier these are the brain regions that are preserved

D in the deser rat the deser rat still has these very coddle brain stem structures um they're two very special brain regions because they get direct input from the vagus nerve so the vagus nerve is the nerve that inates your stomach and intestines and heart and lungs it's sort of the major pathway from gut to brain and provides most of the sensor the neural input from gut to brain telling you about things like this your stomach distension how many nutrients are in your intestine breathing all that stuff and almost all of those vagal nerves terminate

on the these two structures in the brain stem when I hear Posta I think about nausea because I was taught that Posta contains neurons that can stimulate vomiting um and this seems to link up well at least in The Logical sense with the idea that stimulating activating receptors in these neurons within postma might explain part of the transient nausea side effect it does of OIC and and related drugs yeah so the current thought is that a lot of the nausea is coming from activating the neurons in the area Posta and that a lot of 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 and the NTS and the AP they're going to talk to the hypothalamus and all these other brain regions that's going to change the whole brain so it's not just those regions but you know 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 brain stem so that's why people think that this is probably where they're acting and is that because there um there's an abundance of The receptors for the uh these compounds in Posta and um NTS or is it because the blood brain barrier is somehow weaker at that location uh it's because the blood rain barrier is weaker so basically it's a region uh so what's known as a circumventricular

organ meaning it's a 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 um and that's important for these big peptides because these are not small molecules these are Big peptides with lipid chains on them and other things and so they can really get only get into areas of the brain where the blood brain barrier is weakened thank you for tuning in to the hubman lab Clips Channel if you enjoyed the clip that you just viewed please check out the

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