So one of the nice things, actually, about studying these kinds of things, like basic mechanisms of hunger, thirst, because these things are so important for survival, they've been under really strong selection, right? And so many of the components of these systems are genetically hardwired, meaning these are cell types that have a single purpose, in this case, to control hunger.

They're labeled by specific genes, and those are conserved through evolution. We also know that this pathway, this AGR-PNRM pathway, is important in humans due to human genetics. So just to add a little bit more information here, there's a companion set of neurons called POMC neurons that promote satiety. So they're sort of the yin and yang of hunger.

AGRP neurons promote hunger, POMC neurons promote satiety. They're intermingled in the same part of the hypothalamus. They're axons that project to the exact same downstream brain regions, and it's thought that these two neurons compete with each other to control appetite. And that competition occurs through neuropeptides that they release, one of which is an agonist for a downstream receptor, and the other one of which is an antagonist.

We know from human genetics that among severely obese people, mutations in this pathway, AGRP, POMC neurons, and their direct downstream targets, are quite common. So is it fair to say that some amount of obesity is genetic in nature at the level of neuronal firing or circuitry? I think a lot of body weight regulation is genetic.

It's highly heritable. There's a question of how much of it is due to single genes. And the number of people, quote, and this is among people who are severely obese, so not just people who you've seen someone who's overweight, but people have sort of syndromes where they're very obese from a very young age, among those people, something on the order of 10% have mutations in this pathway.

And it can either be this hormone POMC, or an enzyme within those cells that processes POMC into the right form, or, and this is the most common mutation, in the downstream receptor for POMC, it's called the melanocortin-4 receptor. And so among the severely obese, people who have sort of genetically inherited severe obesity from childhood, something on the order of 10% have mutations in this pathway.

So it's very clear that this pathway is involved in body weight regulation in humans. Most obesity, although there is a very strong genetic component, is not associated with single gene mutations like this. It's associated with effects of many mutations. But we know that even in that sort of polygenic obesity that has many different genetic causes, that the brain is important.

And one of the reasons we know that is if you look at the genes through genetic association studies that have been associated with body weight, and there's been lots of genetic association studies trying to find mutations that are associated with whether you're lean or obese, something on the order of 1,000 genes have been linked to body weight regulation.

And the vast majority of those are expressed in the brain. They're highly enriched for brain processes, which makes sense because body weight is controlled by food intake, right? And the brain controls behavior and also the brain controls energy expenditure. So maybe it's not so surprising, but it's clear that mutations in genes in the brain are important for body weight, and which is consistent with the results of twin studies.

So if you look at monozygotic versus dizygotic twins, the estimates for the heritability of body weight is something on the order of 80%. We should explain monozygotic, dizygotic, which I've talked about before on the podcast, to people. Sure, just identical versus fraternal twins, basically. And by comparing their, basically, their body weight when they become adults, you can get a sense for how much of this is genetic versus environmental.

And something on the order of 80% is thought to, the variation between individuals is thought to have a genetic component. Wow. I don't think most people appreciate that. And a lot of the debate we hear nowadays is because there are things that people can do to lose body fat, exercise, eat differently, et cetera, maybe embrace pharmacology if that's appropriate.

There seems to be this, to me, silly debate as to whether or not people should be eating better and exercising or assuming that all of the obesity they might have arises through genetic causes and therefore take a prescription drug. I mean, why wouldn't it be a combination of things?

To me, it just seems like, why wouldn't people embrace some or all of the tools that they could afford and that are safe for them? So, I just want to get that out there because the moment this comes up, people start thinking, "Oh, well, the moment we assign a genetic source to something, we're removing personal responsibility." But of course, there are people, I know people who have struggled with their weight their entire lives, for whom some of these new pharmaceuticals like Ozempic have provided them the opportunity to finally be able to lose weight and feel better and exercise safely, for instance.

- I completely agree with that. I think there is a misconception out there about this, about what it means for something to be genetically heritable. And I think this gets to the root of why so many people find this sort of hard to believe that there's such a strong genetic component to body weight.

And that's the idea that if you look at people, say, 75 years ago, they were much leaner. And you look at people today and there's been this, starting sometime around, you know, the 1970s, there was this explosion in body weight and increase in obesity. - Is that when, that's when it started, mid-seventies?

- Sort of the 1970s is when a lot of that started happening. - Snack food, snacking. - So, there's lots of explanations. - Seed oil snacking. By the way, I don't think that's the reason, folks. I think there are a lot of reasons, but the theories that abound right now on social media are, I have a list of theories as to why the obesity is increasing.

You get everything from seed oils to snacking to smartphones to conspiracies to, it's wild. It's wild. The range of hypotheses is wild. - Yeah, I mean, and the challenges, I mean, some of them could be true, but it's just very hard to test those things experimentally because they're happening in the whole population, right?

But, so I think the thing that people find hard to wrap their heads around, because it is a little bit of a confusing idea, is that how can it be that in say 50 or 75 years, there's been this explosion in obesity, which is, the environment has changed, but human genetics has not changed in that amount of time.

It's just not fast enough for people to evolve. So, it can't be due to mutations in humans. - What about devolve? My understanding is that within a species, evolving new traits is very slow, but mutations arise, like the OB mutation, and then you can get very fat versions of an animal very quickly, right?

All you need is a, if it's a recessive allele, you need two copies, and the next thing you know, you've got a mouse that's four times larger than a typical mouse, and it's all explained by increased body weight. So, that can happen very quickly within a species. What's rare to find is an entire new branch of a species that has a very, a new adaptive function.

That seems more rare. - So, that's true. So, definitely there's some things that take longer to evolve than others, but with humans, we're talking about just two generations. There just isn't enough time for any evolution of any significance to happen. - Baby boomers, right? General Dex, that's new, right?

And then whatever is YZ millennial. - Exactly. - Like I lose track after that. - Exactly. So, I think the thing that people find hard to wrap their heads around is how can it be that this is, that increase in body weight is clearly environmental, right? Because that's all that's changed is the environment.

Nothing's changed genetically. Yet, it's also true what I said, that body weight is extremely heritable. It's one of the most heritable features and something on the order of 80%. The only thing, one of the only things we know about that's actually more heritable than body weight is height, right?

Most diseases are not as heritable as body weight. How can you explain that? And the idea is this, there's a distribution of body weights among people. So, in any given society at any point in time, some people are going to be leaner, some people are going to be more obese.

That distribution, where you lie on that distribution, is determined primarily by genetics. So, you may be the person who has the thrifty genes, so that basically cause you to save energy, and so you would be more on the obese side. Or you may be a person who has different genes that cause you to be a little bit less hungry, so you would be on the leaner side.

What environment does is then it shifts that whole distribution, so that basically the mean shifts so that everyone becomes, or most people become heavier. And so, sort of a phrase that people sometimes use is that genetics loads the gun and environment pulls the trigger. So, basically genetics sets your propensity, and then environment can basically unmask that.

And so, as we've had this change in environment where there's all of this, and we don't know exactly what the things are that have changed that are important, but there's all this ultra-processed food, highly palatable food, just various other things that you mentioned, seed oils, who knows if that's important.

Certain people had these latent mutations that made them, say, very sensitive to palatable food. And in an earlier time, they may have been lean, but now because they have that latent capacity to be sensitive to ultra-processed food, they now gain tons of weight in the environment that we're in.

It's still because of genetics, but it also requires the environmental component. I mean, you just take a step back, right? You can make anyone lean by just putting them in prison and just only feeding them 1,500 calories. I mean, we've done those kinds of experiments. There's this famous experiment, the Minnesota starvation experiment, right?

They basically put people in prison, but this is in World War II. They took a bunch of healthy volunteers, fed them 1,600 calories a day, and just asked what would happen if you basically semi-starved people. And unsurprisingly, they lose an incredible amount of weight. All they think about is food.

Basically, their body temperature goes down. Their heart rate goes down. They just become obsessed with food. And you could always do that for anyone, right? But in a given environment where you're not in that kind of situation, then your propensity to gain weight will be determined by genetics. Thank you for tuning in to the Huberman Lab Clips channel.

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