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

00:00:00.000 | The increased hunger seems to be the main reason

00:00:03.820 | people find it so difficult to keep weight off.

00:00:06.340 | - That seems the perfect segue to talk about GLP-1,

00:00:10.140 | glucagon-like peptide one, ozempic,

00:00:12.920 | Munjaro, and similar drugs.

00:00:14.800 | My understanding of the back history on these

00:00:18.680 | is that a biologist obsessed with Gila monsters,

00:00:22.180 | a reptile that doesn't need to eat very often

00:00:27.420 | discovered a peptide within their bloodstream

00:00:29.860 | called Xtendin that allowed them to eat very seldom,

00:00:34.860 | curbed appetite in the Gila monster of all things.

00:00:40.040 | And it has a analog homolog, you know, we don't know.

00:00:45.820 | I don't know the sequence homology exactly,

00:00:47.720 | but there's a similar peptide made in mice and in humans

00:00:52.340 | that suppresses appetite.

00:00:54.660 | If you would, could you tell us what is known

00:00:56.760 | about how GLP-1 works to suppress appetite?

00:00:59.780 | Where in the body and/or brain,

00:01:01.700 | and your sort of read of these drugs

00:01:05.900 | and what's happening there, good, bad, exciting, ugly.

00:01:10.900 | - Sure, I'd be happy to.

00:01:13.140 | - Anything else?

00:01:13.960 | - So the story of GLP-1,

00:01:16.460 | so the Gila monster is an important turn,

00:01:17.960 | and I'll talk about that.

00:01:18.800 | It actually goes back before that quite a ways.

00:01:20.840 | So I should take a step back and say, you know,

00:01:22.800 | these were developed as drugs for diabetes, right?

00:01:25.620 | And so, and diabetes is a condition

00:01:27.500 | where basically you have elevated blood glucose,

00:01:29.420 | either because you don't produce enough insulin

00:01:31.440 | or because your insulin is not effective.

00:01:33.980 | And so back in sort of the 1920s,

00:01:37.300 | right around the time insulin was discovered,

00:01:40.020 | there was this phenomenon discovered

00:01:41.340 | known as the increten effect.

00:01:42.820 | And what it was-

00:01:45.100 | - Increten?

00:01:45.940 | - Increten, yeah.

00:01:46.760 | - Not the creten effect.

00:01:47.600 | - Not the creten effect.

00:01:48.440 | - You can observe the creten effect

00:01:49.740 | in numerous places in daily life and online.

00:01:52.260 | Just kidding.

00:01:53.100 | - So it's called the increten effect.

00:01:54.980 | You can think of it as increase insulin,

00:01:56.940 | 'cause that's what the effect is.

00:01:58.880 | And the idea was that if you take glucose by mouth,

00:02:01.600 | if you consume glucose orally,

00:02:03.120 | versus if you have the same amount of glucose

00:02:05.920 | injected intravenously,

00:02:07.920 | more insulin is produced when you take the glucose orally

00:02:12.340 | versus if it's delivered intravenously.

00:02:14.200 | Suggesting something about the process

00:02:15.400 | of ingesting the glucose causes more insulin to be released

00:02:19.480 | and causes you to lower your body sugar more accurately

00:02:22.720 | and more strongly.

00:02:24.360 | - Interesting.

00:02:25.440 | - Which is a little bit counterintuitive

00:02:26.720 | because in the pancreas, right?

00:02:28.200 | So insulin is released from the pancreas,

00:02:29.440 | from the beta cell.

00:02:30.800 | The pancreas senses the glucose concentration

00:02:32.920 | in the blood directly.

00:02:33.760 | And so it suggests that insulin is being released

00:02:35.880 | not just in response to changes in blood glucose,

00:02:37.580 | but in response to a second factor.

00:02:39.160 | And so they call that an incretin.

00:02:41.560 | And through various experiments,

00:02:43.160 | it was shown that this incretin effect

00:02:46.600 | comes from the intestine.

00:02:47.520 | That there's some substance being produced by the intestine

00:02:50.560 | that when you eat a meal,

00:02:52.720 | sugar goes through your intestine

00:02:54.400 | that boosts this insulin response to glucose in the blood.

00:02:58.360 | And people immediately realized

00:02:59.500 | this could potentially be very valuable.

00:03:00.960 | And the reason is that you can treat diabetes

00:03:03.060 | with insulin injections, but insulin is dangerous, right?

00:03:05.200 | 'Cause if you inject too much insulin,

00:03:06.320 | you can kill yourself by making yourself hypoglycemic, right?

00:03:08.420 | So you have to be very careful.

00:03:10.480 | But the thing about the incretin effect is

00:03:12.840 | it's not causing insulin release directly,

00:03:14.800 | but it's rather boosting the natural insulin release

00:03:17.480 | that comes when your glucose is higher in your blood.

00:03:19.440 | So it's sort of an amplifier

00:03:20.580 | on the natural insulin release.

00:03:22.740 | So basically in the years that followed,

00:03:23.960 | whenever someone would find a new hormone,

00:03:25.840 | they would test it.

00:03:26.680 | Is it this incretin?

00:03:27.520 | And there's lots of failures.

00:03:28.480 | They weren't the incretin.

00:03:29.760 | But then, so there's this other hormone

00:03:32.480 | that comes from the pancreas called glucagon, right?

00:03:36.360 | And so glucagon, it was also discovered in the 1920s.

00:03:39.080 | Glucagon is kind of the anti-insulin.

00:03:41.240 | So when blood sugar goes low,

00:03:43.880 | glucagon is released in order to cause your liver

00:03:45.920 | to release glucose into the blood.

00:03:47.920 | So glucagon and insulin are these two opposing hormones.

00:03:51.560 | Glucagon was known for a long time,

00:03:52.720 | but people discovered in sort of the 1980s

00:03:55.520 | that the glucagon gene is expressed in other tissues

00:03:58.720 | other than the pancreas.

00:04:00.340 | And it's differentially processed.

00:04:02.100 | The protein is differentially processed

00:04:03.660 | to produce different hormones,

00:04:04.760 | hormones other than glucagon.

00:04:06.800 | And they discovered there was one in the intestine.

00:04:08.480 | And so they called it glucagon-like peptide

00:04:10.400 | because it comes from the same gene,

00:04:12.160 | but it's just slightly different.

00:04:13.360 | It's cut up slightly differently.

00:04:15.800 | And this hormone wasn't incretin.

00:04:17.240 | So basically if you put it on beta cells,

00:04:20.840 | you get this increased response of insulin

00:04:22.640 | in response to glucose.

00:04:23.840 | And so there was the idea,

00:04:26.600 | okay, this could be a great diabetes drug, right?

00:04:28.280 | And I should say there was one other incretin

00:04:30.320 | that's been found.

00:04:31.160 | It's called GIP, G-I-P.

00:04:33.200 | And that will be important

00:04:34.480 | in talking about some of these other drugs.

00:04:36.600 | Also a hormone that comes from the intestine.

00:04:39.400 | And so the challenge with making GLP-1 into a drug

00:04:44.120 | is that it has an extremely short half-life.

00:04:46.480 | So it has a half-life of about two minutes in the blood.

00:04:49.480 | And so even if you inject people with GLP-1,

00:04:52.440 | it won't really be useful for anything.

00:04:53.840 | You don't decrease appetite,

00:04:54.760 | you don't affect blood sugar 'cause it's just degraded

00:04:56.840 | too fast.

00:04:58.320 | And the reason it's degraded is because there's an enzyme,

00:05:00.200 | DPP-4 is what it's called, that degrades GLP-1.

00:05:05.200 | So the first thing people tried was let's make inhibitors

00:05:07.080 | of that enzyme so we can boost this natural GLP-1 signal.

00:05:09.480 | And those are approved diabetes drugs.

00:05:13.200 | They're called gliptins.

00:05:14.040 | You've probably heard about them.

00:05:14.880 | Genuvia is the most common one.

00:05:16.800 | And those boost the level of GLP-1,

00:05:18.480 | the natural GLP-1 produced from the intestine

00:05:21.760 | by about threefold.

00:05:23.080 | And they're effective in treating diabetes.

00:05:24.900 | - Do people lose weight?

00:05:26.140 | - People do not lose weight.

00:05:27.800 | - Interesting.

00:05:28.640 | - And that's one of the key reasons that we know

00:05:30.640 | the natural function of GLP-1

00:05:32.320 | is not really to control body weight

00:05:33.880 | because you can boost the level threefold

00:05:35.680 | with these DPP-4 drugs.

00:05:37.660 | Millions of people have taken them.

00:05:38.720 | They do not lose weight.

00:05:39.960 | That's a great question.

00:05:41.520 | So, but a threefold is great,

00:05:43.800 | but you'd like to increase it even more, right?

00:05:45.440 | And to do that, you can't block this enzyme.

00:05:47.500 | You have to actually produce a GLP-1

00:05:50.080 | that is more stable in the blood.

00:05:52.280 | And that's where this lizard that you mentioned

00:05:54.840 | comes into play.

00:05:56.320 | It produces a stabilized form of GLP-1 and it's a venom.

00:06:00.160 | No one knows why.

00:06:01.040 | One hypothesis is that it's something to do with the lizard,

00:06:04.600 | as you said, basically having this long time period

00:06:06.960 | between meals and it needs to regulate its blood glucose.

00:06:09.280 | Who knows if that is true,

00:06:10.640 | but it turned out to be fortuitous

00:06:12.080 | because then this GLP-1 from this lizard,

00:06:14.960 | it has a half-life of like two hours.

00:06:17.240 | And so the first GLP-1 drug that was approved

00:06:19.480 | was just this molecule from this lizard, basically.

00:06:21.940 | And it's called Xenotide and it was approved in 2005.

00:06:26.940 | Works well for diabetes, has a half-life of two hours.

00:06:31.400 | You inject it and it doesn't cause a ton of weight loss.

00:06:35.660 | But two hours is good, but it's not so great.

00:06:38.360 | So then the pharmaceutical industry tried to say,

00:06:40.640 | can we basically improve this even further?

00:06:42.560 | And so they start engineering this hormone,

00:06:44.320 | making mutations, attaching lipid tails

00:06:46.640 | to make it bind to proteins in the blood

00:06:48.800 | that would stabilize it.

00:06:50.480 | - Chemistry jockey stuff.

00:06:51.760 | - Yeah, exactly.

00:06:52.800 | And I think the next big advance

00:06:54.800 | was this compound liraglutide.

00:06:56.360 | And liraglutide was approved for diabetes in 2010

00:07:01.020 | and then for weight loss in 2014.

00:07:03.440 | And so liraglutide has a half-life

00:07:05.560 | of about 13 hours in the blood.

00:07:07.400 | Now you're getting up to something serious.

00:07:08.400 | We've gone from two minutes, two hours, 13 hours.

00:07:12.000 | And you get better effects on aspects of blood glucose

00:07:15.720 | and diabetes control.

00:07:16.640 | And they started to see that some people were losing weight.

00:07:20.080 | Very variable responses.

00:07:21.120 | Not everyone loses weight on liraglutide.

00:07:23.760 | And one of the things they noticed

00:07:25.000 | that I think is just as fascinating

00:07:26.240 | just sort of example of how drug discovery works

00:07:27.880 | in the real world.

00:07:28.780 | You know, a lot of these people would take liraglutide.

00:07:31.360 | Now it has this longer half-life.

00:07:33.000 | They'll start to get nauseous.

00:07:34.400 | And that would limit how much

00:07:35.360 | of the liraglutide they could take.

00:07:36.520 | And it's a known side effect of these GLP-1 drugs.

00:07:38.400 | It causes nausea and sort of this gastrointestinal distress.

00:07:42.000 | But they noticed that over time,

00:07:43.840 | the nausea would just sort of go away.

00:07:45.480 | And so they would start dose escalating,

00:07:47.280 | sort of raising the dose that the person would take.

00:07:49.320 | So you would go, you know, a month at this dose,

00:07:52.520 | and then a month at a slightly higher dose,

00:07:54.240 | and then a month at a slightly higher dose.

00:07:55.520 | And you could work your way up.

00:07:56.920 | And these side effects would reappear,

00:07:58.560 | but then they'd go away.

00:08:00.000 | And then once you got up to the highest doses,

00:08:01.360 | then people really started losing weight.

00:08:02.720 | And so there's a couple of things

00:08:04.360 | that our pharmaceutical industry realized,

00:08:05.560 | wow, these are potentially

00:08:06.400 | really effective weight loss drugs.

00:08:08.240 | And also this nausea, which we thought was a killer,

00:08:12.720 | people are able to just get used to it,

00:08:14.200 | and then it just goes away.

00:08:15.160 | It undergoes, the word is tachyphylaxis.

00:08:17.840 | So the idea is that the receptor that's affecting,

00:08:21.200 | in the gut that's causing these effects,

00:08:23.760 | it undergoes some sort of down regulation

00:08:25.640 | with chronic exposure.

00:08:28.120 | So liraglutide, you know, it's been around,

00:08:30.320 | you know, it's been on the market for 14 years now,

00:08:32.760 | was used, but still you're only getting

00:08:34.200 | sort of like seven to 10% weight loss,

00:08:37.320 | which is good, but not like, you know, amazing, impressive.

00:08:41.020 | But then semaglutide came along.

00:08:43.880 | And that was approved for diabetes in 2017.

00:08:46.920 | And semaglutide is ozempic,

00:08:48.600 | or also marketed as Wigovi for weight loss.

00:08:53.600 | And semaglutide now has a half-life of seven days.

00:08:56.720 | So now we've gone from two minutes,

00:08:58.680 | two hours, 13 hours, seven days.

00:09:01.880 | And you can really jack up the concentration

00:09:03.640 | with a seven-day half-life.

00:09:06.560 | And then they saw people start really losing weight.

00:09:08.800 | And so in some of those trials,

00:09:10.560 | people lost, you know, 16% of their body weight,

00:09:12.680 | which previously had been unattainable.

00:09:15.440 | - In what timeframe?

00:09:16.980 | - Typically takes about a year.

00:09:18.680 | - Okay, and most of the loss in body weight

00:09:21.720 | is from body fat or from other compartments?

00:09:24.840 | - The typical number is that if you lose weight,

00:09:28.000 | either through dieting or through taking one of these drugs,

00:09:29.940 | and you don't do anything like eat a high-protein diet

00:09:31.880 | or do resistance training,

00:09:33.600 | somewhere between 25 and 33% of what you lose

00:09:36.760 | is gonna be muscle.

00:09:37.880 | The rest is gonna be fat.

00:09:39.040 | - But as you said, some of that could be offset

00:09:41.020 | by resistance training and/or consuming

00:09:43.560 | a higher-protein diet.

00:09:45.880 | - Yeah, you can almost completely eliminate that

00:09:47.760 | if you eat enough protein and do serious weightlifting.

00:09:50.840 | Obviously, not the whole population

00:09:53.400 | is interested in doing that.

00:09:54.360 | And there's been a lot of discussion

00:09:56.080 | of how serious a side effect this is.

00:09:58.100 | You know, among elderly people,

00:10:00.400 | you don't wanna be losing muscle mass

00:10:01.920 | because you're already losing so much muscle mass.

00:10:04.080 | On the other hand, the counterargument that has been made,

00:10:06.600 | which I think is also kind of convincing,

00:10:08.040 | is that, true, you're losing some muscle,

00:10:10.960 | but you're also losing all this fat,

00:10:12.660 | and you no longer need as much muscle

00:10:14.880 | when you're not carrying around as much body fat.

00:10:16.800 | So people who are heavier naturally have more muscle

00:10:18.820 | because they need to to move their body, right?

00:10:20.400 | And so- - Yeah, the calves

00:10:22.160 | on very obese people are often enormous.

00:10:26.200 | - Exactly. - And then they lose weight.

00:10:28.020 | - Exactly. - And I mentioned the calves

00:10:30.240 | in particular because they're carrying

00:10:33.240 | a lot of the body load.

00:10:34.360 | - Exactly, exactly.

00:10:35.200 | So it's still an open question as to how serious a problem

00:10:38.680 | this lean muscle mass loss is,

00:10:40.480 | although the pharmaceutical industry is all in now

00:10:43.040 | on making drugs that basically are gonna prevent that.

00:10:44.900 | So that's something that will be happening

00:10:46.800 | probably in the future.

00:10:47.840 | - Is it a, sorry to interrupt,

00:10:49.200 | but is the weight loss on these drugs

00:10:52.840 | the consequence of reduced appetite

00:10:55.360 | or some other aspect of metabolism?

00:10:57.380 | And if it's the consequence of reduced appetite,

00:11:00.440 | is that occurring at the level of the brain and gut

00:11:03.000 | or a combination?

00:11:05.920 | - So it's almost entirely reduced appetite,

00:11:08.320 | and it's almost entirely occurring

00:11:09.920 | at the level of the brain.

00:11:11.080 | - Which neurons?

00:11:11.960 | - It's thought that the key targets of these drugs

00:11:15.560 | are neurons in these two regions.

00:11:16.760 | One's called the nucleus of the solitary tract,

00:11:19.440 | and the other one's called the area post-trauma.

00:11:21.200 | - So we're back in the brainstem.

00:11:22.480 | - Back in the brainstem.

00:11:23.600 | So these are actually the neurons

00:11:25.080 | in that decerebrate rat story I was telling earlier.

00:11:27.920 | These are the brain regions that are preserved

00:11:29.620 | in the decerebrate rat.

00:11:30.480 | The decerebrate rat still has

00:11:31.560 | these very caudal brainstem structures.

00:11:34.800 | They're two very special brain regions

00:11:36.280 | because they get direct input from the vagus nerve.

00:11:39.400 | So the vagus nerve is the nerve that innervates your stomach

00:11:41.720 | and intestines and heart and lungs,

00:11:43.760 | and it's sort of the major pathway from gut to brain.

00:11:46.000 | It provides most of the neural input from gut to brain,

00:11:49.600 | telling you about things like your stomach distention,

00:11:52.480 | how many nutrients are in your intestine,

00:11:54.480 | breathing, all that stuff.

00:11:56.280 | And almost all of those vagal nerves

00:11:58.120 | terminate on these two structures in the brainstem.

00:12:01.280 | - When I hear post-trauma, I think about nausea

00:12:03.760 | because I was taught that post-trauma contains neurons

00:12:06.860 | that can stimulate vomiting.

00:12:08.600 | And this seems to link up well,

00:12:10.960 | at least in the logical sense,

00:12:12.160 | with the idea that stimulating, activating receptors

00:12:15.720 | in these neurons within post-trauma

00:12:17.680 | might explain part of the transient nausea side effect

00:12:21.320 | of ozempic and related drugs.

00:12:23.400 | - Yeah, so the current thought is that a lot of the nausea

00:12:25.920 | is coming from activating the neurons

00:12:27.360 | in the area of post-trauma,

00:12:28.520 | and that a lot of the sort of physiologic satiety

00:12:31.060 | is coming from activating the neurons

00:12:32.680 | in the nucleus of the solitary tract.

00:12:34.400 | Now, the whole brain is connected to each other,

00:12:35.800 | and so if you really turn on these neurons

00:12:37.400 | in the NTS and the AP, they're gonna talk

00:12:39.000 | to the hypothalamus and all these other brain regions,

00:12:40.640 | it's gonna change the whole brain.

00:12:42.080 | So it's not just those regions,

00:12:43.360 | but these drugs don't have great access to the brain.

00:12:46.800 | They can penetrate a little bit into the brain,

00:12:48.200 | but they don't penetrate into the whole brain.

00:12:50.080 | And it's thought that if you take

00:12:52.080 | fluorescently labeled versions of these drugs

00:12:54.440 | and see where do they, so you can visualize

00:12:56.080 | where do they actually go,

00:12:57.340 | they're enriched in these structures in the brainstem.

00:12:59.280 | So that's why people think

00:13:00.240 | that this is probably where they're acting.

00:13:02.040 | - And is that because there's an abundance

00:13:05.080 | of the receptors for these compounds in post-trauma and NTS,

00:13:10.080 | or is it because the blood-brain barrier

00:13:12.880 | is somehow weaker at that location?

00:13:15.320 | - It's because the blood-brain barrier is weaker.

00:13:16.880 | So basically, it's a region,

00:13:18.440 | what's known as a circumventricular organ,

00:13:21.880 | meaning it's one of these rare places in the brain

00:13:24.120 | where the blood-brain barrier is weakened,

00:13:25.640 | and so substances can come from the outside into the brain.

00:13:28.920 | And that's important for these big peptides,

00:13:31.760 | 'cause these are not small molecules.

00:13:32.920 | These are big peptides with lipid chains on them

00:13:34.760 | and other things.

00:13:35.600 | And so they can really only get into areas of the brain

00:13:38.040 | where the blood-brain barrier is weakened.

00:13:39.960 | - Thank you for tuning in

00:13:40.840 | to the Huberman Lab Clips channel.

00:13:42.640 | If you enjoyed the clip that you just viewed,

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

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