Is Obesity Genetic? | Dr. Zachary Knight & Dr. Andrew Huberman
00:00:00.000 | So one of the nice things, actually, about studying these kinds of things, like basic
00:00:05.560 | mechanisms of hunger, thirst, because these things are so important for survival, they've
00:00:09.860 | been under really strong selection, right? And so many of the components of these systems
00:00:14.800 | are genetically hardwired, meaning these are cell types that have a single purpose, in
00:00:18.640 | this case, to control hunger. They're labeled by specific genes, and those are conserved
00:00:22.440 | through evolution. We also know that this pathway, this AGR-PNRM pathway, is important
00:00:29.480 | in humans due to human genetics. So just to add a little bit more information here, there's
00:00:34.520 | a companion set of neurons called POMC neurons that promote satiety. So they're sort of the
00:00:39.680 | yin and yang of hunger. AGRP neurons promote hunger, POMC neurons promote satiety. They're
00:00:45.680 | intermingled in the same part of the hypothalamus. They're axons that project to the exact same
00:00:52.600 | downstream brain regions, and it's thought that these two neurons compete with each other
00:00:57.440 | to control appetite. And that competition occurs through neuropeptides that they release,
00:01:02.280 | one of which is an agonist for a downstream receptor, and the other one of which is an
00:01:06.240 | antagonist. We know from human genetics that among severely obese people, mutations in
00:01:15.120 | this pathway, AGRP, POMC neurons, and their direct downstream targets, are quite common.
00:01:21.040 | So is it fair to say that some amount of obesity is genetic in nature at the level of neuronal
00:01:30.080 | firing or circuitry?
00:01:31.420 | I think a lot of body weight regulation is genetic. It's highly heritable. There's a
00:01:36.200 | question of how much of it is due to single genes. And the number of people, quote, and
00:01:40.880 | this is among people who are severely obese, so not just people who you've seen someone
00:01:44.160 | who's overweight, but people have sort of syndromes where they're very obese from a
00:01:47.560 | very young age, among those people, something on the order of 10% have mutations in this
00:01:53.000 | pathway. And it can either be this hormone POMC, or an enzyme within those cells that
00:02:01.600 | processes POMC into the right form, or, and this is the most common mutation, in the downstream
00:02:07.480 | receptor for POMC, it's called the melanocortin-4 receptor. And so among the severely obese,
00:02:15.320 | people who have sort of genetically inherited severe obesity from childhood, something on
00:02:19.040 | the order of 10% have mutations in this pathway. So it's very clear that this pathway is involved
00:02:24.600 | in body weight regulation in humans. Most obesity, although there is a very strong genetic
00:02:28.960 | component, is not associated with single gene mutations like this. It's associated with
00:02:34.520 | effects of many mutations. But we know that even in that sort of polygenic obesity that
00:02:39.800 | has many different genetic causes, that the brain is important. And one of the reasons
00:02:46.720 | we know that is if you look at the genes through genetic association studies that have been
00:02:50.440 | associated with body weight, and there's been lots of genetic association studies trying
00:02:52.880 | to find mutations that are associated with whether you're lean or obese, something on
00:02:57.760 | the order of 1,000 genes have been linked to body weight regulation. And the vast majority
00:03:03.280 | of those are expressed in the brain. They're highly enriched for brain processes, which
00:03:06.280 | makes sense because body weight is controlled by food intake, right? And the brain controls
00:03:10.560 | behavior and also the brain controls energy expenditure. So maybe it's not so surprising,
00:03:14.720 | but it's clear that mutations in genes in the brain are important for body weight, and
00:03:20.680 | which is consistent with the results of twin studies. So if you look at monozygotic versus
00:03:24.400 | dizygotic twins, the estimates for the heritability of body weight is something on the order of
00:03:29.200 | 80%.
00:03:30.360 | We should explain monozygotic, dizygotic, which I've talked about before on the podcast,
00:03:34.040 | to people.
00:03:35.040 | Sure, just identical versus fraternal twins, basically. And by comparing their, basically,
00:03:43.000 | their body weight when they become adults, you can get a sense for how much of this is
00:03:45.800 | genetic versus environmental. And something on the order of 80% is thought to, the variation
00:03:52.840 | between individuals is thought to have a genetic component.
00:03:56.040 | Wow. I don't think most people appreciate that. And a lot of the debate we hear nowadays
00:04:01.080 | is because there are things that people can do to lose body fat, exercise, eat differently,
00:04:07.840 | et cetera, maybe embrace pharmacology if that's appropriate. There seems to be this, to me,
00:04:16.120 | silly debate as to whether or not people should be eating better and exercising or assuming
00:04:22.280 | that all of the obesity they might have arises through genetic causes and therefore take
00:04:29.640 | a prescription drug. I mean, why wouldn't it be a combination of things? To me, it just
00:04:33.920 | seems like, why wouldn't people embrace some or all of the tools that they could afford
00:04:39.040 | and that are safe for them? So, I just want to get that out there because the moment this
00:04:41.800 | comes up, people start thinking, "Oh, well, the moment we assign a genetic source to something,
00:04:46.640 | we're removing personal responsibility." But of course, there are people, I know people
00:04:51.720 | who have struggled with their weight their entire lives, for whom some of these new pharmaceuticals
00:04:56.840 | like Ozempic have provided them the opportunity to finally be able to lose weight and feel
00:05:02.960 | better and exercise safely, for instance.
00:05:06.120 | - I completely agree with that. I think there is a misconception out there about this, about
00:05:11.000 | what it means for something to be genetically heritable. And I think this gets to the root
00:05:13.920 | of why so many people find this sort of hard to believe that there's such a strong genetic
00:05:17.120 | component to body weight. And that's the idea that if you look at people, say, 75 years
00:05:22.280 | ago, they were much leaner. And you look at people today and there's been this, starting
00:05:26.400 | sometime around, you know, the 1970s, there was this explosion in body weight and increase
00:05:29.640 | in obesity.
00:05:30.640 | - Is that when, that's when it started, mid-seventies?
00:05:32.200 | - Sort of the 1970s is when a lot of that started happening.
00:05:34.720 | - Snack food, snacking.
00:05:35.720 | - So, there's lots of explanations.
00:05:36.720 | - Seed oil snacking. By the way, I don't think that's the reason, folks. I think there are
00:05:40.960 | a lot of reasons, but the theories that abound right now on social media are, I have a list
00:05:47.020 | of theories as to why the obesity is increasing. You get everything from seed oils to snacking
00:05:51.720 | to smartphones to conspiracies to, it's wild. It's wild. The range of hypotheses is wild.
00:06:01.000 | - Yeah, I mean, and the challenges, I mean, some of them could be true, but it's just
00:06:03.400 | very hard to test those things experimentally because they're happening in the whole population,
00:06:07.000 | right? But, so I think the thing that people find hard to wrap their heads around, because
00:06:10.000 | it is a little bit of a confusing idea, is that how can it be that in say 50 or 75 years,
00:06:15.560 | there's been this explosion in obesity, which is, the environment has changed, but human
00:06:19.600 | genetics has not changed in that amount of time. It's just not fast enough for people
00:06:22.080 | to evolve. So, it can't be due to mutations in humans.
00:06:24.560 | - What about devolve? My understanding is that within a species, evolving new traits
00:06:29.920 | is very slow, but mutations arise, like the OB mutation, and then you can get very fat
00:06:36.320 | versions of an animal very quickly, right? All you need is a, if it's a recessive allele,
00:06:44.600 | you need two copies, and the next thing you know, you've got a mouse that's four times
00:06:47.380 | larger than a typical mouse, and it's all explained by increased body weight. So, that
00:06:51.540 | can happen very quickly within a species. What's rare to find is an entire new branch
00:06:57.880 | of a species that has a very, a new adaptive function. That seems more rare.
00:07:03.840 | - So, that's true. So, definitely there's some things that take longer to evolve than
00:07:07.520 | others, but with humans, we're talking about just two generations. There just isn't enough
00:07:11.040 | time for any evolution of any significance to happen.
00:07:13.180 | - Baby boomers, right? General Dex, that's new, right? And then whatever is YZ millennial.
00:07:19.160 | - Exactly.
00:07:20.160 | - Like I lose track after that.
00:07:21.160 | - Exactly. So, I think the thing that people find hard to wrap their heads around is how
00:07:23.700 | can it be that this is, that increase in body weight is clearly environmental, right? Because
00:07:28.000 | that's all that's changed is the environment. Nothing's changed genetically. Yet, it's also
00:07:31.540 | true what I said, that body weight is extremely heritable. It's one of the most heritable
00:07:35.440 | features and something on the order of 80%. The only thing, one of the only things we
00:07:38.720 | know about that's actually more heritable than body weight is height, right? Most diseases
00:07:42.240 | are not as heritable as body weight. How can you explain that? And the idea is this, there's
00:07:47.360 | a distribution of body weights among people. So, in any given society at any point in time,
00:07:52.260 | some people are going to be leaner, some people are going to be more obese. That distribution,
00:07:56.920 | where you lie on that distribution, is determined primarily by genetics. So, you may be the
00:08:00.880 | person who has the thrifty genes, so that basically cause you to save energy, and so
00:08:04.360 | you would be more on the obese side. Or you may be a person who has different genes that
00:08:08.680 | cause you to be a little bit less hungry, so you would be on the leaner side. What environment
00:08:13.160 | does is then it shifts that whole distribution, so that basically the mean shifts so that
00:08:17.640 | everyone becomes, or most people become heavier. And so, sort of a phrase that people sometimes
00:08:24.320 | use is that genetics loads the gun and environment pulls the trigger. So, basically genetics
00:08:30.720 | sets your propensity, and then environment can basically unmask that. And so, as we've
00:08:37.740 | had this change in environment where there's all of this, and we don't know exactly what
00:08:41.000 | the things are that have changed that are important, but there's all this ultra-processed
00:08:43.920 | food, highly palatable food, just various other things that you mentioned, seed oils,
00:08:48.620 | who knows if that's important. Certain people had these latent mutations that made them,
00:08:55.000 | say, very sensitive to palatable food. And in an earlier time, they may have been lean,
00:08:59.840 | but now because they have that latent capacity to be sensitive to ultra-processed food, they
00:09:04.160 | now gain tons of weight in the environment that we're in. It's still because of genetics,
00:09:08.000 | but it also requires the environmental component. I mean, you just take a step back, right?
00:09:11.400 | You can make anyone lean by just putting them in prison and just only feeding them 1,500
00:09:16.760 | calories. I mean, we've done those kinds of experiments. There's this famous experiment,
00:09:19.440 | the Minnesota starvation experiment, right? They basically put people in prison, but this
00:09:23.880 | is in World War II. They took a bunch of healthy volunteers, fed them 1,600 calories a day,
00:09:28.640 | and just asked what would happen if you basically semi-starved people. And unsurprisingly, they
00:09:32.080 | lose an incredible amount of weight. All they think about is food. Basically, their body
00:09:34.840 | temperature goes down. Their heart rate goes down. They just become obsessed with food.
00:09:38.520 | And you could always do that for anyone, right? But in a given environment where you're not
00:09:43.560 | in that kind of situation, then your propensity to gain weight will be determined by genetics.
00:09:47.800 | Thank you for tuning in to the Huberman Lab Clips channel. If you enjoyed the clip that
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