Defeat Your Culinary Kryptonite! New Science of GLP-1 and Satiety

Take a moment to imagine your culinary kryptonite, that food when it's placed out in front of you, you just can't resist, you need to have it. For me as a kid, that was Walnut Dream Bars from Rosie's Bakery in Boston. If they were anywhere around, if we drove by Rosie's or if I got a whiff, I would hunt them down like a Walnut Dream Bar assassin. Now I want you to imagine your culinary kryptonite. Imagine it was in front of you. Imagine that feeling of desire you would have. Now I want you to imagine what if you could snap your fingers, and you had the power to just kill that desire entirely, modulate your brain activity at will so your culinary kryptonite was entirely defused? Well, I can't grant you that superpower, but what I can do is tell you about brand new science in the journal Science about a neural mechanism behind the pre-ingestive desire and how a hormone can shut it off. Welcome to my channel. Stay curious. This paper, again published in the journal Science, one of the top journals in the world, is entitled "GLP-1 increases pre-ingestive satiation via hypothalamic circuits in mice and humans." Now, I don't know, I'm still holding that J-Ball. Now, what the researchers behind this study wanted to do was decode some of the neural mechanisms by which GLP-1 receptor agonists this new class of drugs that's all the rage for weight loss, like Ozempic and Wegovy, by which they affect the brain to promote satiation and thereby promote weight loss. And what they found was really interesting, that humans given GLP-1 receptor agonists had greater satiation, in particular during the pre-ingestion phase when provided with a food cue. So that's like me going by the Rosie's Bakery as a kid, and rather than needing that walnut dream, I'm like, Eh, whatever. So humans provided with GLP-1 receptor agonists in general as a population have greater pre-ingestion satiation, and this effect is actually much larger than during ingestion satiation. So it's more about seeing the food and not really wanting it than starting to eat the food and getting full quickly, which is the common messaging. Now, that doesn't mean that isn't an effect, but based on these data, there was a larger group difference in the pre- ingestion phase, which is quite novel and very fascinating. They then went on to show that this phenomenon was conserved in mice, that if you gave mice GLP-1 receptor agonists, they also had higher pre-ingestion satiation. Now, you might be asking, well, why would you even go to the lowly mouse? You already know that there's an effect in humans, so what's the point of going back to mice if we care about humans? Well, what you really want to do is figure out what is the neural circuitry that is mediating the effect. And in order to do that, you need to manipulate the circuitry, which you can do more easily and ethically in mice than in humans. So what they did is they identified both in mice and humans, there's an area of the brain called the dorsal medial hypothalamus, which expresses GLP-1 receptor-containing neurons. So the neurons have GLP-1 receptors, therefore they might be mediating the effect of the GLP-1 receptor agonist. But in order to prove that, they needed to go into mice and change activity in these neural circuits, which you can do with different techniques. One of my favorite, and an increasingly common one, is called optogenetics, where basically you express different channels on these cell surfaces that you can hit with light. And when you hit them with light, you literally kind of drill through the mouse's skull, and then you can like, you know, shine a light on these neurons. You can turn on and off the neural circuits to show, is it sufficient to promote or inhibit an effect? Now, I have a whole different video breaking down optogenetics, so go to this time point on this video if you want to learn more about that. But moving on, they were indeed able to show that the dorsal medial hypothalamic neurons expressing GLP-1 receptors were sufficient to promote satiation when turned on. And when they were turned off, there was that effect of, oh dang, I need that walnut dream, when it's present. So you can think of these as the pre-ingestion satiation neurons, at least the subpopulation of them. Now I say a subset of neurons because what I want to transition to talking about next is broadly heterogeneity. So take a look at this graph. Now the emotion I want to be evoked by saying, take a look at this graph and show you this intimidating graph, is an intimidation factor. What you see here is what looks like a lot of messiness, but basically what it's saying is there is heterogeneity in the neurons in the brain. So there are some neurons that are active during pre-ingestion. There are some neurons that are activated during ingestion, and then there are different populations of neurons that are all kind of jumbled together, some expressing leptin receptors, other GLP-1 receptors, some expressing both. It's all very messy. We like to imagine mapping out neural circuitry as like, you know, breaking up the subcomponents of a rainbow where they are very clearly delineated, but it's really more like looking at a bowl of soggy Froot Loops with a bunch of different colored Froot Loops in some sort of like liquidy mess. Hopefully your cerebral spinal fluid isn't milky, that will be bad. But point being, things are quite messy appearing, and there's a lot of heterogeneity geographically in the brain. But that is within a brain. More interesting perhaps, and more relevant, is heterogeneity between brains, among brains, between minds, between people. And so a really, really interesting graph going back to the human data is this one, because what it's showing you is the effect of the GLP-1 receptor agonist treatment on pre-ingestion satiation. And I mentioned before, in the population— I did emphasize population— there is greater pre-ingestion satiation when given the GLP-1 receptor agonist. That was the main effect. However, what this graph is showing is the effect broken down person by person. And greater pre-ingestion satiation in the GLP-1 group would be represented by an upward slope, so going from the bottom left to the upward right. And you see that in most people. However, you'll note there are certainly people who have the opposite effect. Some people who in the control group have a larger pre-ingestion satiation signal relative to the GLP-1 group. And this is really important because we like to use these, you know, randomized trials that we use to validate different drugs and just assume that effects will generalize across populations. But the thing that's really important to acknowledge is there is enormous amount of heterogeneity among humans, in part due to the fact that we have different brains. And so you're going to get different responses. You're going to get people like that patient who, rather than having a positive response to the GLP-1 receptor agonist with a massive increase in pre-ingestion satiation, might have no response or even a negative response, which when you're talking about real human beings, n 1 lives is really important to acknowledge. Now I want to zoom back to this other graph, and I realize I'm jumping around, that's intentional, I'll explain why in a moment. But I want you to narrow in, I want us to narrow in on panel S. And what you see in panel S is a graph of neuron activities in these different subpopulations of neurons. You have the pre-ingestion neurons active during the pre-ingestion phase, and then the ingestion-active neurons active during the ingestion phase, with activity being on the y-axis labeled z-score. And so you'll see in the pre-ingestion phase, shaded in green, the pre-ingestion neurons spike. And in the ingestion phase, shaded in purple, the ingestion neurons spike. Makes sense, right? But you see something else that's quite conspicuous. The pre-ingestion neurons spike after ingestion. So they're not just pre-ingestion neurons, they're actually post-ingestion neurons too. So what do we make of this? The authors were actually surprised by this finding, but here's how I would frame it. To be clear, the authors didn't say this, this is my interpretation. Basically what's happening is now that you've eaten, these pre-ingestion neurons are thinking, okay, these are satiation neurons, right? They're more active. When they're more active, there's more satiation. And so it's kind of anticipating the next food bolus. You just ate, right? So the neurons that will be engaged in seeking out food and driving you to grab that walnut dream are gonna be like, well, we just ate. So we might as well promote satiation because we just ate. We don't need more food. But food's on the mind because you just ate and food is presumably around. So you're thinking about it. That is a high-level overview. But what I really want to get to now is let's contrast that to something I think a lot of us experience, which is the inverse of the so-called sensory-specific satiety effect. You could call that inverse the "there's always room for ice cream" effect. Because what we're looking at here is again another generalization. Oh, you just ate, so these satiation-promoting neurons then become active. However, that doesn't necessarily account or necessarily correlate with behavior we see every day, where even if you're stuffed full of, say, turkey or steak, you might still have room for ice cream. So these neurons, these activities in the brain, become much more complex when you fold in different levels of heterogeneity, different geographies in the brain. Different humans, different brains, different minds, different psychologies, different environments, different foodstuffs. The emphasis here is on the complexity, on the messiness. But really, I don't think of it as messiness, it's more elegant complexity, which I want to highlight because I think people get frustrated with the nutrition world. They want the simple answers, things like calories in, calories out. We gravitate towards that, but we always need to appreciate that is incomplete. It does not do justice to the incredible beauty, complexity, which sometimes looks like messiness, that is inherent in our biology. And I think the moment you can accept that messiness, or what is really elegance, you can start to appreciate how cool your body is and embark on understanding it as a forever learning journey. I hope I'm getting you to appreciate some of that awe that I have for physiology, metabolism, biology. That's why I'm here talking to you. So I hope you have it, and I hope it's growing. It's something that I think you really should cultivate. But with that, let's get to less pie-in-the-sky abstract ideas, some more actionable takeaways. What are my prescriptions for you? Well, as always, my number one prescription is please administer— please self-administer deep thought at least Q4 hours plus PRN. Just kidding. No, but in all seriousness, I hope what these data and me sharing these data do for you is inspire you to reflect and think about things like pre-ingestion signals in your environment that are specific to you and might hit your specific dorsal medial hypothalamus. So observe your brain activity. Now, it's true you can't actually observe your brain activity, but you can observe the manifestations of your brain activity. Hold them in your awareness and then curiously explore how you might manipulate them to achieve the ends you want. And that could include developing the superpower to resist your culinary kryptonite. Hope you found this video fun.