This is a transcript of the Gastropod episode, You’ve Lost That Hungry Feeling, first released on May 23, 2023. It is provided as a courtesy and may contain errors.

PAUL FORD: The way I would describe it is stuff is always screaming at you. Like the snacks are always screaming, and the fridge is screaming, and everything is like making its little noise. Like just imagine a world where everything’s a little gremlin going, “please!” And so suddenly I realized that I wasn’t, aware. Like I just wasn’t noticing that noise. It didn’t come as like, oh, I’m not hungry. It came as, huh, it just seems quiet.

NICOLA TWILLEY: This is Paul Ford, he’s a software entrepreneur and also a writer with a column for Wired magazine. And he used to be a very hungry man.

CYNTHIA GRABER: Until he started taking a new diabetes drug.

BROADCASTER: Scroll through TikTok and you’re sure to see Ozempic. Some now calling it the skinny pen.

PRESENTER: Imagine it’s lunchtime and instead of craving this giant bacon double cheeseburger to feel full, all you needed was this little slider.

VOICEOVER: Celebrities like Elon Musk and Jeremy Clarkson have helped fuel the excitement with Hollywood stars and social media influencers touting the effectiveness of these miracle drugs.

TWILLEY: Unless you’ve been living under a rock, you’ve heard of these new drugs—in fact, lately the news has been full of stories about them. They’re called Ozempic, Wegovy, and Mounjaro.

GRABER: While they were developed to treat diabetes, as the broadcasters pointed out, and as Paul himself experienced, they’ve also been helping people lose weight. But the weight loss itself isn’t what we’re interested in here at Gastropod—and yes, you are listening to Gastropod, the podcast that looks at food through the lens of science and history, I’m Cynthia Graber.

TWILLEY: And I’m Nicola Twilley. And instead, what we wanted to know, and what we’re exploring this episode, is the thing that seems to be causing that weight loss, which is a total transformation of people’s experience of hunger.

GRABER: So, what is hunger? Why do we get hungry, why do we stop feeling hungry, and why can it be so incredibly different from person to person?

TWILLEY: What are these new drugs doing that can so radically change the experience of hunger, and what does that mean for us all?

GRABER: Listeners, we did want to preface this episode by saying there will be some discussion of weight loss because that’s one part of how people are experiencing these drugs. But we also want to assure you, this is not a weight loss episode. It’s about these really profound human experiences: hunger and satiety. They’re ones we all share but that we all seem to experience differently, and yet they shape our lives.

TWILLEY: This episode is made possible in part by the Burroughs Wellcome Fund, in support of our coverage of biomedical research, and by the Alfred P. Sloan Foundation for the Public Understanding of Science, Technology and Economics. Gastropod is part of the Vox Media Podcast Network, in partnership with Eater.

[MUSIC]

TWILLEY: I know Paul, and I asked him to talk to us about a piece he wrote for Wired called, “A New Drug Switched Off My Appetite. What’s Left?”

GRABER: To be honest, Paul was a little reluctant to talk to us, and he hadn’t even really wanted to write the piece in the first place.

FORD: I will say that was one of the things I felt I needed to write that I least wanted to write. I just had no desire to share this part of myself.

TWILLEY: And that reluctance is in large part because, as a culture, we are typically not very thoughtful or kind with people whose bodies don’t fit a particular mold.

GRABER: Paul appreciated that we had no interest in asking him how many pounds he lost. Instead, we wanted to know how he experienced hunger. Like, in the past, before these drugs, how often was he hungry?

FORD: The, the easiest answer is always. Right. Like, just that I would wake up and I would say, today I think I’m going to organize my, my life and my food. And I think I’ll have a good day. And then in the evenings I would find myself eating—and there are different words to describe it. Compulsively, obsessively, whatever. And I would go to bed and I’d go like, whoops, ehhh. There we go again. But that’s life, and we’ll give it another go tomorrow.

TWILLEY: The way Paul explained it to us, hunger and satisfying it was just omnipresent, it was always in his mind.

FORD: So, like, I’m in an office right now and if I look to the left, there’s a pile of treats. That pile of treats was there before I started on these meds. And I was always aware of that pile of treats. I was aware that there was ice cream in the freezer. I was aware of where all the calories were around me.

GRABER: He describes this experience, this need to meet whatever his body was asking for, as overwhelming.

FORD: Imagine that this particular body, this body is optimized to get a certain amount of food into it a day. And to sort of hit that level. And if I didn’t hit that level, it would, I’d really feel it.
It’s not hunger like, boy, I could really go for lunch. It, it’s more like if I don’t hit that level, I become really, really anxious and I’ll do anything I can to avoid that anxiety.

TWILLEY: Paul is pretty sure his experience of hunger is not the same as everybody else’s.

FORD: Oh, I’m definitely wired a little differently. I wrote about this in the piece, when I went to my uncle’s funeral. Everybody was my size. And it was wild because it was like, oh my God, like, you know, my, my, Someone in my family leaned over and was like, how much does this funeral weigh? Right? Like, it’s just, there’s obviously this intense genetic component. I think everybody has their own intense relationship with food and it’s incredibly intense for every human being because it’s food. And what I know is that mine was radically different. And mine, I couldn’t, I tried a lot of different things to get it under control and it just didn’t want to get under control.

GRABER: Paul has type 2 diabetes, and recently his doctor suggested he go on Ozempic.

FORD: I was on insulin for a while. He was like, you don’t need it. He was like, let’s put you on one of these. They, they encourage the production of insulin in your body.

TWILLEY: So Paul started taking Ozempic. And he found that there was another, quite welcome effect.

FORD: So you take a shot once a week and you eat less. So I, I did that with Ozempic for about a year and I did lose some weight. Small amount, like 5, 10% and of my body weight. But not, not enough to make a huge difference.

TWILLEY: This was good, losing a little weight was great, maintaining that lower weight was great—because diabetes is easier to manage at a lower weight. But, his doctor thought he could do better.

FORD: My endocrinologist very casually was like, oh, you’re not losing a lot of weight. Try this one. It’s new. And I didn’t think much of it. I was like, all right, cool. That’d be good. So I used up the Ozempic I had, and then I switched over to the new one. New one’s called Mounjaro, M O U N J A R O, which is… maybe the worst brand name for anything I’ve ever heard in my life. Just awful. But yeah. So same, same mechanism. You just put your, a shot in the belly and or maybe the thigh. And you alternate the sides and you just—[IMITATES CLICK]. The shot is like, really easy, like it comes all pre-made. You just do a little twist and go click and it goes in your body. And you don’t feel it.

GRABER: After Paul started injecting Mounjaro, at first nothing seemed different.

FORD: You know, I just kind of like, went about my day. And then two weeks later, about. I went, wait a minute. That’s interesting. And I realized that like kind of a fundamental as—like, I, I couldn’t understand what was going on. Because I was like, suddenly kind of. Suddenly I went—I, I realized that I wasn’t… aware. Like I just wasn’t noticing that noise.

TWILLEY: Remember how Paul described the little snacks like gremlins, screaming at him? They’d shut up.

FORD: It didn’t come as like, oh, I’m not hungry. It came as like, huh, it just seems quiet. Like it really felt that way. Like it was just like, like a kind of Christmas morning quiet. Like the snow is falling.

GRABER: This drug completely and radically changed Paul’s relationship to food.

FORD: There was always something else to do and, and to eat. And instead I was like, boy, that’s way too much. That’s enough for me. I’ll go home. And then a radiant confusion after that. Because, really the organizing principle of my life for the last…20 years?…has been that I have a sick relationship with food and I, I have to manage it or I’ll die. And instead it was just like, yeah. You know.

TWILLEY: This really was confusing—like things that Paul knew about himself were suddenly not true. He told us that one afternoon he went to an old school Chinese restaurant and he ordered General Tso’s chicken, deep fried everything, and he just didn’t want it. He wanted the broccoli.

FORD: And what I realized is just that… kind of all the good habits that I had forced myself to learn were in there, I just wasn’t able to access them. And then all of a sudden the person shows up who’s like, cool, I don’t really need meat for this meal. I don’t, like, I just didn’t need the density anymore.

GRABER: Paul is a little bit obsessive, so when he suddenly had this blank space in his brain that hunger and food used to take up, he went searching for something else.

FORD: So for me, I mean, I’ve been teaching myself piano. Like I’m just like, I needed something to do, like kind of with my hands. And so music and messing around with sound. Sound actually— a bath of sound in my ears, chords and synthesizers and so on is soothing. And it soothes that part of my brain that I think was filled with food. So instead of food, sound.

TWILLEY: To the point where even that’s a little bit of an issue now.

FORD: So you know, my spouse and I had a little conversation about maybe I could stop buying synthesizers.

GRABER: Paul’s kind of joking about this—I mean, maybe he is buying too many synthesizers, I don’t know, can you have too many?—but the real change for him is how much more space there is in his life now that his hunger has been reduced to a more moderate and manageable size.

TWILLEY: This drug has transformed Paul’s life. But it’s also done what it’s supposed to do in terms of his type two diabetes.

FORD: My A1C levels are good. Like, I have a well managed condition in my type two diabetes. And so, like, that’s the important part. And then we get to the other stuff after that. But I mean, the beautiful thing here is that I’m able to manage that condition much, much better the smaller I am.

GRABER: For Paul, this is a success story. But it also made us wonder: what really is hunger?

JULIA BELLUZ: Hunger is a sensation that is telling us to eat, that we have to eat. I think we all know that it’s like, a really uncomfortable feeling. You know, when you’re hungry, you want to alleviate the hunger. And the way to alleviate the hunger is by consuming food.

NICK BETLEY: And you know, one of the interesting aspects of hunger is, it’s not really a deficit of nutrients that will lead to lack of survival, right? Because all people feel hunger no matter how much body mass you have. So hunger, I think, can best be described as the sensations you produce when you haven’t ate food in a while.

TWILLEY: Meet Julia and Nick, our guides to understanding what on earth hunger actually is. Which seems like it should be simple but as you can probably already tell, isn’t at all. Nick Betley has a neuroscience research lab at the University of Pennsylvania.

GRABER: And Julia Belluz is a health journalist, she’s working on a book about obesity, nutrition and metabolism. Julia says you can’t talk about hunger without also talking about the flip side, feeling full.

BELLUZ: You can think about, like, life, our lives, as being punctuated by these periods of hunger followed by food seeking. Or maybe we’ve already found the food. Followed by periods of eating and then fullness and then hunger again. And this cycle just repeats.

TWILLEY: Scientists divide fullness into two technical terms: satiety and satiation—satiation is the feeling you get as you’re eating, to tell you you’re getting full and you should stop, satiety is the feeling of fullness after a meal, that gradually wanes over time as you get hungry. We’re going to use these two terms interchangeably this episode to mean fullness.

GRABER: At the most basic level, the sensation of hunger is reminding us that we need to consume food to get energy, and the fullness sensation lets us know that we should stop eating so that frankly we don’t hurt ourselves.

TWILLEY: Hunger and fullness are universal. But until quite recently we haven’t known a lot about how these feelings are created on a physiological level. Some of the earliest insights came from an Austrian scientist back in the early 1900s, he wrote a paper about some patients who had spontaneously put on a lot of weight.

BELLUZ: And they also had other symptoms. Like, kids who weren’t developing in puberty normally, or adults who had memory loss and headaches and other issues with like, basic functioning that they didn’t have before. And when they did more research, they realized that these people often had tumors on, on the hypothalamus in the brain.

GRABER: The hypothalamus is a small area of the brain, it’s kind of hidden deep inside, and it like, most areas of the brain, is pretty complicated. It does a lot of things, including both producing hormones and reacting to hormones that regulate body temperature, blood pressure, the reproductive drive… basic survival behaviors.

BELLUZ: So the idea was that if you’re impinging on this, like, important part of the anatomy of the brain, you’re also changing eating behavior.

TWILLEY: So clearly the hypothalamus had something to do with hunger and fullness.

GRABER: The patients had existing tumors, so it was kind of a natural experiment. But then in the 1940s, a researcher in Chicago decided to see what happened if he deliberately damaged the hypothalamus in rats. And his rats became really fat.

BELLUZ: And so, yeah, you’re physically changing the structure of the brain and influencing appetite and, and what and how much the animals are eating. But basically for a long time there was just no sense of how this was actually working in humans.

GRABER: These experiments basically seemed to prove that the brain is involved in whether an animal, including human animals, experience hunger in some way. And that at the very least, the hypothalamus is involved in regulating that feeling in the brain.

TWILLEY: Another clue came from a mouse in Maine. In 1949, a researcher at mouse central, this place called the Jackson Lab in Bar Harbor, where they do biomedical research. And so they’ve developed 8000 specific kinds of genetically different mice to study all kinds of things—this researcher noticed a very large mouse.

BELLUZ: So it was like, I think three times the size of a regular mouse. If you look at pictures, it’s like this little very, very round furball of a mouse. And he’s, he’s wondering like, what, what is causing these animals to gain weight? Like why are they eating more than other mice?

GRABER: As we said, the scientists had bred all sorts of mice in that lab. So they bred these particularly plump mice to make more, to create a line of mice that would inherit the genes that would make them heavy. They called these mice OB/OB mice, and the researcher guessed that some kind of genetic mutation had maybe stopped the mice from ever feeling full.

BELLUZ: He, he called it the satiety factor and he never figured out what this satiety factor was. And then in the mid 1990s researchers that were working at Rockefeller in New York figured it out. It was this hormone called leptin.

TWILLEY: The OB gene codes for leptin production, and, in the OB/OB mice, both copies of it were broken, so the mice couldn’t produce this particular hormone.

GRABER: Just to let you all know, because we’ll be talking a lot about hormones, hormones are basically chemical messengers in our body. We hear a lot about reproductive hormones, but there are lots of different kinds of hormones and they do all sorts of things. One of them is leptin.

BELLUZ: And, basically leptin is secreted in the fat cells of animals and it tells the brain how much energy is stored on the body. And when leptin levels are dropping really low, it sends a signal to the brain that you need more energy, you have to eat more. And so finally, like this was like a peek into, how are these systems working?

GRABER: Yes, it took until the *1990s* to start to figure this out. Even though hunger and fullness are so important, the science behind them is really recent.

TWILLEY: Obviously, mice are not humans, but shortly afterwards a scientist called Stephen O’Reilly at the University of Cambridge in England discovered the same mutation in some children.

BELLUZ: Basically he said, you know, I was sort of judging the parents when they came into the clinic with these kids and thinking they’re just not feeding their, their kids appropriate diets. But basically they discovered that the kids, just like the mice were leptin deficient. And it was the first genetic form of obesity that had ever been discovered.

GRABER: Finally, two important players in our hunger system had been found: one brain area, and one hormone. So maybe that could lead to a drug that might help curb people’s hunger.

BELLUZ: There was an idea that it would help people lose weight and, through this action of like, helping them sense their fullness.

TWILLEY: Ka-ching!

BELLUZ: And it was a massive failure. It didn’t work. Leptin helps only if you’re leptin deficient.

TWILLEY: Turns out, the systems behind those universal feelings of hunger and fullness are much more complicated than one hormone and one brain region.

GRABER: So how did we get to today’s drugs, which do work? Coming up after the break.

[BREAK]

TWILLEY: After finding those first two big clues as to how our appetite works, scientists just kept going. And since the 90s, they have uncovered a lot of different hormones and brain regions that are involved in hunger and fullness. To walk you through it all, we are going to have a meal. Imagine it’s been a while since you last ate.

BETLEY: You have an empty stomach. And your stomach begins contracting and you release hormones during those contractions.

ANDREW SHIN: And one of the hormones is called ghrelin. It is called an orexogenic hormone, meaning it is a meal stimulating hormone. So that hormone then is increased in your blood circulation, reaches your brain, tells your brain, hey, you’re hungry.

GRABER: Andrew Shin studies the neurobiology of nutrition at Texas Tech University, and the hormone he’s talking about, ghrelin, it’s the main hormone scientists have identified that actually causes you to feel hungry. Leptin works on feeling full, the other side of the equation. Ghrelin, it’s all hunger.

TWILLEY: Until recently, ghrelin was it, it was *the* hunger hormone. But Nick told us scientists have recently found a friend for ghrelin and there might be more out there. Still, to the best of our knowledge, when you’re hungry and you decide to start making dinner, what you’re doing is being triggered by a couple or so hormones that are released when your stomach shrinks down because it’s empty.

BETLEY: But, we don’t know. There could be more than those pathways. And those hormones change the activity of thousands and thousands of neurons in the brain. And I call that what quote unquote, “the hungry brain” looks like.

GRABER: The other thing that’s happening to you when you’re anxiously watching the stovetop, waiting for the pasta to cook, is that your fullness hormones are at a kind of low level, and that’s also leading you to feel a little hungry, because you’re un-full. And as opposed to hunger, where there seems to just be maybe a couple of hormones, scientists have identified a lot of fullness hormones.

TWILLEY: OK, now the pasta’s finally cooked and dumped into the bowl and you start inhaling it and then the moment finally arrives where that food is hitting your stomach and filling it up. And that is the trigger for the first signal of fullness—it’s a physical feeling.

SHIN: Because it’s a mechanical distention due to the food coming in. And then as the semi-digested food enters a small intestine, there are a number of enzymes that are just dumped out from the pancreas to digest the food.

GRABER: And the release of the enzymes to break down the pasta and the broken down pasta itself, this all kicks our digestive system into gear and it creates hormones that tell the brain that we’re eating and we’re feeling pretty good about it, and we don’t have to keep eating forever.

BETLEY: There’s your stomach and your GI tract, which take in the food, detect food and relay to the brain how many nutrients you’ve consumed. Or, you know, if we can anthropomorphize, they’re basically calorie counters for how much you’ve consumed and the volume and quality of food you’ve consumed. So that will send a signal to the brain that will shut off the hunger circuits and turn on satiety circuits, networks in the brain. Twenty, 30 different regions of the brain are active during hunger, and another 10 or 20 are active during satiety.

TWILLEY: Oh yeah, it’s not just the hypothalamus anymore, kids. As well as discovering all these different hormones that are traveling to the brain to tell it we’re hungry or full, it turns out this multiplicity of hormones are also traveling to a whole bunch of different destinations in the brain.

GRABER: We mentioned the hypothalamus. Another important part of the brain involved in hunger is near the hypothalamus in what’s called the hindbrain, and it’s an area of the brain that controls things like your heartbeat, and breathing. It’s also where the nerve that travels from your gut to your brain connects to your brain.

TWILLEY: This is the vagus nerve, you might remember it from our episode Gut Feelings, on how your gut microbiome can affect your mood. Scientists think a lot of the hormones that signal hunger or fullness travel along the vagus superhighway.

GRABER: In case this doesn’t seem complicated enough, there are other things going on as that pasta is being broken down that also affect whether we feel hungry or full. Other hormones matter like your insulin levels, those go up and down related to glucose, or sugar, in your blood.

TWILLEY: Then there’s other areas of your brain involved too, like your reward circuits that get activated when you’re doing anything enjoyable.

BETLEY: So eating food is pleasurable. Also, it turns out that nutrients detected in the stomach is pleasurable. And that leads to a release of dopamine, much like you would get dopamine when you get any other reward

GRABER: That’s our brain telling us we’re happy because we’ve eaten. Another thing going on is our brain senses specific nutrients like protein and carbs in our food and it lets us know whether we’ve had enough of those.

BETLEY: We clearly know that, you know, there is hunger for protein that’s coded a little bit different than hunger for fat. And there’s even hunger for things like sodium. I think the best way to probably describe it is: have you ever had a craving for something sweet? Or ever had a craving for, you know, a big steak? And you don’t even know where that came from. And I think part of that might be, you know that there’s a lot of protein in a chicken breast and you order a chicken on your salad when you normally wouldn’t because you’re having this craving that’s mediated by your physiology and your need for protein.

TWILLEY: So, basically, at this point, 120 years after that first breakthrough with the obese patients and their brain tumors, the long and short of it is that almost everything but your big toe is involved in some way in whether you feel hungry or full. I’m exaggerating, but not by much.

BETLEY: What we’re discovering is that, basically, every system in the organism is employed to regulate food intake, and we’re discovering more systems every day.

GRABER: You listeners probably won’t be surprised to hear that what this tells us is that this is an incredibly important system. We have so many different body parts and chemicals involved, some can probably can take over in case one part of the system fails…

BELLUZ: We’ve developed all these signals that are reminding us that, that, yeah, we need to basically seek our next meal. And this developed in the, obviously the context of human evolution and food scarcity and. We have many redundant signals that are working internally. And it just shows, yeah, how, I think, how important it is, how important food is, to survival. Like this is a, a basic instinct.

TWILLEY: Feeling hungry and motivated to eat—that is obviously essential to survival. And feeling full is too.

BETLEY: The logical jump would be there that, there is some adaptive features to regulating your food intake. Somewhere in evolution, we had to know that it’s not good to just eat, eat, and eat, or else you wouldn’t survive.

GRABER: But as Paul’s story shows—we don’t all experience this critical sensation the same way.

ROLLY: I’m hungry, mother. I’m hungry.

MOTHER: Now, Rolly, you’ve just had your dinner.

ROLLY: But I am just the same. I’m so hungry I could eat a… a whole elephant!

MOM: Ian. Are you hungry?

IAN: Uh, no, I already ate.

MOM: OK, I make you something.

IAN: …Okay.

FRIEND: What are you eating?

MIKE: I don’t even know. I just know that I’m hungry… allll the time!

TWILLEY: Rolly in 101 Dalmations, Ian the groom in My Big Fat Greek Wedding, and Zac Efron in 17 Again—these are not only central figures in our culture, they’re also more or less hungry or full, and it means really different things to all of them.

GRABER: When Nicky and I were talking about this idea, we realized we experience hunger differently from people we know, and from each other. I get really really hungry, really hangry, pretty easily. When I traveled with my mom, she called it “feeding the beast.” But I also feel full kind of quickly too.

TWILLEY: This is extremely true and often means I get to eat most of what we try on Gastropod because Cynthia fills up too quickly. Whereas I have a fantastic ability to tune out both signals—I don’t necessarily notice that I’m hungry, and I definitely don’t notice when I’m full.

GRABER: So basically as someone who can never skip a meal, I always make sure we eat, but then Nicky makes sure there’s no leftovers.

TWILLEY: Teamwork making the dream work.

GRABER: But I’ve also noticed that I get particularly hungry like the day or two before my period. And Julia’s now pregnant with her second child, and she experienced an extreme version of this reproductive hormone-induced hunger.

BELLUZ: I had almost this like… something that I didn’t experience in the first pregnancy and I don’t really get why there was this difference. But a really extreme sudden increase in hunger and, and appetite. And it was, like, all-encompassing. So, so it was funny, I was in London and I was going to this obesity conference in the autumn, and I was interviewing all these researchers and I was like—I don’t know, I was obsessed with food the whole time I was there, and all I could think about was my next meal, and it was even distracting for the reporting. And then suddenly when I reached my second trimester, this just eased up and it hasn’t come back.

TWILLEY: For Cynthia and me and Julia, this all just translates into stocking up on snacks before your period or taking care of all the leftovers. Or planning lunch while you’re eating breakfast. But for scientists, these things all offer clues—especially the more extreme examples. Coming up, how scientists have finally translated these insights into drugs that can transform hunger.

[BREAK]

GRABER: We’ve kind of made it sound like scientists have figured out how hunger works. But they’re still discovering new stuff basically all the time.

BETLEY: I think we’re discovering surprises every day. I think we probably know 25% of it. And of the 25% we know, we don’t know all the details.

TWILLEY: Honestly, saying we know a quarter of it is just a best guess—like if we know that little, we definitely don’t know the scope of the whole. And that kind of blows my mind. A system that’s so fundamental to our survival, something that shapes how we behave every day—and it’s still so mysterious.

GRABER: And scientists like Nick and Andrew have been trying to figure out what we still don’t know. Lately Nick’s been doing that by studying people who have a genetic disorder called Prader Willi Syndrome. It involves lots of different genetic mutations, not just one, and there are a lot of impacts of the syndrome. Babies have a hard time surviving without medical intervention, there are developmental delays, they often grow up to be obese…

BETLEY: But one of the more well-studied or well-talked about features of the disorder is that individuals have an insatiable hunger. They, they are constantly hungry. Even if you were to give the person a complete meal, they finish the meal, and then ask them a minute later, are you hungry? And they’d be like, yeah, I’m starving.

BELLUZ: The big thing that drives the obesity is this extreme, extreme hunger. It’s like an all-encompassing, overwhelming drive.

BETLEY: And this is a, this is serious from a clinical perspective because caretakers have to basically barricade any place where there’s food. There are reports of people actually popping their stomach from eating too much. They, they don’t even respond to the mechanical distension that would be severely uncomfortable, and stop feeding. So there’s some massive inability to get feedback to these centers that would normally stop feeding in this disorder.

TWILLEY: While she was reporting her forthcoming book, Julia spent time with a girl who has Prader Willi Syndrome, or PWS for short. Julia calls this girl Samantha to keep her identity private. Samantha was taken in as a baby by foster parents.

BELLUZ: For the first couple of years, everything was like, relatively normal, although she needed like, extra healthcare and attention.

GRABER: This family ended up adopting Samantha. She’s now 12.

BELLUZ: And so, they showed me around, just on Zoom. This was during the pandemic. They showed me around their kitchen. And, the pantries are locked, the cabinets are locked. They have to lock the, the waste bin because Samantha will go in and like, scavenge raw meat or like, you know, left food that’s totally rotted. They describe like, cooking together. You know, you, you bring up, put out all the ingredients and maybe you forget something. And, they said she’s like a magician with like a great hand. Like she’ll, she can snatch food away really quickly. And just cooking as a family project is really difficult.

TWILLEY: For this family, this is a daily struggle to keep their daughter from eating so much she causes herself serious harm. But for scientists, it’s also really fascinating because it offers another way to explore hunger and fullness, by seeing what these systems look like when they’re completely broken.

GRABER: Nick wanted to try to understand where the system broke down. He had a colleague who had imaged the brains of PWS patients; at the time, she’d been looking at the reward system. Nick and his team asked her to go back to her data and take a closer look at their whole brains, compare them to non PWS brains, and see if anything unusual was going on anywhere.

BETLEY: And she sent us the data and we were looking at the pictures and I was looking at them and I’m like, I’m not even sure what that is. That’s the cerebellum. I’ve never studied the cerebellum. And at first we’re like, this, you know, has to be some kind of mistake. Is there anything else?

TWILLEY: If you’re like me and you’re like, cerebellum who? You may not understand why this finding was so confusing to Nick and his colleagues. But it turns out that the cerebellum was one of the brain regions that *wasn’t* thought to be involved in appetite.

BETLEY: The cerebellum was such a surprise because it’s largely thought of as a region of the brain that controls and modulates motor output. Basically, how the cerebellum is thought to be working is providing quality control on your movement.

GRABER: Nick said to imagine reaching out to grab a glass of water. You kind of know where your hand is and where the glass is, and if you miss the glass, your brain learns and then corrects for the future.

BETLEY: If things don’t match up, the cerebellum gets that signal and says, You were off by so much and helps you to update your motor plan for the next trial. Now you do all this without thinking about it, right? But this is what everybody kind of thought the cerebellum’s processing power was used for.

TWILLEY: Like we said, it wasn’t thought to be involved in hunger or fullness regulation at all, and yet it showed up as the big difference in the brains of PWS patients. So, Nick has started working on trying to figure out what’s going on in this entirely new piece of the appetite puzzle. He’s been developing mouse models of the cerebellum that seem to match what he’s seeing in the PWS patients. And now he’s studying what’s going on in those mouse brains, and how that’s affecting their appetite.

GRABER: Nick’s in the early stage of this research, he doesn’t have any answers yet. We did ask him what in particular the cerebellum might be contributing to our appetite, could it have to do with PWS patients feeling extreme hunger or maybe they’re missing some new satiety signals? What’s the cerebellum bringing to the whole thing?

BETLEY: Why do you need this new system. Right? You have a system that can detect nutrients and shut off feeding. You have a system that can be turned on by nutrients, and then you have another system that can reward the consumption of nutrients. What more do you need? Well, here’s an interesting thought, and we haven’t proven this yet, but it’s where we’re going. How do you know how much food to eat? In an individual meal?

TWILLEY: Remember how Nick explained what the cerebellum does—this comparing and adjusting function between expectations and reality. He thinks that it might also be doing that with, say, a burrito—you see how big it is and how it tastes, but how do you know how much energy it contains compared to another similar looking and similar tasting burrito?

BETLEY: How does your body have the ability to detect that difference in calories and make sure you don’t undereat or overeat in your next meal? And so what we think the cerebellum is doing is serving as a comparator for the expected caloric content of food and the actual content of food. Just like it’s serving as a comparator for the expected motor action and the outcome of that action.

TWILLEY: This is still very much a hypothesis, but Nick thinks that might be what’s broken in terms of appetite in PWS patients.

GRABER: Prader Willi Syndrome is one useful model to try to tease out new and surprising aspects of the hunger regulation system, because again, scientists don’t know why patients are always so hungry. Another kind of surprisingly useful model is bariatric surgery—it’s a weight-loss surgery, it’s been around for more than 50 years, and it involves cutting out or restricting access to the stomach and gut. People do lose weight after these procedures, but nobody actually knows why. And Andrew’s using the results of this surgery to try to tease out some of the mysteries that still remain about hunger.

TWILLEY: In theory, the explanation for the effect of bariatric surgery on weight could be as simple as the fact that you can’t fit very much food in your stomach after this surgery so you can’t eat very much in one go. But Andrew doesn’t think that’s the only thing going on. After all, if you had the surgery and you were hungry, you could still eat small snacks all day long, and you wouldn’t lose any weight.

SHIN: So what people have found out is that, if you ask the patients who had just had a surgery, and then a few weeks later, you, they a, you ask these questions, so how hungry are you? They will say they are less hungry.

GRABER: So what is making them less hungry? Andrew is trying to figure this out by studying it in mice and, like Nick, he doesn’t fully have the answers yet. But he is seeing some differences in their bodies and brains, and these just might be what are making bariatric surgery patients not so hungry any more.

TWILLEY: One thing he and his colleagues have noticed is that people who have had bariatric surgery seem to have super high levels of some fullness hormones. No one knows why.

GRABER: Andrew says the nerves in the gut have been cut and have been reduced, and maybe that’s why.

SHIN: So there’s clearly a neuro-circuitry that is significantly changed, that increases your satiety and satiation, for example.

TWILLEY: Just in case you’re thirsty, get ready to drink: microbes may also be involved. Bariatric surgery seems to really transform your gut microbiome, and those microbes can affect the hormones the gut is producing and they can also communicate directly with the brain. So those microbial changes could also be changing the experience of hunger and fullness.

SHIN: But it seems that there is another striking increase after bariatric surgery, bile acids. And it turns out that bile acid signaling is not only important for emulsifying the fat, but also for glucose and appetite.

GRABER: What Andrew is pointing out is that bile acids do break down fats in our diet to make them more digestible, but they also actually can help signal fullness to the brain. So maybe extra-high levels of bile acids are also helping these patients feel more full.

SHIN: It’s probably that there’s not a single smoking gun that does this. It’s probably working in harmony.

TWILLEY: In short, bariatric surgery does seem to effectively rewire our appetite—but it’s a little bit drastic, honestly. It’s surgery! It’s expensive, patients can experience complications, it’s a big deal. Also, some patients who go through with this eventually gain back a lot of what they lost. So, if Andrew could tease out all the ways bariatric surgery is changing people’s fullness and hunger—could he make a drug that does the same thing, no surgery necessary?

SHIN: That is the billion dollar question. [LAUGHS] We are all trying to come up with. But I think as of now, even though there’s a really—this research area is really flourishing in the last 10, 20 years. Because of the complexity and the interactive nature of these different systems, it’s going to probably take a few more years. A few more decades probably. To come up with this drug.

GRABER: But in the meantime, research like this is revealing fascinating new pathways that are regulating our feelings of hunger and fullness. Like Nick and Andrew have both said, there’s still a lot to learn. And, as we’ve said, people are different in their experiences of these feelings, and that’s still being teased out, too. We know genetics are involved. We know hormones are involved.

TWILLEY: There’s a new hypothesis that maybe when someone gains a lot of weight, their brain responds by becoming less sensitive to leptin, which means it’s less sensitive to feeling full. Researchers think that may be part of the reason it’s hard to lose weight once you’ve gained it.

GRABER: There could be lots of other factors that influence the differences between individual experiences of hunger, such as stress. This is all stuff scientists are still working out.

TWILLEY: But so, if we still know so little and it’s so hard to understand, how come we already have a drug that can change people’s appetites as drastically as it did Paul’s?

GRABER: Well, like we said, these drugs weren’t developed to modify someone’s appetite. The first one, Ozempic, it was developed to help people manage their diabetes by stimulating insulin production and by lowering levels of a hormone that would otherwise increase your blood sugar level.

BELLUZ: And in the diabetes trials, researchers started to notice, hey, like, people are losing weight. And maybe we should test this for obesity and see if it’s helping people without diabetes to also just lose weight.

TWILLEY: This side effect of weight loss shouldn’t have been a huge surprise, because we know blood sugar and insulin levels are part of how you feel full or hungry. These drugs are versions of hormones that are affecting appetite in our bodies already. For Ozempic and Wegovy, it’s just one hormone.

BETLEY: It’s a modified version of a single peptide that’s released following a meal. And that peptide is called GLP-1.

GRABER: In this case, peptide is another word for hormone. Not all peptides are hormones, but that’s for another day.

BETLEY: And when you eat food, food passes through your GI tract. And some cells in your small intestine release this protein called GLP-1 that binds a receptor locally on the vagus nerve and sends the signal up to your brain that you’ve ate food. And you stop eating.

TWILLEY: But that’s not the only thing that this hormone does and it’s not actually the thing that scientists cared about at first. This hormone plays a super important role in stimulating insulin production and helping regulate blood sugar levels and so, in the 1990s, researchers were all excited about that aspect of it—they thought that if you could just boost levels of this hormone in people with diabetes, it could help manage their condition.

GRABER: But scientists couldn’t use that exact hormone for the drug, because it just breaks apart too quickly, we have enzymes that break our homegrown one down in only a couple of minutes.

BETLEY: And people started wondering if you could stabilize this peptide. And a while ago now, probably over 20 years ago, somebody found another version of GLP-1 in what I believe was lizard saliva.

TWILLEY: This is possibly the weirdest part of this story, but it is indeed true. Back in the 90s, a scientist in the Bronx came across some earlier experiments on what lizard and snake venom did to the human body. And he noticed that this one lizard, called the Gila monster—its venom seemed to affect the pancreas in intriguing ways. And the pancreas is where insulin is produced.

GRABER: The Gila monster is a pretty impressive lizard, it lives in the desert of the southwestern US and in Mexico, they have really beautifully patterned skin. The particularly weird thing about them though is that they can eat three or four big meals in the spring and be satisfied for the rest of the year.

TWILLEY: And that turns out to be at least partly thanks to their version of this hormone that helps regulate insulin—they have an ultra long life version of GLP1

BETLEY: They called it extendin-4 at the time. And so what happened was people caught onto the fact that longer lasting peptides can be made. And they worked with, you know, different substitutions of amino acids. They changed the peptides configuration. So the enzyme in your blood that chops it up couldn’t do that anymore.

GRABER: These are not only longer-lasting hormones than the ones we make ourselves internally, but also the injections contain about eight times as much as someone might make on their own. They worked to help control blood sugar and help people manage their diabetes. And, as we’ve said, a side effect was this loss of hunger.

TWILLEY: Which in turn had an effect on body weight. People taking the drug for diabetes were losing 5 to 10 percent of their body weight, no sweat, which is actually a big deal clinically speaking.

GRABER: Part of the reason for the weight loss seems to be because the patients just weren’t as hungry anymore. Scientists aren’t exactly why, it seems to not just be because it’s affecting insulin production. For one, about a decade ago, scientists realized this hormone also affects fullness.

BELLUZ: So people are feeling fuller and they’re, they’re not as inclined to eat. I guess another one is that, I think, that it’s slowing this rate of gastric emptying. So it’s like, it’’s also causing the food to empty from our stomachs at a slower rate. But they’ve also discovered now GLP-1 receptors in the brain’s reward system. And this might be another way GLP-1 is working on us and causing us to lose weight and maybe having other effects we don’t even understand. But basically the bottom line is, that even though it’s been used for so long and we sort of think we know why it works, we really don’t understand. Like we’re really still learning about exactly how this is causing the weight loss.

TWILLEY: Scientists aren’t even sure how these new drugs are reaching the brain—is it through the vagus nerve from the gut? Or do they get into the brain directly through the blood? Or both? No one knows.

GRABER: Now it might seem a little weird to have drugs on the market and we don’t know how they work. But frankly that’s not uncommon. For instance, we still don’t fully understand how antidepressants work, when they work, but people have been taking them for decades.

BELLUZ: So I think the reason researchers are so confident about the drug and doctors feel good about prescribing it to patients is that versions of the GLP-1 on the market now have been in development and tested on people for like 20 or 30 years. And they seem to be broadly safe.

SHIN: For pharmaceutical industry, understanding the mechanism is not that important. As long as it works and as long as it doesn’t really give a lot of side effects. Understanding the mechanism is probably our job.

GRABER: Over the next few years it’s going to be increasingly normal to go on drugs like this to help manage hunger and satiety, and at the same time, scientists like Andrew and Nick will still be hard at work trying to figure out all the intricate details of how they work.

TWILLEY: These new drugs do have some side effects, of course—like every other drug, you’re given a laundry list of things to watch out for so that everyone has their arses fully covered.

FORD: I mean, it’s all the regular side effects. Like, you know, your eyeballs will explode. No, you know, when you, when you read the, read the documentation. But for the most part no it’s really, it’s pretty safe. It’s pretty effective. And there aren’t strong side effects.

GRABER: Paul himself just felt a little bit of nausea at the beginning but that didn’t last long.

BETLEY: The only downside of the entire drug that I’ve heard so far is that—well, there’s two. The first is that when people go off the drug, they gain all the body weight back. So. It has not changed your metabolism or something long term so that you can be, be thin without it. But. And the other downside is still these peptides activate systems in the brain that are known to cause nausea.

TWILLEY: Again, that issue of it not working once you stop taking it—that’s really normal for a drug. Most treatments for chronic conditions require you to take the drug for life. Think about treatments for cholesterol levels or blood pressure.

GRABER: Paul doesn’t mind the potential of side effects or the lifetime prescription.

FORD: You know, people are like, well, I can’t wait to see what the 10 year results are. And I’m like, yeah, me too. Like, ah, who knows man? Like, God bless us all. I’m still sort of steadily losing weight. I don’t have any side effects. Nobody seems to be having tremendous side effects from this. Maybe I’ll grow a huge horn in the year 2025, but that’s fine. I’ll just, I’ll cut it off.

TWILLEY: A unicorn among men. I mean, it’s an upside depending on how you look at it. After all, remember, not all side effects are bad. This weight loss was discovered as a side effect of a diabetes drug. There might be more benefits.

BETLEY: What’s really interesting and compelling is that the receptor for this hormone is in many different regions of the brain.

GRABER: This might sound alarming, I mean, could it be harming other parts of the brain? But, again, it’s been tested for a long time, and scientists are actually excited about the ways this hormone can help a lot of other systems in our body.

SHIN: For example, GLP-1 has been shown to be beneficial for your heart function, for example. It is also good for your kidney function. It probably has a role in cognitive function. In fact, what is also being extensively sought nowadays, in the last 10, years is the effect—potential effect of GLP-1 in Alzheimer’s disease.

TWILLEY: Again, a lot of this work is still being done in mice, but some scientists are excited about the possibilities for this drug as a Alzheimer’s treatment.

GRABER: But it’s still really early days for a lot of this research. The main thing is that the drugs do help patients with diabetes, and they help patients who want to lose weight for medical reasons—and that’s important because there aren’t many good options in some of these cases.

TWILLEY: Today, there are a couple different versions of these types of drugs on the market. One, Mounjaro also influences an additional hormone, not just GLP-1, to make it even more effective.

GRABER: And now that scientists know they work, they’re quickly trying to develop newer, even better drugs to control appetite.

SHIN: Another thing, I think it is more practically promising, will be the combinatorial therapy. Mixing or combining different gut hormones or other other factors, even bile acids.

TWILLEY: Andrew says people are also working on non-hormone based treatments, these bile acids, and also ways of stimulating the vagus nerve so that it tells the brain you’re full for longer. Lots and lots of different research is going on. And in case we didn’t say this enough already, that’s because we really don’t understand this system yet.

BETLEY: What we’re really still trying to do with, say, the hunger system is show up at an auto show, never having seen a car before. And figure out what each part does. Right? So we’re taking the car apart, we’re putting the car back together. We’re seeing if the car runs without a certain part, and then we’re seeing what happens to how the car runs when we take out that certain part. And, once we have all of the knowledge of all of the different parts and how those parts interact and how they affect the performance of the car, we can start tweaking those parts to get a little bit more horsepower. Or, you know, to take turns better. And I think once we have that part list and we know exactly what we’re doing, we’ll be able to design some really good therapeutic options that won’t have side effects.

TWILLEY: In the future, Nick thinks we’ll be able to diagnose different areas of the appetite system that aren’t working well and treat them specifically, rather than with a blanket approach.

GRABER: But for now we do already have drugs, and they do work.

TWILLEY: Ozempic was approved in 2017, the others joined it more recently, and they are game changers for people who need them.

GRABER: Obviously at least some of those people are diabetics. But when it comes to prescribing the drugs purely for weight loss, you might have heard people on the news kind of wringing their hands. Like, on average people didn’t weigh as much in the past, so aren’t there other things we should be doing instead of giving people shots?

TWILLEY: This argument is honestly kind of a red herring. Obviously our food system is messed up, we report on this all the time. We’re surrounded by tax-payer funded, ultra high processed, calorically dense, hyper palatable foods and that’s not the food environment our appetite regulation system evolved to work well in.

GRABER: And of course that’s not the only thing that leads to weight gain these days and for some people to obesity-related health issues. We talked about this in our episode on personalized diets. Genetics, poverty, inequality, racism, stress. The built environment contributes to the problem, there aren’t always places for people to walk easily. There are all sorts of big picture policy changes that could help people live healthier lives.

TWILLEY: And we need to make those changes, we will have failed if we don’t. But at the same time, we also need to do what we can to help people who are struggling with obesity-related conditions right now, and these drugs are some of the very few things we have to offer, short of bariatric surgery, that can help.

GRABER: As Paul has already explained, it transformed his life. But today, rich people are paying a lot of money to give themselves injections to lose maybe ten pounds, which means it’s harder to get a hold of. And this has him super anxious.

FORD: Oh, absolutely. Oh, I’m stockpiling. I, I, I stretch it out so that I can have ex—No, I’m really nervous about losing it. It’s hard to get, I have to call multiple pharmacies. And I’m sure there’ll be a month where I can’t have it. Or, or multiple months. And a lot of that I think is because of the off-label prescription.

TWILLEY: Taking this drug is not a vanity thing for Paul. It’s about his ability to lead a healthy life. But it has also really shifted how he thinks about his body, his weight, his appetite, and the idea of self control.

FORD: I have read and come to understand everything about health at every size and obesity science, and, sort of all that stuff. Over the last years. I have tracked every calorie, I’ve read about anti-caloric models of nutrition. On and on and on. And… turns out that it’s a, it’s a more of a medical condition and less of a psychological one than everybody maybe assumed. The last five or six years, I noticed my GP’s gotten a lot more empathetic when I go to the doctor because I think that medical science has kind of got the, got the message that… you can’t fix this. You can’t just tell someone to kind of exercise and diet their way out of it. The only option before this that was really working for people was gastric bypass. And even that has a, has a pretty high failure rate. These drugs are wild. They’re like 95% successful and you lose about 25% of your body weight. It gets measured in body weight, but the reality is what it, it’s control. And it’s, it’s a… I no longer have that siren going off and a side effect is that my body keeps getting smaller.

GRABER: As we said at the beginning of the episode, and as Paul experienced himself in his life, we as a society are not very kind about how we talk about or to people who are heavy. And Paul hopes that the experience of people on these drugs, and the new insights these drugs are giving us into hunger and appetite can help change that.

FORD: And I think what I realized on the other side of this is… how much other people need to work this stuff through. Like I’d already figured it out. I already knew about this relationship in my life. I knew that I had a really bad problem. It was a hell of a thing to find out how much of it was purely in my body and not in my brain. That was a revelation. But ultimately, I, I think like if you’re a big person listening to this, like lean in and do whatever the hell you can because it, it’s better, at least so far. And I, I just, everybody else could take a breath and be nice to a fat person in your life for fuck’s sake.

[MUSIC]

TWILLEY: Thanks this episode to Paul Ford who did not really want to talk about this but then did so, so eloquently. We are incredibly grateful.

GRABER: Thanks also to Julia Belluz, Andrew Shin, and Nick Betley, we have links to their articles and research on our website, gastropod.com, and we’ll let you know when Julia’s book about metabolism comes out.

TWILLEY: Thanks as always to our fabulous producer, Claudia Geib, and our delightful supporters without whom we couldn’t make the show. We’ll be back in a couple weeks with a brand new episode.