Gut-Brain Communication, Vagus Nerve, Fats & Sugars, Food Addiction, Gut Hormones & Weight Loss Drugs | Will de Lartigue | #143

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.

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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