- As a biologist, as a neuroscientist, how do you think about this thing that we call hunger and feeding? - Absolutely, absolutely. So I think at a very high level, a good way to think about the regulation of food intake by the brain is that there's two systems, a short-term system and a long-term system that are primarily localized to different parts of the brain, operate on different timescales, one on the timescale of a meal, so 10, 20 minutes, and the other on the timescale of sort of weeks to months to years and tracks levels of body fat.

And these two systems sort of interact so that these short-term behaviors we do eating are matched to our long-term need for energy. And so I think one of the initial experiments that really led to this idea is this great experiment by Harvey Grill about 50 years ago. It's called the decerebrate rat.

And so essentially what he did was he made a cut in the rat brains. He took these rats in the lab, made a cut so that he separated the brainstem, so the most posterior part of the brain, from the entire forebrain, basically got rid of 80% of the rat's brain.

So he's basically creating these zombie rats, all they have is a brainstem, and asked, what can these rats still do? And as you might imagine, they can't do a lot of things because they basically have lost most of their brain. But he discovered that one thing they can still do is regulate the size of a meal.

And so-- - Very informative experiment. - And so, you have to be careful how we talk about this, 'cause the way this meal works is you have to actually put food into their mouth, and then they'll swallow it as you put food into their mouth. But eventually at some point, they'll start spitting it out.

And that basically is an indication that in some sense they're becoming sated, and they're just using the brainstem that they have left, they're able to sense those signals from the gut and drive the termination of a meal. And he did other experiments showing that many of these signals that come from the gut like gastric stretch, hormones that come from your intestine in response to food intake like CCK, these deserebrate rats just have a brainstem.

If you inject those or manipulate the gut in those ways, it can in an appropriate way change how much the rat eats. Now, what can't the rat do when it doesn't have a forebrain? And the thing it can't do is it can't respond to longer term changes in energy need.

Meaning, if you fast the rat for a couple days, this deserebrate rat, then start putting food in its mouth, the amount that it eats doesn't change. So basically it doesn't eat a larger meal the way you would if you were fasted for several days and then refed. And that experiment along with other evidence has led to the idea that in the brainstem and then the most posterior part of your brain, there are neural circuits that control sort of a meal and then the timescale of 10 minutes or 20 minutes deciding when a meal should end.

And in the forebrain, primarily in the hypothalamus, there are neural circuits that then track what is my overall level of energy reserves? What is my level of body fat? Things that would fluctuate on timescale of say days when you're fasting. And those forebrain centers feedback to talk to the brainstem and modulate those brainstem circuits that are controlling the size of a meal to sort of match these two timescales.

So that's at the highest level how I think about the neural circuitry that controls feeding. There's obviously a lot more going on underneath that. - Fascinating. You mentioned body fat and that somehow the brain is tracking the amount of body fat. That caught my ear because while it makes total sense, I'd like to know how that happens if we happen to know the mechanism.

And the second question is why body fat and not body fat and muscular mass or body fat and overall body weight? What is being signaled between body fat in the brain that allows the brain to track body fat? And why do you think body fat is the critical signal?

I realize it represents an energy reserve, but certainly there are other things about the bodily state that are important. - Yeah, well, there are certainly other things about the bodily state that are important and there are other things about physiology definitely that are regulated other than body fat. But body fat is unique because it represents this energy reserve.

So the neural circuitry that regulates eating behavior is in some ways very unique because it has this reserve of energy. So we also study thirst in my lab and drinking and you don't have a reserve of water in your body, right? And that's true for basically everything else. But for fat, we have this reserve of energy.

And so it's very important that the brain know how much remains and then adjust behavior in coordinates with that so that you know how urgent it is to get the next meal. And so the thought is that the major signal of the level of body fat that we have is leptin.

It's this hormone. It was discovered, it was cloned in 1994, actually by my postdoctoral advisor, a scientist named Jeff Friedman at Rockefeller University, although its history goes back way before 1994. So the sort of story behind leptin is that there's a facility called Jackson Labs that you I'm sure are familiar with in Maine that since the 1920s has been raising mice and selling them to academics basically who study physiology and behavior.

And so they breed thousands of mice. So there's sort of a nonprofit organization that distributes mice to the scientific community. And at some point in the 1950s, they spontaneously, just because they were breeding so many mice, they came across some spontaneous mutations, mutant mice that were extremely fat, like the fattest mice they had ever seen.

These mice just eat constantly. They're just enormous, three times the size of a normal mouse. And it's all body fats. They're just these huge fat mice. And they came across several different mutant strains that all had the same phenotype in the sense that they were all extremely fat, all extremely hyperphagic, but they could tell even in the 1950s that these mutations were on different chromosomes.

They didn't know anything about how to identify the genes at that point. That was just science fiction, but they knew that there were chromosomes and they were on different chromosomes. And so they labeled one obese, one of these mouse strains obese, and the other one diabetes, but they're basically the same.

As people wonder for a long time, well, what's going on in these mice? Then there was a scientist at Jackson Labs, Doug Coleman, who had the idea, what if we do an experiment where we connect the circulations of these two different strains of obese mice and test the hypothesis that maybe there's a circulating factor, a hormone that is produced by one of these strains and that controls appetite?

Because at that point, insulin was known, glucagon was known. There were some hormones that were known that were involved in metabolism. So it was logical that there could be a hormone that perhaps regulates body fat levels. And what they found, which was remarkable, when you attach the obese strain to the DB strain, so you basically connect their circulation, so hormones are transmitted between the two, the OB mouse, that strain dramatically loses weight.

In fact, within a couple of weeks, it looks like a normal mouse. It just stops eating. It loses almost all of its body fat. And it essentially, in all aspects, becomes a normal mouse. The DB mouse, nothing really happens. It still remains obese and still remains hyperphagic. And based on just that piece of data, Doug Coleman hypothesized that what was going on is these two mutations were mutations in a hormone and a receptor.

The OB mouse had a mutation in the hormone that comes from fat, so it couldn't produce this hormone that comes from fat and signals to the brain how much fat you have. And the DB mouse has a mutation in the receptor, so it can't sense the hormone. And that was just an idea.

It was a hypothesis. But in the 1980s, as technology advanced, as molecular biology had been invented, it became possible to clone genes. A number of people tried to identify what are the genetic mutations that are occurring in these mice that make them so obese. And Jeff basically cloned leptin and showed that, in fact, Doug was exactly right.

The OB mutation is a mutation in this hormone, leptin. And later, Millennium Pharmaceuticals showed that the DB mutation is, in fact, a receptor. And it was an important discovery for a couple of reasons. One, because this OB gene is just expressed in fat. It's exclusively expressed in adipose tissue.

And how much it's expressed is directly proportional to how much body fat you have. So as you gain weight, the expression of this hormone increases in a linear manner, and then it's secreted into the blood. So the level of leptin in your blood is a direct readout of your body fat reserves.

This receptor for leptin, leptin receptor, the functional form of it is expressed almost exclusively in the brain. And it's expressed in all of the brain regions that we knew from previous work were important for appetite. So basically, the expression of this receptor gives you a map in the brain of the neurons that control hunger.

And so what happens is, basically, when you lose weight, the levels of leptin in your blood fall, because basically you've lost adipose tissue. The absence of that hormone sends a signal to all these neurons that have leptin receptors in the brain, they're not getting that signal that I'm starving.

And it basically, that initiates this entire homeostatic response to starvation. So a big part of that is obviously increased hunger, but it's also decreased energy expenditure, decreased body temperature, even decreased fertility, because you don't want to reproduce if you're starving. - Less spontaneous movement. - Less spontaneous movement, all of this.

And so the thought is, which I think is absolutely correct, is that this hormone leptin is part of this negative feedback loop from the fat to the brain that basically tells you about your level of body fat reserves and how urgent it is to find the next meal. - Fascinating.

As I recall, Amgen Pharmaceuticals owned the patent for leptin in hopes that it would become the blockbuster diet drug. The logic being that if you were to take this hormone somehow, or activate this pathway, that the brain would be tricked into thinking that there was more body fat, more energy reserves than there was, and then people would basically be less hungry, eat less, and lose body fat.

- Yes. - What happened with that? Do we know why it did not work? - Yeah, so that's a great question. So there was a lot of excitement when leptin was cloned, 'cause it was thought basically we've cured obesity. There was an auction for the patent, Amgen won, I think it was something like $20 million up front payment, plus royalties, which at the time was, I mean, it still is a lot of money, but even more money.

- Nowadays it would be a drop in the ocean compared to what companies will invest into potential diet drugs. - Exactly, but you know, at the time, and still a lot of money today, and they did a clinical trial, gave obese people leptin, subcutaneous injections of this hormone, and they didn't lose a lot of weight, and the question was why.

And so what was subsequently revealed is that the challenge with leptin is that individuals who are obese do not have low levels of leptin for the most part, they actually have high levels of leptin. And so what they have is a state of leptin resistance. So it's analogous to someone who has type two diabetes.

It's not because they lack insulin, it's because they actually have, over time, a high level of insulin, and so target tissue stopped responding to insulin. And the thought is that it's the same way in obesity and leptin. Now, subsequently, they went back and did a reanalysis of that clinical trial, and asked, what if you take all of these people and stratify them according to their starting leptin level?

So some people have relatively low levels of leptin, some have higher, some have really high levels of leptin, and then ask, if we reanalyze the data, how effective is leptin? And as you might expect, the people with the lowest levels of leptin, they lost the most weight when you gave them this drug, and the people with the highest levels of leptin lost the least weight.

So there is a rationale there for why, for a scenario in which leptin could work, either among the subset of people who just have, for some reason, lower levels of leptin, these aren't people with mutations like the OB-MALS, they have some leptin, they just don't have unusually high levels, or, alternatively, after weight loss.

So after you've lost a lot of weight, your leptin levels plummet, they become very low, and that part of the reason, it's a big part of the reason it's so difficult to keep weight off, is because those leptin levels are so low. And so it's been thought for a long time that that is a scenario where treating people with leptin could be really useful to help them keep the weight off.

Why it never made it as a drug for that application, I really don't understand. It has something to do, I think, with the pharmaceutical industry, with the economics, with a bunch of other issues that aren't necessarily scientific. But I think there still, in the future, is a possibility that it could come back for that indication, especially now that we have these GLP-1 drugs, and now there's just millions of people losing so much weight and perhaps they want to transition to a different kind of drug to keep the weight off.

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