About the Guest: Guillaume (Will) de Lartigue, PhD is a neuroscientist at the Monell Chemical Senses Center. His lab studies the neurobiology of eating, including how the vagus nerve senses internal stimuli in the gut.
Episode Summary: Nick and Dr. de Lartigue discuss: gut-brain communication; the vagus nerve; gut hormones like leptin & GLP-1; weight loss drugs like Ozempic; glucose vs. fructose vs. non-caloric sweeteners; how the vagus nerve connects the gut to the dopamine reward system in the brain; the sensation of fats and sugars in the gut; food addiction & obesity; and more.
*This content is never meant to serve as medical advice.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Will de Lartigue 6:02
So I'm an associate member at Manal Chemical Senses center. And I have an appointment at University of Pennsylvania in the Department of Neuroscience. And I guess my background, I studied the neurobiology of feeding.
Nick Jikomes 6:24
And so what I want to talk about today, basically, if I sort of what I'm envisioning here is the biology of feeding after food is swallowed, and gets gets past the tongue. And so you know, one of the interesting things, one of the interesting pieces of biology here is that, you know, the body can sense what we eat, and how much we eat in various different ways. And so, you know, obviously everyone has experienced eating food, we know that it has taste, we can taste sweet things, and sour things and savory things. But there's some interesting biology and some interesting, you know, sensory biology that's happening after we swallow our food that allows our brain to know what we actually ate. And so to start off, can you just start talking about what are some of the major ways that the gut is communicating with the brain? You know, I know that there are nerves that are coming down from the brain to the gut, the gut is releasing hormones that circulate in the bloodstream and go back up to the brain. What are the basic kinds of ways that gut brain communication happens?
Will de Lartigue 7:26
Well, that's a very big topic right there. But essentially, food comes into the stomach. And the amount of food that we consume is sensed through the stretching of the stomach itself. And that information can be relayed to the brain in multiple different ways. The main way is that there's different nerves like the vagus nerve, for example, that is probably the longest and biggest nerve in our body innervates, all the different organs. And it highly innervates the stomach in the intestine. And so when these nerve terminals and stomach, feel the stomach expand as we get more full, that sensation is, is triggers the vagus nerve and signals to the brain that there's food in the stomach, and it kind of gives us some information about the amount of food that we've consumed. And then the food kind of gets broken down, and it gets into our intestines where it gets absorbed. And there, there's two things that happen. So the the cells that line, the intestine will release hormones, as they sense the different types of nutrients, those hormones can enter into the circulation and act directly on the brain. Or they can act in a paracrine manner, which means that they're just being released from the cells and activating the nerves that are nearby. And then the vagus nerve can also signal to the, to the brain that way, and then the intestine content, information about again, stretch, so how much the quantity of food that's reaching the intestine, but also the different types of nutrients. So fats, sugars, proteins, that are actually in the intestine is getting broken down and absorbed is also being sent to the brain. So there's a lot of information in response to a meal that gets processed at the level of, of the gut, and that gets sent to the brain.
Nick Jikomes 9:36
So the nervous system can actually detect that something's in the stomach of the GI tract. And not only that, get information about what's in there before it's all those nutrients are even fully absorbed and circulating throughout the body.
Will de Lartigue 9:49
Yeah, and it's so it's thought that the stomach doesn't really process the types of food that we have more the volume of food and then the intestine probably does a little bit of both and the combination of those informations, then lead to different types of behavioral consequences. So when you feel stretch and you feel full, then it makes you stop eating. But when you sense the nutrients that can sit maybe to some degree control food intake, but we think it's more dictating what types of food we want to eat and actually causing reward that might prolong the meal or increase the rate at which we're eating that meal. So
Nick Jikomes 10:26
so there's this mechanical sensation that happens starting in the stomach. So there's this thing called the vagus nerve is literally reaching down from the brain. And it's, it's touching the stomach? Can we think about this? Almost like, you know, the sensory neurons in our hands? Like if I, if I go and grab something I can I can feel it, stretch or compress? Because I have sensory neurons that give me my sense of touch in my hand, is it kind of like that, where we've got a nerve reaching down to the stomach? And it's sort of wrapped around it and literally just feeling it physically?
Will de Lartigue 10:57
Yeah, I mean, it's quite similar that it's, it's something that allows us to sense what's going on internally as, as opposed to what's happening externally. Those two processes have been through different types of nerves. But the concepts and the ideas are, you know, they translate across both. And, you know, one thing I didn't mention, I just want to clarify, the vagus nerve is probably the main one that integrates the stomach and the intestine. But there's also some evidence that the spine, the nerves from the spine can also sense what's going on their role, what they're doing, what types of information, they're signaling, that's less clear. There's also some evidence that they might be conveying information about the volumes. So it's not just one nerve that's communicating all the information, but that vagus nerve seems to be the critical one.
Nick Jikomes 11:44
And okay, so there's multiple, you know, nerves in the body that can do this type of internal sensation. The vagus nerve is a big one, literally. Can you talk a little bit more about the basics of the vagus nerve? Where in the brain? Are the cell bodies located? How many neurons are a part of this nerve bundle? And can you talk a little bit of a little bit more about all of the places, you know, just give us a sense of like, all of the places it goes? Is it just the stomach and intestines? Is it all throughout the body? Is it certain parts of the body?
Will de Lartigue 12:14
Yeah, that's a that's a good question. So so the vagus nerve is an so it's a nerve, it has two different components that are bundled within it. It has fibers that send information from peripheral organs, to the brain, and then also separate nerves that are bundled in the same nerves that go from the brain down and they control the function of those organs. The types of organs that are innervated are pretty much everything you can think of below the neck, so your heart, your lungs. And then below the diaphragm, the stomach and the intestines are probably the ones that are most heavily innervated by the vagus nerve. But there's a whole range of and you can think of pretty much every organ down there is probably kidneys, the liver, the pancreas, for sure. Other ones are more debated, but there's a lot of integration, probably the one thing that's not innervated by the vagus nerve is your fat cells. So that's the one exception, but everything kind of below the diaphragm pretty much receives vagal innervation. And so because you've got both the sensory component that senses what's going on in the organs, sends information up, it sends information, it sends a lot of different types of information, right. So if you think about the heart, for example, it sends information about blood pressure, heart rate, you think about the lungs, it sends information about your breathing. And at the level of the GI tract, it sends information about the types and the quantity of foods that we're eating, but also some immune responses if you if you're sick, all of that information also sent through through by the vagus nerve. So there's a lot of information that's continuously being sensed, and signal to the brain by this nerve.
Nick Jikomes 14:02
And, okay, so we can think of the vagus nerve as being largely about sensing and controlling what the organs of the body are doing. Yeah, I think that's right. And maybe let's define the term term nerve here and give people a sense of like, you know, is this one big neuron or is this 1000s of neurons? So
Will de Lartigue 14:18
yeah, yeah, you did ask that. And I forgot to answer that. So there's, so the cell bodies have the vagus nerve, the sensory component and the motor component, the ones that control the function from the brain down, are anatomically separated. They're located in different places. So the motor neurons, the ones that control the function of the organs from the brain are located in the brain. They're actually in the hindbrain, that kind of a primitive region of the brain that's able to control the function of these organs, then the cell bodies for the sensory neurons are actually located outside of the brain. So it's called the peripheral nervous system. It's found in a ganglia AR, which is just a fancy word for a bunch of cells that are in one like altogether in a tissue. And there's, there's 1000s of cells within ganglia. And the important part is that there's two different nerves that run parallel through our body that maybe have slightly different innervation patterns of different organs. But there's about 1000 in each notice ganglia and a mouse and human, it's significantly larger, maybe 20,000. So it's, there's a lot of these cells, and each cell can innervate a different organ and a different part of the organ. So almost like, basically, looking at one cell gives you information about one organ, one type of information from the organ, but you'd have to look at the totality to get the whole information that's being sent via the vagus nerve.
Nick Jikomes 15:50
I see. So you've got this big nerve bundle than if you were just start randomly picking neurons individual neurons out, you might have one that's talking just to the heart, another one that's talking just the stomach and so on. Yeah. And is it projecting elsewhere into the brain? Or is this strictly talking, you know, like, is it protecting to other parts of the brain like cerebral cortex or the hypothalamus or anywhere else, so
Will de Lartigue 16:15
not directly, so it terminates in the hindbrain. The vagus nerve, starts in the organs goes up, and then terminates in the hindbrain. But then those neurons in the hindbrain that receive the information project to lots of different regions in the brain. So information from the vagus nerve is actually received by the vast majority of the brain. And it's used in decision making processes and, and memory and, and reward and all these different aspects that dictate how we behave. So that information that we get from the body is actually critical for everything that we do on a day to day basis. But the actual terminals themselves are in the
Nick Jikomes 16:55
brain. I see. Yeah. So it's communicating with virtually every part of the brain. But there's there's other neurons
Will de Lartigue 17:02
in between, right? So it's not a direct communication, but it's it's multi synaptic connections that allow for this communication throughout the whole brain. Correct. And
Nick Jikomes 17:10
so like you said, in the stomach, it's primarily this this mechanical stretching stimulus that's being sensed by the vagus nerve. By the time we get down into the small intestine, there's also some sensing of individual nutrients and different things, fats, sugars, other things we might be ingesting. Can you talk a little bit more about that? What types of what are all the types of nutrients that we know are being sensed? is? I mean, is it basically every type of nutrient we can think of? Or is it only certain select ones? What does that look like?
Will de Lartigue 17:43
I would say, almost every single nutrient can be sensed by the vagus nerve to some degree. The exact mechanisms and so this is all kind of, you know, we're in the infancy of this field we're learning as we go along. Right now, it looks like most things can be sensed by the vagus nerve to some degree, and by most things, I mean, yeah, the three major macronutrient types, fats, sugars, proteins, but also things like fibers that are not necessarily digested by the body. So then we're thinking probably bacterial products. So we've got a whole bunch of bacteria in the GI tract. And it looks like they can communicate with the vagus nerve. I mentioned that there's immune cells within the GI tract. And actually, that's not really surprising, because if you think about it, the lumen of the GI tract is kind of the external world in many ways, right? It's directly connected to the outside world. And so you'd want to have a protective barrier and an immune system that is very active around where there's interplay between the outside world and the internal world.
Nick Jikomes 18:52
And so if you've got some kind of like gut inflammation, and there's a bunch of immune selectivity, the vagus nerve can sense that's going that
Will de Lartigue 18:57
can definitely be sensed. And then things like osmolarity, so you know, how many ions there are, and the pH can probably also be sensed. There's evidence that maybe water can be sensed as well. So so the vagus nerve really senses just everything that's going on, it doesn't project into the lumen. So it's not directly sensing what's in the actual gut itself. But in sensing, there's information from the gut that's being communicated to the vagus nerve. So it's kind of an indirect communication, or as things get absorbed. Those things are then since it, yeah, it's really sensing what's entering into the body rather than what's in the actual gut, per se.
Nick Jikomes 19:42
And so, like what happens, you know, I imagine as people started studying the vagus nerve, you probably started with some pretty crude manipulations, like people might cut the vagus nerve or just sort of stimulate all of it all at once. As we were starting to do those experiments and just starting to learn what the vagus nerve is. doing? What are some of those results look like? What happens if you damage the vagus nerve, you know, entirely? Or mostly what happens if you start stimulating it, you know, electrically or optogenetically or something like that?
Will de Lartigue 20:11
Yeah, you're absolutely right. So we, we started off with more primitive tools, they got a means, which is just cutting the vagus nerve was kind of essential and kind of a fundamental part of how we understand what the vagus nerve is doing. And there's a lot of caveats that I'll talk about in a second about how we interpret those data. But what we learned from those experiments, and essentially, if you cut the vagus nerve above the diaphragm, the animals don't tend to survive those surgeries, especially if you cut both sides, because now you're no longer controlling your breathing rate and your cardiovascular response. I said, actually, the animals tend to gasp and don't survive. So when we talk about vagotomy, is what's what tends to be done is sub diaphragmatic. They got it nice. So that's below the diaphragm, that's all the organs that are in our abdominal cavity. We can cut those, we can cut those bilaterally. And there what we see is an impairment in the size of the meal that we eat. So it's really having a very specific effect, very targeted effect on just manipulating how much we're eating at a specific meal without really having massive effects outside of that. So when you do these gummies the animals first, first of all, they're a bit sick, they struggle with this, right, so this isn't just something that you can do, and then immediately record their behaviors afterwards, they need a little bit of time to recover from this, it's a harsh thing to do to an animal, it was done in humans as well, for a while actually thinking about it. For certain treatments early on, especially specifically related to gastric issues. For cancers, I think that they cut the vagus nerve, it seemed to help a little bit. So there are in the 70s. A lot of people were undergoing, they got a means for treatments of this type of disease. And even in those patients didn't really have massive effects, and impacted a little bit about how they ate but not really very much else. And again, there's a lot of caveats to these types of experiments. Because as I mentioned at the beginning, the vagus nerve is bundled, and it has the motor component and as the sensory component. So when you cut the entire vagus, you're influencing not just the information that's going up to the brain, but also how the nutrients and and how the organs are functioning. So how the nutrients are being processed, it impacts our ability to break down the nutrients to absorb the nutrients. And so it's actually very hard to interpret what these what the vagus nerves role is, in anything, when you basically are impacting how the body is processing, what you're saying as well, right. So since then we've we've kind of refined the tools that we have at our disposal, we develop this approach that allows us to selectively target just the sensory component. And there we got like a little bit of a better idea of what the vagus nerve is doing. And recent experiments from my lab have demonstrated that, essentially, if you do this in Lean animals, so these are animals that are just maintaining their normal Chow diets, influences, meal patterns, and kind of interesting way. So before when we cut the vagus nerve, we would see that it reduces the meal size. But here we were seeing that in addition to meal size, we were also getting effects on the duration from one meal to the next. So those two are thought of as different entities. One is called satiation, what is called satiety. And so when we were selectively impacting the inflammation from the gut to the brain, then we were impacting both Association and satiety. But it didn't, it still didn't lead to these long lasting chronic effects on on how much we eat over a 24 hour period, for example, until we give them access to things like a high fat diet or high sugar diets that really push the system a little bit further. And they're the animals are no longer able to interpret that the meal is gone, the the amount of calories that they've consumed is larger, and so they're not compensating by reducing their meals appropriately. And so what we're seeing in those animals, and now they're eating way more than than the animals that don't have these Deafferentation I see.
Nick Jikomes 24:41
So if I'm hearing you correctly, there's a dissociation between like the total volume, total mass of food that's been consumed, and the caloric density of whatever mass has been consumed.
Will de Lartigue 24:52
Correct. So yeah, right. So the mechanical stretch that we were talking about earlier, that's the amount of food that we're consuming the nutrients is thought of as As calories, and so those two are kind of dissociable in terms of the neurons that are involved in the process, but also when you impair the entire ability of the vagus to sense what's going on in the gut and send that information to the brain, then you're impairing the animal's ability to sense that there's more calories, maybe more food, but really more calories. And therefore, they're not able to compensate by reducing appropriately the amount of food that they're eating. Because a normal animal, if you give it a high fat diet for just a couple of days, well, the first day it goes crazy for it, because it's delicious, and they really like it. But over the next few days, they regulate and they say, Okay, well, there's more calories, actually, I'm going to eat less total amount of food, so that I eat the same number of calories. Yeah, they're companies that don't have their vagus nerve that allows the communication from the gut to the brain, they do not compensate.
Nick Jikomes 25:54
I see. Interesting. Interesting, and there's all sorts of places this is going to connect you because you know, a lot of the stuff that we're interested in as humans has to do with our ability or inability to make various compensatory changes in our diet, given the food environment we live in. But you know, one thing that I think is implicit in what you're saying is, so the vagus nerve can detect lots of different things. It's not just mechanical stretch, and the amount of the mass of food that you've eaten, you've said that it can detect, say, like things like fats and sugar separately, I would imagine that what you're probably going to tell us is, if you look at individual neurons from the vagus, they're not all identical. So they are molecularly distinct, some of them probably have sensory receptors that detect amino acids, some of detect glucose, and so on and so forth. Is that what's going on? Yeah,
Will de Lartigue 26:45
that's exactly what's going on. And that was actually kind of both surprising and kind of nice to see. I mean, that the reason it's surprising is I said at the beginning, there's only about 1000 neurons, maybe even fewer than that within a single notice ganglia files in a mouse, right. And so it's, it's surprising that you can get that level of separation, in terms of one neuron sensing one macronutrient, that that was somewhat surprising to us. But that is exactly what we see. And, and so we do these experiments where we're recording the activity of these neurons, we're visually looking at the entire notice scanner, the entire area where the vagal sensory neurons are located. And we're recording the activity of these neurons. And we're seeing that when we give sugars, there's this population of neuron that's activated. And then when we get fat in the same animal, now, a spatially separate population of neurons is being activated. I mean, it's it's very clear cut, it's there's very little overlap between these two populations. And then not in this paper book, we're carrying forward with proteins. And again, we're seeing similar things. And actually, what's interesting is when you get into kind of more nitty gritty, it looks like these different populations of even within the sugar sensing neuron, there's different neurons that sends different types of sugars, even at that
Nick Jikomes 28:10
level. Yeah. I mean, that's, that's exactly what I'm going to ask you about, like, how specific does it get?
Will de Lartigue 28:14
I mean, it looks like it's very specific. And so the question is, it's just one neuron sending very specific information to the brain? Or is it more than one, the exact number of neurons that are involved in detecting, say, a specific type of sugar moiety? That's not clear. It's, we're not when, like I said, we're kind of still in the infancy of this field, but it does look like it's a lot of specificity is happening within these neurons, it
Nick Jikomes 28:45
could very well be that level of specificity, like, wonder on one sugar molecule could well be and, you know, I'll let you direct us based on where there's more information and where we know more. But um, okay, so we've got sugars, that type of carbohydrate, we've got fats, and other macronutrient class, you know, I've been very interested in a while for how the body processes in response to different specific fats and different specific sugars differently. So, you know, I'll let you guide us again, but you know, for fats, right, you've got saturated fats, you've got long, medium, short chain ones, on chain ones, even chain ones, etc, etc. You've got, you've got omega threes, you've got omega sixes, et cetera, et cetera, et cetera, different types of fat molecules on the sugar side, right? You've got glucose, you've got fructose, you've got various caloric non caloric sweeteners that are meant as substitutes for those. You know, taking either class of macronutrients, what do we know about the response that the body has to different sugars, even when they are calorically equivalent or different fats
Will de Lartigue 29:53
so what do we know? So I think at the level of A is never we don't know a lot that's that's probably The truth but but we do know that, for example, glucose and fructose, which are the two sugar components that make up sucrose that even these two fairly similar sugars actually have very profound differences in terms of how the body processes them, and what the result of these two has on the body both in terms of how we metabolize them, how the liver ends up dealing with that, and the consequences on insulin and energy production, but also how the brain processes that and then how we make decisions based on that. So like glucose, for example, it's far more satiating than fructose, which is very surprising. We don't really understand why glucose is more reinforcing more rewarding than fructose is.
Nick Jikomes 30:51
Glucose is more reinforcing than fructose is, yeah.
Will de Lartigue 30:53
So by reinforcing I mean, you're more likely to want to consume glucose. If you give an animal glucose, for example, directly into its gut, it's more likely to prefer that than if you infuse fructose directly into its gut. And if you pair a flavor with that, they'll learn to flavor for glucose more efficiently than they will for fructose. And then at the end, if you give them the two flavors, they'll prefer the glucose flavor. So there's a lot of evidence that animals will prefer glucose or fructose. And in fact, if you give them in a bottle, glucose and a bottle for fructose, they'll, at the beginning, they liked them, maybe equally, because they're both sweet. And maybe like fructose a little bit better because it's sweeter. But over a number of trials, they'll almost exclusively drink glucose. So glucose is the preferred the preferred sugar in this case,
Nick Jikomes 31:42
is that true with humans? I had a conversation. So that's, that's
Will de Lartigue 31:46
where it all gets a bit unclear. I don't know. I don't know is the answer. There's probably literature on this. I'm not familiar with it. I don't know.
Nick Jikomes 31:55
I see. Because I had a conversation with Robert Lustig, physician scientist. And one of the things he really emphasized was, and he's I think he's thinking more of human literature in his mind. But I'm not sure where the how much overlap there is here. If he was basically saying fructose interacts with the addiction circuitry of the brain, and glucose doesn't nearly as much. Okay, well, so
Will de Lartigue 32:21
part of the reason for being here, right is to discuss this paper that we've just published. And, and in there, we clearly show that sugars are driving reward. We didn't specifically test it in our paper, but there's lots of evidence, at least again, in the animal literature, that glucose is the one that's driving this this reward circuit that we're identifying. So you know, fructose can have some benefits, maybe in some other ways, but it's not engaging this gut brain reward circuit in the same way that the glucose is I think most of what I'm going to be talking about today is really driven by glucose rather than fructose. Okay,
Nick Jikomes 32:59
yeah. And so yeah, let's get into that a little bit. So the vagus nerve, it's reaching down, it's touching, and sensing information about almost all of our organs in the body, the stomach, the GI tract, etc, etc. You've got distinct neurons that are specialized to some extent to send specific types of nutrients, specific sugars, specific fats, and so on and so forth. What did you look at in this recent paper where you were looking at neurons that detected fats versus sugars? Yep.
Will de Lartigue 33:29
So I guess the starting point for kind of the entire study was the observation that we're eating foods that are bad for us, right? We're eating lots of fats and lots of sugary foods. And and we just wanted to understand what why are we doing this when we know that they're bad for us? It's not like there's any secret out there that we shouldn't be eating fats and sugars. And yet, here we are eating all the time. So what is it about fats and sugars that that makes them so enticing, so rewarding that we want to eat them? And that was kind of our starting point. And really, we kind of, were thinking along the lines of, well, if we can understand the molecular mechanisms by which these different, these different macronutrients are sensed, maybe it'll give us insights into why we're doing this. So that's kind of our starting point. And so when we, and I've kind of taken a step back, I guess we are also already previously identified a gut reward circuit. So we already knew that when nutrients enter into the gut, that when there's energy in the gut, that it activates a circuit that we've identified, that ends up with dopamine being released in the brain. So dopamine is this chemical that is pleasure chemical, I guess or motive. It increases motivation. There's debate about exactly what dopamine is, but essentially it it's like a measure of reward in some some way. And we know that when nutrients enter into the gut that it causes this dopamine release. And so the question was, well, do all macronutrients do this, specifically to the fats and sugar do this given that we're so motivated to go and consume them? Yeah,
Nick Jikomes 35:26
yeah. So yeah, do do owner drinks do this? Or do they do to the same extent, presumably, right, common sensical, you would imagine things we'd like the more like sugary foods are gonna result in a bigger dopamine spike in the reward centers of the brain. Yeah,
Will de Lartigue 35:40
so that was our starting point. That's, that's kind of what we knew already. And we came in thinking, well, there must be something different about fats and sugars, that would make it worth studying them and understanding exactly what they do. And so when we did that first experiment that I've already kind of alluded to where we were recording the activity of the neurons in the vagus nerve, and found that there was separate populations of fat and sugar neurons. That was really exciting to us, because it suggests Well, it's not just calories that are being sensed here. It's it's, we're sensing at the macronutrient level. So that was the first kind of wow moment for us. And then then we started wondering, Well, okay, well, what are these two different populations of neurons doing? And can we break it down and study them individually, to figure out whether they play a role in reward? And so we we use kind of a fancy tool, I don't know how much you want me to get into it. But essentially, it allows us to selectively target the different populations, either the fat neurons or the sugar sensing neurons. And then genetically manipulate those populations. Yeah,
Nick Jikomes 36:47
I don't think we need to go into details. But but you know, people should know that you guys have the ability experimentally, to use tricks from molecular biology to, you know, only look at or only say, activate or manipulate the sugar sensing ones or only the fat sensing ones. Yeah,
Will de Lartigue 37:02
exactly. So we're genetically tagging the neurons that are sugar sensing, or fat sensing, and then allows us to go in and manipulate them. And so I think probably the coolest experiment that we did, is we selectively deleted the neurons that sense either sugar, or the neurons that sense fat. And then we looked at the rewarding effects or how the animal behaves as a consequence of that. When
Nick Jikomes 37:26
you say deleted the neurons, do you mean you deleted the neurons ability to detect that nutrient? Or that you ablate you killed? They
Will de Lartigue 37:32
were gone? They okay. Yeah. ablated. So we replayed either the sugar neurons or the fender ons. I guess the first thing to notice the animals are fine, that has no effect on the animal they behave normally, they don't really, you know, there's there's no kind of odd behaviors that were observed. Except that when we did an experiment where, and this has been done a lot in the literature, where you essentially give the animals access to two different flavors. So in one bottle, you've got a novel flavor they've never had before, and then a different flavor in another bottle, and you give them a choice between these two flavors, you tend to like them equally. And then you associate one of those flavors with the infusion of the nutrient, be it sugar or fat. And the other flavor with water or saving. What happens over time is the animals become conditioned to like the flavor that's associated with the arrival of nutrients.
Nick Jikomes 38:30
I see. And when you say infusion, you mean like putting it directly into the stomach?
Will de Lartigue 38:33
Yeah, it's just it's just basically just directly infused into their Yeah,
Nick Jikomes 38:38
yeah, okay. Okay. So they've got two bottles, they can go taste, whatever is in each bottle. But then separately, you choose to or not put in some kind of nutrient directly into the stomach. And it's their ability to make that association we're talking about, right?
Will de Lartigue 38:53
Right. So they're, they're basically learning. It's very similar to Pavlovian conditioning that most people are aware of. It's that that experiment with Pavlov's dog, where you ring the bell, and you associate that the sound of the bell with the arrival of food. And then if you do that enough times just the sound of the bell goes, causes the dog to salivate. It's it's a very similar concept to that. But here we're doing it with flavors and nutrients. Yeah.
Nick Jikomes 39:16
And it's like, it's just we take it for granted as living breathing creatures, like because right, naturalistically. We walk around and we eat things. We're always sort of making this association between the taste and whatever is actually in the food, because we swallow the food. And that's just the way it works. But you guys can actually dissociate these things and manipulate them sort of one at a time.
Will de Lartigue 39:35
Exactly. And yeah, you're right. It's happening all the time. We're learning every time we have a bite of something that that whatever that taste is, that we have, is predicting calories as we get the calories in our gut. We then subsequently learned that that flavor that was that we had in our on our tongue earlier actually predicted the arrival of the calories and so actually, we become really good at that. Subsequently, by just taking bites. We can kind of predict how many calories there are, and whether it's something that we liked or not. But I will also add that it goes beyond just taste, or you're conditioned to the smell of things, the side of things, if I show you a picture of cake, you're going to know, calories involved. And actually, you're probably going to like it and maybe even start salivating at the side of it. So there's a whole, it's not just that it's a multimodal representation to manipulate here.
Nick Jikomes 40:22
Okay, so So you, you kill these neurons, either the fat sensing ones or the sugar sensing ones. And it is disrupting this ability to make this kind of association.
Will de Lartigue 40:33
Right. But what's really cool about the experiment, so if you delete the sugar neurons, the animal loses the ability to form a preference for the flavor that's associated with the infusion of sugar. But it does not impact the ability to form the preference for the flavor that's associated with that. So it's very macronutrient specific in that way. You're leading the sugar neurons, you're deleting the ability to form that sugar, new flavor preference, but not the fat flavor preference. And so that, I mean, to me, that was that was very shocking. That finding was just a wow moment. And
Nick Jikomes 41:10
so you've got these labeled lines of information, it seems they're, they're specific to different nutrients, just for completion. I think, based on what you said before, I'm assuming the sugar here was glucose, when you say you're giving them fat, what kind of fat? Are you giving them?
Will de Lartigue 41:27
Yeah, so we're actually the majority of the experiments in this paper was with sucrose,
Nick Jikomes 41:32
okay, so it's a mix of it's a mix of coke and fructose.
Will de Lartigue 41:35
And for the fat, we're using something called micro lipid, which is just a mixed mixed fat.
Nick Jikomes 41:43
Okay, so it's gonna have some combination of saturated, unsaturated Yeah, so
Will de Lartigue 41:47
not actually 100% Sure, off the top of my head. But yeah, yeah, I mean, it is, whatever micro lip it is. Yeah.
Nick Jikomes 41:56
I mean, I study feeding behavior for five years, I have to say, I have an SOP standard, shall we use high fat Chow? I don't, I don't think I have a single memory in my mind of anyone ever talking about the specific metric macronutrient content beyond just knowing what was high fat?
Will de Lartigue 42:13
Yeah, I mean, normally, I look these things up, but at the MCS, it's not on top of my head. So whatever my whatever's in micro lipid, is what we used here to represent basically that, okay,
Nick Jikomes 42:27
and then, so talk a little bit more about. So you got these separate neural populations, one of them that texts, presence of sugars, one of them detects fats, you can kill either one of them, and it disrupts the animal's ability to make associations with that specific macronutrient. How does this stuff tie in and hook into the dopamine reward system in the brain? Yeah,
Will de Lartigue 42:51
that's a good question. So what we find is that if you so as as mentioned earlier, if you give the nutrients into the gut, it'll cause dopamine release. What we went on to show is that, actually, I'm not sure if this ended up making the paper or not. But anyway, what we have done in the lab, is we've shown that if you remove the vagus nerve, then you lose the ability of dopamine to respond to the infusion of nutrients into the gut. So the vagus nerve is essential for this, this connection between the nutrients arriving in the gut, and then being communicated to cause dopamine I
Nick Jikomes 43:32
see. So that would mean so you put food directly in the gut, but the vagus nerve is cut, you don't get any kind of dopamine response in the brain. So there's no sort of reward response to the food, which means there's nothing there's no other way to elicit that response. There's no parallel. And that's
Will de Lartigue 43:50
basically, if you don't have an intact vagus nerve, you don't have the ability to form the preference, the learning that is associated with the nutrients arriving via the dopamine.
Nick Jikomes 44:06
And then, so when you measure reinforcement, like how, how do you measure reinforcement? How reinforcing are is sugar versus high fat?
Will de Lartigue 44:15
So the experiment that we did in this paper, so what I told you about before where we deleted them, that's kind of a necessity experiment, what you're talking about is insufficient, like, how sufficient is it right? So to do that, we we use another kind of trick in our tool belt where we're able to selectively activate the neurons, so we either activated the sugar neurons, or the fat neurons, or we also took control animals where we infuse them with saline, and then activated the neurons that respond to saline. So we activated these three different populations. And what we were asking the animal to do is basically to put its nose in a hole. So it's kind of an arbitrary behavior that it doesn't necessarily want to do. It has no incentive to do. But every time it does it in the right nose hole, it triggers the activation of these neurons. And so if it's something that is reinforcing that it's rewarding, then they will perform this task. And if it's has no effect, then they probably won't even notice because they're not interested. And so when you do it in the control animals, that's exactly what you find. We have two nose holes, we have one that causes the laser to be accurate, and one that doesn't. And they will equally nose broken both and they don't notice both very much of that. But when we have that, so that we're targeting the neurons that sense either the sugar or the fat, the animals learn very quickly, which one is the active nosal which one actually causes the triggering of the of this circuit, and they will do it a lot. So that was kind of our, our measure of that these neurons are actually reinforcing.
Nick Jikomes 45:53
So you've got the detection of sugar, the detection of fat, both of them can be reinforcement, stimulating either pathway can be reinforcing, stimulating either paths or pathway is going to give you, you know, dopamine response up in the central nervous system, the classic dopamine reward circuitry. Most. So if we sort of step back and think about the the motivation for doing this kind of work that you were talking about earlier. You know, as humans, we live in this food environment where, you know, we've got cheap, easy access to virtually anything that we want. When we think of a classic junk food, the things that we know, we all like to eat because they taste good, but are clearly bad for us. Typically, they're both high fat and high sugar. So in terms of the reinforcement in the behavior in terms of the reward response in the brain, when you give an animal fat, and sugar separately, and fat and sugar together, what does all that stuff look like? Do these things stack on top of each other? Do they have some kind of interaction? That's interesting here? Yeah,
Will de Lartigue 46:53
that was that was? So that's the key question, right? That that's really where this was leading us to, we essentially identified two different wiring diagrams, one for sugar, one for fat that are separate, they run parallel to each other, but they they don't crossover very much. And that happens at the level of Vegas. And I should say, also happens at the level of the brain. So if you look downstream, to in the brain regions that then communicate to the dopamine producing neurons along that entire circuit, those things are largely separate.
Nick Jikomes 47:23
ICS, just completely segregated are mostly segregated pathways for each nutrient. Yeah.
Will de Lartigue 47:28
And so the kind of the implication is, well, if pathway sugar and pathway fat are separate, what happens when you have a food that has both together? And so we did experiments, we did a number of experiments. The first one was, we gave animals access to either sugar, or a water solution, or sorry, sugar solution, that solution or a fat plus sugar solution to lick, give them ad libitum access for 30 minutes, and we just want to find how much they consumed of it. And what's really interesting is, although we control for the number of calories, so everything has the same number of calories, the animals consumed nearly twice as much of the fat plus sugar combination than they did if either of the two solutions.
Nick Jikomes 48:16
I see. So they will consume more of fat plus sugar, they will have either fat or either sugar, even when each each choice has the exact same number of calories inside of it.
Will de Lartigue 48:26
That's correct. Yeah. So that was the experiment we did. And then, of course, there there were consuming orally. So there was a an oral component, there was a taste component, we wanted to bypass that. So we repeated the experiment where they were looking for the exact same thing every time. But they were getting infusions into the gut of either the sugar, the fat, or that that blood sugar combination. And again, we got very similar patterns, they consumed pretty much twice as much of the fat plus sugar than they did of either macronutrient alone. And
Nick Jikomes 48:52
what do you think this means? what's the implication?
Will de Lartigue 48:57
Well, it means that when we have foods that have the combination of fat plus sugar, that we're more motivated to go eat, and we'll eat more. So if you extrapolate further than that, I mean, that increases our susceptibility to develop obesity. And it could explain why we have seen huge rises in obesity rates in the last 50 years, as we've manipulated our food environment more and more. So I think, you know, you look back before the 80s 70s, obesity rates were around 15%. And now today, right now we're at 42% of these cigarettes, and that's obesity. I'm not talking about overweight, overweight plus obesity is like 75% of the US adult population. And it's, it's thought that by 2030 50%, like one out of every two adults is going to be obese. I mean, these numbers are just staggering, right. And, and it's happened very quickly. In just 50 years, we've gone from 15% to nearly 50%. So what is it about this, what is driving this? Well, we think that the fact that we've created an environment where we have foods that and increasingly are highly processed to have fats and sugars. And I think you can extrapolate beyond sugars, you could probably say carbohydrates as a whole, the combination of that suppose carbohydrates is just something that increases our motivation. And just to reinforce that, what we found, in addition to them consuming more, we found that there was significantly more dopamine being released and more neurons in this whole circuit that are activated. So you know, when you have foods that have the vegetable sugars, you're engaging the these two separate wiring circuits for fats and sugars together simultaneously, and it's causing double the effects.
Nick Jikomes 50:40
I see. That was gonna be my next question. How big is this effect? When you combine the fats and the sugars compared to either one alone, but you're holding calories constant? Are you getting twice as much reinforcement? 50% Depends
Will de Lartigue 50:51
on how you look. So in terms of reinforcement, so in terms of how much they're consuming, you're getting pretty much twice as much. When you look at the number of neurons that are active, we get more than twice. So it's, it's more than just adding sugar plus fat together, it's it's super additive, right? And then when you look at dopamine release, well, we didn't really do we just did, compared one macronutrient to the combination, we didn't do the three. So it's hard to know exactly if it's additive or not. But it looks to me like it would be more than just the addition of the fat or the sugar alone. So it's very reinforcing.
Nick Jikomes 51:29
Yeah, it's very reinforcing. And, you know, we start to think about like, oh, you can imagine like, why the system would evolve to strongly reinforce something like this, right? You're trying to get an animal's body is trying to make sure it gets enough calories, which naturalistic conditions are often very scarce, to, you know, to survive and eventually reproduce. Do you see do we simply just, but we don't see like obese animals out in the wild, we see them in captivity, we see them in the city adjacent to when they're in our food environment that we have created. Do do certain, like macronutrient compositions just not exist out in nature. And we've just figured out that we can create them and we like to eat them. And that's what's going on? Yeah, I
Will de Lartigue 52:14
think you're hitting the nail on the head. So in nature, what we normally find is foods have a composition, that is sugar or composition is that it, it's rarely you rarely see things in nature that have a combination of both. And even when you do like avocados, for example, it's, you know, skewed one way more than the other. But most foods that you can think of that are that are natural, are one or the other. And so we've kind of it makes sense that we would evolve a system that would allow us to be reinforced to eat the foods that have the sugars, because they exist in nature, and then the foods that are that, that are high in fat, because they exist in nature, and they're separate, and they're probably going to be in separate places. And so we need, you know, when we were talking earlier about the learning about the taste, and the sight and the smell of foods, well, how did animals go about finding their foods, it they use all of these different senses to navigate their environment, and they find where that food is, and then they remember, okay, well, all of these cues, say, this is where I'm going to find this food. So when they were looking for sugar foods, while they had to remember where in their environment it was located, they use all these cues, and then they went back there. So it was an efficient way of being able to find the foods that you want, remembering where they were located, and going back to the same place every every time. So I think from an evolutionary standpoint, it makes sense that we would have evolved these two separate circuits. And what's happened now is we've created this kind of Frankenstein environment where we can control everything within it, which in many ways is beneficial to us. Because now we don't have to worry about where am I going to find my food, I know, I can just go to the supermarket, I can go to my fridge at home, maybe even my drawer at work. And in my desk, I've got you know, candy bars, maybe so I know where I can find food, I don't have to worry about that. And what we're left with is this one decision that we have to make Well, what food should I buy on a database, day to day basis? Humans just have this one decision to make when it comes to food, where am I going to eat? What am I going to eat? And we've, we've made it so that we've created this food environment, like you've said, but really what we've done is we've we've created foods that are more likely to cause us to want to eat them. And it makes sense. I mean, if you think from from a company's perspective, right, they're making foods, they don't want to make something as bland that you don't want to eat that that's not reinforcing. That's not good. You're not gonna go buy it again.
Nick Jikomes 54:41
You'll be it'll be put on business by their competitor. Yeah. And so it's like, it's like no one, no one architected this, you know, hundreds of years ago, just through trial and error and through the competitive, you know, market process. Companies naturally converged on things that people would buy more or, and, you know, in the absence of education, knowing like that things can be bad for you. And even even in the presence of that education very often, people simply will eat the thing that they find tastiest the most reinforcing.
Will de Lartigue 55:13
I mean, you know, how can you blame anyone for taking something that and it's not just that it's tasty. So I think another thing that to think about from this research is that it's tasty, because it activates this gut reward circuit. Right? So actually, if you think about it, the reason that we find things that we find something tastes good is because we've learned that it tastes good because it predicts the arrival of the calories. And in fact, as an example, kind of an extreme example, but you might really like pizza, right, which has a lot of fats has a lot of sugars, it's probably most people are going to like the taste of it. But if I give you a pizza, and it makes you sick, then actually, if I give you that same pizza the next day, I don't think you're going to eat it, you're going to figure out that this is an aversive thing. And I don't know you, it might last forever, it might last a few days. I don't know how that happens.
Nick Jikomes 56:11
I mean, a lot of people I think I've experienced with this, I can think of multiple examples in my life where someone I know, eats something early in life, and they never touch it again, if they start cooking afterwards.
Will de Lartigue 56:20
So you can have it, it can be really strong stuff. But sometimes you can kind of relearn and kind of come back to it and say, Okay, well, actually, I quite like this again. But it's all about the learning process. And it's all catered by the gut. And I think that's that's kind of a key thing that that was kind of an interesting takeaway from this is that the reason that we're eating isn't because it tastes good. It's because of the calories that are in the food that reinforce that that tastes is good.
Nick Jikomes 56:49
And those two things are very correlated. Yes,
Will de Lartigue 56:53
of course, yeah. They happen together. I mean, nature. So we were able to dissociate the two experimentally, right. Yeah. In in our day to day lives, then those two things kind of go hand in hand. Of course, what
Nick Jikomes 57:04
about, you know, what about? You know, we've got an obesity epidemic, we've got a diabetes epidemic, you know, there's definitely some education awareness around, you know, added sugars. At this point, many people know that you probably shouldn't have too many added sugars to, you know, at least. And so people, some people at least are being more mindful of that. This has given rise to things like non caloric artificial sweeteners, right, that don't have the calorie content, but do give you the tasty component that we enjoy. Is there anything interesting going on there in terms of the vagus nerve, or the reinforcing effects and the rewarding effects that these sweet things have things like stevia things like other artificial sweeteners that don't have the calorie content of glucose, but still tastes sweet? Yeah,
Will de Lartigue 57:53
that's that's a really great question. And actually, it's really interesting, because these non nutritive sweeteners tend to not activate the vagus nerve. So the vagus nerve is basically blind to these things. So it really activates the taste receptors on the tongue, it tastes sweet, but then when it gets to the gut, it's basically a wash, it doesn't do anything. And and it doesn't cause the dopamine release, either as a consequence of not activating activating the vagus nerve. And so if you kind of follow through with that logic, what it's what is happening, every time we taste a non nutritive sweetener, is we're now disconnecting the sweetness with calorie, and so it's actually messing up our prediction, our ability to make these predictions. So now next time, when you eat something that is sweet and has calories, you're no longer as good at predicting the how many calories are in that thing, based on the sweetness, and actually that really nasty consequences, because it means you're going to end probability you're going to eat more of it, because just don't know that there's this based on the sweetness.
Nick Jikomes 59:04
Yes, that's what I was going to ask is okay, so So the idea is, if I'm eating a non nutritive sweetener, the it doesn't have caloric value, the vagus nerve is not detecting it and tapping into the dopamine reward system in the brain. It's actually causing them my brain to sort of miss calibrate the association between how much calories in the caloric sweetener or the sugary substance. And so I might actually do more of it later, because I'm no longer the prediction is no longer as strong as to what its core content will be. Yeah, I
Will de Lartigue 59:38
think. I mean, that's, that's the logic, you know, that probably needs to be tested in a lab setting, but but that that's kind of the thought process. Yeah, I think that's what's happening.
Nick Jikomes 59:49
Yeah, I mean, it makes logical sense. Okay, so it hasn't been directly tested? I don't think so.
Will de Lartigue 59:55
So, there are some cool studies that are done in humans that show um, that there's a ideal level. So if your sweetness matches the calories, you're more likely to prefer that. And so I don't even know if this is published. But I've seen the data where people have tested Coke versus Pepsi. So coke actually hits that sweet spot where it's just the right amount of sweetness for the number of calories. And Pepsi is a slightly off. And so actually, when people do the coke Pepsi Challenge, people tend to prefer coke. And we think that might be in part, the reason for that, but but actually, if you artificially in the lab, decouple the sweetness from the amount of calories that the these are humans are receiving, they they're really good at figuring out which one is the right one. And if you disconnect that it, there's evidence that it might actually cause metabolic effects in the long run. So I think there is evidence to support what I said earlier, it's not just a wild speculation of this. But the actual direct evidence that if you chronically consume these non nutritive sweeteners that it will make you over consume the sugars. I think that's probably the bit where we need a little bit more evidence for Yeah,
Nick Jikomes 1:01:10
yeah, I mean, it should be readily testable, and rodents. Absolutely horrible. Absolutely. Interesting. But that makes sense. Okay, so the non nutritive sweeteners, you know, when you when you first started saying, like, oh, they don't activate the reward circuitry in the same way, you know, naively you go, Oh, that's good. But, you know, unless you're going to completely give up caloric sugars, which is effectively impossible, it could actually break your brain's ability to accurately assess to tie the reward the reward component to the calorie component. Exactly. Yeah. Interesting. Um, what can you just I actually don't know beyond like stevia, and maybe one more, what are the major non caloric sweeteners that are out there? How do they actually work?
Will de Lartigue 1:01:55
Well, this is not my area of expertise. So I don't want to kind of go too much into this, but but they all activate the same receptors in the tongue that T one or three receptors that are give you the ability to taste sweetness. That's pretty much the same thing that the sugar that caloric sugars do. And so they activate the same sweet receptors on the tongue. But But whereas glucose is taken up by a specific transporter in the gut, those do not take up the non nutritive sweeteners.
Nick Jikomes 1:02:32
Got it? Got it. I want to ask you a little bit about gut hormones as well, and how gut brain communication is happening via that route. And there's two that I'm hoping that you can talk about a little bit. Let's start with leptin. So what is leptin? Where does it come from? And what does it what's the basic explanation for what it does?
Will de Lartigue 1:02:55
So, Leptin is a hormone that's released from adipose tissues, or from fat cells, it's the amount that is released is proportional to the amount of fat that you have. So the more fat you have, the more leptin you have. And it's thought to be kind of a long term sensor of energy status. So it kind of doesn't necessarily fluctuate very much from meal to meal, but it does fluctuate as your body weight changes, and it's an important signal to kind of maintain your, your kind of body weight over a long period of time. So that's kind of mostly what leptin does, but there's also a popular pool of leptin that's released from the GI tract. And so that accounts for about 25% of the total leptin that's circulating anytime in your body, and that does fluctuate in response to a meal. So after a meal, you get more leptin released. And so actually, while leptin generally is thought to control your your body weight, there is kind of an acute response in response to meal that does control how much you eat. And it's possible that it works through different mechanisms.
Nick Jikomes 1:04:10
And this is meant to signal satiety. Oh,
Will de Lartigue 1:04:14
yeah, sorry. Yeah. So in both cases, it controls how much you eat, or it's just the timing. So
Nick Jikomes 1:04:21
more more leptin means you would then eat less.
Will de Lartigue 1:04:25
So that's mostly true. There are there's this weird kind of dichotomy that happens in obesity, where, of course, I say, the more fat you have, the more leptin you have. And so actually, there's, it's kind of this reverse effect, where actually in obesity, although you have more leptin, you're less responsive to that leptin. So the ability of the cells to respond to the higher levels of leptin is impaired. And so, in that sense, it's called leptin resistance. When you have leptin resistance, although you have more leptin, you're kind of insensitive. To the effects of leptin, but yeah, general leptin and equals satiety in the exception being obesity.
Nick Jikomes 1:05:07
So leptin resistance, your cells are no longer responding to leptin in the way that they're supposed to. Is there an analogy there with insulin resistance? Is it the same kind of phenomenon? Yeah,
Will de Lartigue 1:05:18
I think it actually works in quite similar the underlying, there's a lots of different ways that this is thought to happen. There's, at the molecular level, the way that this happens, are going to be slightly different. But overall, it's very similar. Yeah.
Nick Jikomes 1:05:31
And can we think about these things, these metabolic issues, leptin resistance, insulin resistance, are they like, like a drug addiction, where it's like I've, you know, you've taken so much of a drug, that your your cells are no longer responding to it, because they've either downregulated the receptors or the receptors have become insensitive or something. But in essence, it's a response to too much of something. Yes. Yeah,
Will de Lartigue 1:05:55
I think that's I mean, that's, that's the way I understand it. So the, when when leptin activates the receptor, there's this negative feedback loop that happens, and that's kind of Traditionally most of physiology, or you get feedback loops. And what that means is that as there's more leptin, and there's more signaling, then it also has some sort of inhibitor that is kind of built into the system so that it feeds back onto the receptor, and essentially shuts it off. And so even though you've still got left in present, then it doesn't really signal anymore. So what starts to happen with leptin resistance is that that feedback mechanism is kind of hyper activated. And so you're kind of turning off the ability of the receptor to respond to something, even though you're not even responding to it in the first place.
Nick Jikomes 1:06:44
I see. So. So if you've got a normal lean individual who's not leptin resistant, you would expect them to feel more satiated, more or less hungry, when their leptin levels are higher. But if you had a obese person, especially if they had been obese for a long time, if they were leptin resistant, you would actually see higher levels of leptin in them, even though they are eating more than the lean person. Yeah,
Will de Lartigue 1:07:09
I think that makes sense that, like, maybe I tuned out a bit, but just to be clear, when there's more leptin in the lean person, you're going to eat less. Yes, yes.
Nick Jikomes 1:07:18
But if your leptin resistant, you could actually have elevated leptin levels that,
Will de Lartigue 1:07:22
but with no effect. Yeah. Okay. Yeah.
Nick Jikomes 1:07:24
What about so there's this other gut hormone that people have been talking about a lot recently, because of some of the new drugs that are out there? GLP one, so what is that?
Will de Lartigue 1:07:35
Yeah, GOP one's a fascinating drug. It's, well, first of all, it's ozempic. And these other drugs that that have GLP, one activate on the GLP one receptors, and they're very effective at causing weight loss, reducing food intake, have a lot of these effects. But in the body, we have GLP, one in two different places. One is in the gut. So there's, there's specialized cells in the gut, and make up about 1% of the total cells in our, in our gut, and they will release GLP, one in response to the arrival of food in our intestines. So when there's food in the intestine, GLP one is released, gets into the circulation, it's not clear if it's working through the vagus nerve, or if it goes into the circulation and acts directly on the brain. But it essentially causes you to eat less. The one thing about GLP one is under normal conditions they are endogenous dopamine is it's very rapidly degraded. And so it's not that's why it's not clear if it's actually effective at the level of the brain, but it will definitely activate the vagus nerve. There's lots of GLP one receptors on the vagus nerve, and activation of GLP. One receptor expressing neurons causes significant reduction of food intake. So this pathway gets activated when you eat a meal triggers these GLP one receptor vagal neurons to tell the brain to stop eating. And then there's a separate population of GLP, one producing cells in the brain. And they when they're activated, usually in response to a very large meal will also tell you to stop eating. Okay,
Nick Jikomes 1:09:09
so this is a mechanism. Food gets into the intestine GLP one is released, and it's causing you to eat last. So it's a way for the body to tell itself hey, we've got food in the intestine, we don't need to eat as much in the near future. Yeah,
Will de Lartigue 1:09:25
definitely the level that got in there to level the brain. It seems like that happens in very large meals. So when you're, when you're at that point where you're feeling really, really full and maybe a little bit uncomfortable, that's when your GLP one in the brain is telling you, okay, you really need to stop eating now. And
Nick Jikomes 1:09:40
so you said leptin gets released from fat cells? Did you say where GLP one gets released? What kind of cells? Yeah, so
Will de Lartigue 1:09:46
it's so either in the gut, the specialized cells in the gut or this very unique population of cells in the brain
Nick Jikomes 1:09:53
in the brain. And then you said this other feature it has it's very rapidly degraded. You know, That's a feature that various other signaling molecules have. And it's often a very important component of their temporal regulation, you only want the signal to be there for a certain amount of time. It sounds like the the new drugs like ozempic. They are. They are like GLP one and that they activate the GOP one receptor to drive less eating. But they are unlike it in the sense that they aren't as rapidly degraded. Why were they made that way? If you know, and do you think that we should be paying attention to that.
Will de Lartigue 1:10:33
So that's a that's a feature rather than a bug. I mean, that was the that was the underlying reason for making these drugs was to make them like GLP. One, but longer lasting the the idea was that GLP was really effective at causing you to reduce your food intake. But it's short, so short lived, that if you give that in the body, or you know, if you give that to somebody, it just wouldn't have a long enough effect. And so they extended the half life of GLP, one in the circulation. And with the latest version, the cemac the tide ozempic You only take it once a week. So it's it's really prolonging the half life of the GLP. One,
Nick Jikomes 1:11:13
do you think that could pose a risk of these people developing GLP? One resistance?
Will de Lartigue 1:11:20
Yeah, that's so that's interesting, because it doesn't look like that's what's happening. So like I said, mostly, usually in physiology, what you see is that there's these feedback loops, and they turn themselves off. But it seems like maybe because the body has developed a system by which you don't need a feedback loop. Because if it gets degraded quickly, maybe there's a I mean, I don't know if this is true, but maybe this is why there doesn't seem to be a feedback loop. And so it allows for these longer lasting drugs to continue to have beneficial effects. And
Nick Jikomes 1:11:52
is there any, so it is clearly very effective at helping people lose weight, we've seen that already. Obviously, they did the trials to show that that enabled it to achieve the success it has commercially any potential like downsides, or thinks we should be looking out for in terms of this drug based on what you know about the basic biology here?
Will de Lartigue 1:12:14
Well, I'm not sure based on the biology, but from what I'm hearing, there's a few things that we need to kind of pay attention to that maybe people are not aware of, first of all, it's not effective in everyone. So it's talked about as this miracle drug. And yet, that's because you only hear about the people who in which it's working. They're the ones that are kind of telling everybody how effective it's it's it is on them. And and you don't really hear people talking about it when it doesn't work, because they start probably because they're wondering, well, why isn't it working on me, I don't want to tell everybody, it's not working on me. So you don't really hear about the the stories of it not working. There's some concerns about how the weight is lost. So it's very effective in weight loss on a halt. Right. So now I'm not talking about individuals, some individuals, it works great, some individuals, it doesn't work at all, but as a whole, it's very effective, you get around 15 to 20% of weight loss. So like massive weight loss. And but how that weight is coming off is kind of something that we need to be paying attention to, it doesn't look like it's all coming off in terms of your fat mass, a little bit of there's some lean mass, some some muscle mass, maybe even bone mass. So you know, this is just something to pay attention to. I'm not saying that, that we know for sure that this is a problem, but it's something that we need to be paying attention to. Yeah. And then the kind of other thing that
Nick Jikomes 1:13:39
actually I'm sorry, can you actually unpack that a little bit more? Why would we want to pay attention to it? If you're losing muscle and or bone mass in addition to fat mass? Why is that an issue?
Will de Lartigue 1:13:50
Yeah, I mean, then it's you're affecting your kind of, if we're using it to treat obesity, what we want to do is get rid of the excess body weight, we don't want to get rid of our, what makes us you know, basically the part of our body that is burning off energy, we don't want to be affecting that we want to ideally we'd want as a drug that just causes the fat to melt off without impacting anything else. And so here, the concern is that it's impacting more than just the fat. And, you know, it causes you problems to gain muscle mass or to to regain kind of your normal body tone, essentially, that can be problematic. Now, I'm not saying that that is what is happening. I'm saying that this is just something that we need to be paying attention to, because from what I'm seeing, it's not 100% that mass loss. And then the other thing that I think that we need to be paying attention to with these drugs is that it seems to be impacting the reward system, which can be both good and bad, right. So it would be great actually, if we could, as we talked about earlier, inhibit those. That and trigger reward systems so that when we eat them, we're not so motivated doing them again. But the problem here is that it seems to be globally reducing reward as a whole. So there's just a loss of hypnotics. And in some cases is great. I've heard of people who were addicted to gambling, for example, for a very long time, they started going on these drugs, and now they're no longer gambling anymore. I mean, so like these remarkable stories. Now, these are some anecdotal, I don't want to make too much of a big deal out of this. But it does point to this idea that maybe it's kind of globally reducing our reward circuits. And and the problem with that is if we don't have any reward, if nothing is rewarding, and nothing is pleasurable anymore, then maybe it's not a
Nick Jikomes 1:15:45
great way to live. Yeah. Well, I mean, do you do you remember the drug Romana bond, right?
Will de Lartigue 1:15:50
Yes. So that's a CB one receptor antagonist. Yeah, yeah.
Nick Jikomes 1:15:54
And just for the people that don't know, this was a similar story. In essence, it was a weight loss drug, it was effective. It was approved in Europe, it acted through a different mechanism. It was a cannabinoid receptor antagonist. So just kind of like THC gives you the munchies. It's sort of like the opposite. It's like the an anti THC type of drug. And it worked. The problem is it had this global sort of effect on reward, and people started getting depressed and even committing suicide. Yeah,
Will de Lartigue 1:16:23
so I haven't heard anything about people committing suicide and then pick that that would be the concern, right? That would be why you'd be paying attention to this, making sure that this isn't something that we have to worry about long term. But I think, even if it doesn't cause depression, it just reduces your ability to enjoy the day to day life. I mean, right? Right, that's maybe a reason that people would no longer want to be on there. So there's that initial benefit of I lose all the weight? And then do I want to continue on this drug, when I'm not getting other pleasures, now you're having to balance make that choice. And the problem is, as soon as you come off the drug, you regain the weight. So it's something that you're either on pretty much forever, or? Yeah, so that's kind of the problem that we have right now. If it's a forever drug, you're gonna have to take it every single day, or not every day, every week. And as soon as you come off of it, you're going to regain it back. So
Nick Jikomes 1:17:23
yeah, I mean, sort of the sort of future I can see emerging, as you know, there's gonna there's like two populations of people that we're gonna see more and more of those that self regulate their behavior by, by by shaping and controlling their own habits, actively, and those that are basically just on drugs their entire life to mess with the outputs of the habits that they're not controlling.
Will de Lartigue 1:17:50
Yeah, although I want to push back on that a little bit. I mean, you're kind of right, that there's certainly a drug versus no drug approach. And both are different approaches. The problem with all of this is that this gut to brain circuit that I was talking about, that causes this reinforcement that wants that makes you eat more, it's also conscious, it's not something that you're you're controlling, right, you have no control over this, how nutrients activate the dopamine, that is below your level of detection. You don't even
Nick Jikomes 1:18:20
Yes, but I mean, but you but but but if you have all the knowledge that you just gave us, you do have the ability to control what you purchase, at least to some extent, you
Will de Lartigue 1:18:29
absolutely do it, there's there's a component of decision making there. But when you get this reward, it doesn't, it's not a one off, it's not that in the moment, you're eating it, and it makes you eat more in the moment, it actually guides your future decision making as well. And so, so next time, when you see something that triggers this memory of, oh, I'm going to get calories. If I eat this, and it's something that I want it as pleasurable, then while you can consciously make the decision, okay, I'm not going to eat this, this is not what I want. The problem is when we start getting conditioned in situations where in our daily lives where we're stressed, where we don't have that much, you know, we're not paying attention to these types of decisions every minute of the day. And as soon as we turn that off, we're not consciously aware of this anymore, then we suddenly find ourselves reaching for that donut or whatever. And so I agree with you to a certain degree, like we need to be paying attention to these things. But I think there's we can't undermine the fact that there is a subconscious component to this that's really undermining our ability. To me, I
Nick Jikomes 1:19:41
think what you're saying is the biology here tells us that to some extent, potentially to a very large extent, it is going to be very difficult for a lot of people to willed themselves into, you know, the the behavioral place they want to be, because all of this stuff is happening at the level of things like The vagus nerve and and a lot of it is not subjected to direct conscious control. We are to some extent slanza slaves of our environment. Yeah,
Will de Lartigue 1:20:09
exactly. And beyond that, like the our environment isn't just the spirits that have these mixes of fats and sugars, but our environment is also the constantly being inundated by all these food cues. And by that, I mean, like, we see logos of different restaurants, for example, we see packaging, when we go to the supermarket, even they put certain foods in certain places, so that we're more likely to go grab them, right. So all of this is part of our food environment. And all of this triggers us to go in, can pick these up to consume these at a subconscious level. And so that's where it's so difficult. That's where all the this is just basically, our whole environment is working against us to making the right decisions.
Nick Jikomes 1:20:55
You know, thinking about all of this stuff, and doing the research that you do, I mean, has it affected the way that you operate your own life when it comes to food?
Will de Lartigue 1:21:06
You know, it has to some degree, I certainly am more aware of what I'm doing a pay attention to what it is that I'm eating, what is in the foods that we're eating, where I eat, what I eat. So, it definitely has played a role. It's not working great. I mean, I still, you know, eat the bad foods all the time. So it's not preventing me from from enjoying certain things. But I'm very mindful about not doing it all the time, and paying attention to when I have certain cravings, that what that means and, and really, it's just my gut, kind of reinforcing these these actions. And really, I can fight back against that. So actually, the knowledge is helping me control my urges to some degree.
Nick Jikomes 1:21:52
What are some of the things that the lab is working on right now some of the big questions that you guys think you're gonna have interesting answers to in the next few years.
Will de Lartigue 1:22:01
So there's a bunch of stuff that we're working on right now. The two that I'm super excited about is, on the one hand, we're looking at how information is processed at the level of the gut. So I told you that there's the ability to sense stretch and the ability to sense, say nutrients. Well, how does it do that? So we said that there's different cells that are doing this, but are they organized in certain ways that allows us to separate them out. And so what I'm really excited about is this idea that the left vagus nerve and the right vagus nerve might be actually signaling different types of information that might be controlling your behaviors in different ways. So that's one concept that I'm really excited about that that hopefully will come out soon. And the other one is, we talked a lot about reward today. But the other thing that we're interested in is about memory formation. And, and, you know, everything that that we do around food has some sort of memory associated with it, like, I can eat something and it triggers memories from when I was a kid, or there's certain foods that might relate back to you know, this one time, I remember doing this. And so there's very deep memories that are formed around food. And so how does that happen? And what does that mean? It's another aspect that we're really interested in.
Nick Jikomes 1:23:19
All right, well, this, this was fascinating stuff. All these gut brain communication things, I think, are super interesting. And obviously, it has a lot of implications for, you know, for stuff that people care about. And and you know, how we, how we interact with our food environment. So I'm definitely interested to see see what you guys come up with coming down, coming down the line? Is there anything you want to reiterate or repeat or see again, or emphasize based on anything that we talked about? No, I
Will de Lartigue 1:23:47
mean, I guess the take home message from this study was that there's two different pathways for sugars and fat, that when they are combined together in response to foods that have both the fats and the sugars, that it increases our reward, and that that causes us to be more motivated to go eat those foods. And so I guess, kind of the take home message that the thought to be left with is while we don't have ways right now of dealing with that, how do we kind of interfere with this system to prevent it, just knowing about it can be helpful in terms of altering our behaviors, but also kind of my longer term plan here is to try and figure out what it is that these neurons are what are they doing? How do we like what receptors do they express? Can we develop drugs that specifically impair fat versus sugar reward so that we're less motivated that just makes our life a little bit easier? So not these drugs like ozempic that cause us to lose weight, but drugs that just help us with our willpower to to improve our ability to go about our daily lives without going and reaching for that donut? Yeah, I
Nick Jikomes 1:24:58
think what you're saying is empty. principle, if there was a medication that you could develop that, based on the molecular distinctions between these different sensory neurons, those that attack say fats versus sugars, if you could selectively inhibit just those vagal neurons, you would be interfering with an a person's ability to sense and therefore develop a craving to just that nutrient without interfering with reward processing, generally speaking, yeah,
Will de Lartigue 1:25:24
exactly. Yeah, that's, so that's, that's kind of what we would love to be able to do. And, and it would just make our lives easier, right, we could walk around, still do what we want to do still eat what we want to eat. But now we're not grabbing for things subconsciously.
Nick Jikomes 1:25:38
Do you think you know, based on everything you told us? Do you think it's worth just having in mind that So you told us about this effect, where if you combine fats and sugars, you get more eating in more food addiction, basically, than if you had calorically equivalent amounts of either one? Just knowing that? Is it worth people just thinking about like, hey, if I want to have a snack, I've got one that's got fats and sugars. I've got one that's mostly carbs got one that's mostly fats, maybe choose one that's mostly fats are mostly carbs rather than the one that has both?
Will de Lartigue 1:26:09
Yeah, if you can, that would be graded. It's difficult to do, right? Because when you when you think about a snack, can you name a single snack, except for very healthy ones that are not a combination of the two. I mean, I'm struggling right now to think of what that would really look like. So you could go and eat a piece of cheese or you could eat a fruit, right? But but it would be hard to think of a pure snack, that you could get in a bag that you could buy from the supermarket, that would just be one or the other. So I agree with what you're saying. I just know how easy that is in practice.
Nick Jikomes 1:26:41
I don't I don't think it's easy. I do it. But I don't think the things I consider snacks I have I've had to train myself to, to, to relearn what a snack is. Exactly.
Will de Lartigue 1:26:52
Yeah, that's so that's key if you can, if you can find a snack, that would be just one or the other that you that you would consider a snack for yourself. That's perfect. That's exactly what you want to be doing.
Nick Jikomes 1:27:05
All right. Well, Dr. Weil, Dr. Teague, thanks again for joining me. This was fascinating and have a good day.
