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Metabolism, Obesity & Psychedelics for Metabolic Disease | Christoffer Clemmensen | #105


Full auto-generated transcript below. Beware of typos & mistranslations!

Christoffer Clemmensen 4:11

scientific detail you go into oftentimes so and that's also why I enjoy listening to it because I actually feel like I learn a lot because many of the topics are outside of what I do. So I've learned a lot, especially pertaining to psychedelics. So for me, it's been very useful.


Nick Jikomes 4:25

Oh, great, great. Well, I'm glad I'm glad you listened to it and you like it? Do you want to just start off by just telling everyone a little bit about who you are and what your lab does?


Christoffer Clemmensen 4:35

Yeah, yeah. So. So I'm Christopher climpson, and I'm an associate professor at University of Copenhagen in Denmark. And I run an academic lab at the it's called the Novo Nordisk Foundation Center for basic metabolic research. And in my lab we're predominantly interested in in two things


One is to study and hopefully learn something about the biological mechanisms that regulate bodyweight. And then to take advantage of and exploit such insights into designing and developing new pharmacological strategies for weight loss or weight loss maintenance. So those are the two key focus areas of my lab.


But it's very, I mean, it's very basic oriented research profile we have so so we don't do we do a few human intervention studies, but we predominantly use experimental animals for for work.


Nick Jikomes 5:39

And, you know, you do a lot of stuff that's related to feeding behavior and weight and obesity. And obviously, I think everyone knows that, you know, obesity has been a growing problem across the globe really, for quite some time now. Can you just give us a basic technical definition of what obesity is and how that is measured?


Christoffer Clemmensen 6:01

Yeah, so. So when we talk about obesity, and in academic literature and clinical practice, etc, we typically use the body mass index as a measure of BC it's a relationship between our, our height and our body weight, and it's very crude measure. But at the population wide, kind of level, it, it's very useful measure also, because you can get a lot of data from from hundreds of 1000s of individuals, because it's quite easy to measure people's height and weight. But it doesn't say much about the level of actual excess adiposity of body fat or level of fatness. So you can imagine a relative muscular individual will have a high BMI or body mass index were but could still be relatively lean with respect to the level of adiposity so that's one of the caveats with this with this measure, but it's very useful at the at the kind of population wide level and and, and it also basically go goes on to show that we can easily see from those type of data that the rise in BMI has increased or it has been dramatically increasing over the last decades in in in more or less all countries across the globe. So, that is the the typical measure we use when we look at when we talk about obesity and then many studies when we when we study weight regulation obesity, we typically use bodyweight as as a primary measure. And then if we have access to different ways of measuring it will, of course also use fatness as as a more direct measure of adiposity or body fatness.


Nick Jikomes 7:54

So it's a fairly crude measurement. And it sounds like on the one hand, it is it's very convenient, because all you need is someone's body weight and their height very easy numbers to get. And it can tell you give you a general sense of whether or not they're likely to be obese or not. But for an individual, you would want to get more precise measurements about their actual level of adiposity that the actual fat content of their body, how muscular they are, and so forth to get a more sort of pinpoint accuracy readout of their metabolic health basically.


Christoffer Clemmensen 8:26

Exactly, yeah.


Nick Jikomes 8:28

And so obesity. You know, there's been some talk recently about how how we talk about it and what it is, is obesity considered a disease, or is it something else? Like what what is it in that sort of clinical nomenclature?


Christoffer Clemmensen 8:45

So that that's a very good question, and I'm not sure I can, I can answer it, but I can give it a try. So it depends, I think, if you talk to the Danish health, Danish health care system, I think they wouldn't agree to that it is a disease, but it's a disorder. That means that it predisposes to disease, but in and of itself, it might not be a disease. But according to the US healthcare system, it might be characterized as a disease, or at least you're kind of the FDA that that is responsible for, for approving drugs for a variety of diseases in the US have at least approved specific drugs for treatment of obesity, per se. So in that regards, you can say that it is it is by some healthcare authorities being characterized as a disease but it's, it's it's heavily debated and I guess they are. They're arguing arguments in both claims that I think can be viewed as as relevant. But I think there's no doubt that excess body fat is especially associated with a variety of, of, of severe adverse effects and, and highly predisposes for a large number of other chronic diseases, then, but if Obesity is a disease in and of itself, I think that that is still debated.


Nick Jikomes 10:31

Okay, so you know, people debate whether we call it a disease or disorder, but having excess body fat certainly predisposes you to a number of negative health outcomes. And I'm sure we'll talk about some, and you know, this phenomenon that everyone can see around them of obesity becoming more and more prevalent over time, I want to get you talking a little bit about the causes of obesity, and it'll be sort of a vague question, and I'll sort of let us take the conversation wherever it goes. But you know, when we think about what causes obesity, or just weight gain, generally, you know, we can talk about, obviously, diet, composition, the composition of your diet, as well as the total number of calories you're consuming. Obviously, physical activity levels are relevant, how active are you? How much are you moving your body? And there's also psychological factors that people often talked about, right? Like how much willpower or motivation you have to exercise or to regulate your diet. And then lastly, maybe, you know, there's what we can just call like, intrinsic biological differences between individuals, you know, different people have different genetics and different metabolism, or enzymes, you know, don't all work exactly the same way and so forth? Can you start to talk to people a little bit about how you think about all of these factors and how they interact? And you know, if any of them are particularly important?


Christoffer Clemmensen 11:47

Yeah, so that's, of course, that's a big topic. And it's, it's one of the things that's clear, when you start diving into the, to the causes of obesity is that you need to cover a variety of, of different fields of expertise. So you have your epidemiologist, and you have your you have your cell biologists and pharmacologists, and etc. So it's a tough topic, because it's very complex, right. So just one example is the, the contribution from social socio economic factors. So there's a huge contribution from from socio economic factors to obesity predisposition, and that's clearly a super complex component to study. And on the other side of the coin, you have your genetic factors that it's been estimated, for example, from family and twin studies, etc, that the genetic component of our variability in body weight can be ascribed to up to 70%. So you have your genetic contribution, they have your food environment and your environment in general, including mental health, upbringing, socioeconomic status, education. And in some complex interaction between all of these, all of these components, we develop certain, a certain body morphology, body weight, and a certain amount of, of body fat mass. So it's to a large extent, genetically predisposed, but it's in the face of the environment we live in that we kind of realize that genetic predisposition is for many other traits. So so in that way, it's I mean, that's the that's the easy explanation, right? It's it's complex interaction between our genes and the environment. But that seems to also be the truth for for the development of, of obesity, or the variability in our body weight.


Nick Jikomes 13:49

And what about, like, some of these intrinsic biological differences between people in terms of how their basic metabolism is working? And, you know, what I'm thinking about here is, I think we've all we've all had experience in our lives, you know, seeing people that we interact with and stuff, where there's certainly some people who don't put on that much weight, they don't have to work very hard to not worry about obesity, or things like this. And there's other people who work really hard. They, they're, they're careful about their diet, they are trying to exercise as much as possible, and they still struggle with weight gain. And it's striking that for some people, it's relatively easy. For some people, it's very hard. And for many people, there's somewhere in the middle. But you know, do we know what's kind of going on there for why some people are naturally lean and less prone to weight gain and why some people can put on weight very, very easily, even when they're consuming a diet and they're active that that would not make other people obese.


Christoffer Clemmensen 14:45

We don't know. But those are the most, some of the most interesting questions in the field that you're you're alluding to here. So So even in the most obesogenic environments or environments where a large degree of the adult population is obese You have individuals that remain remarkably slim. So why is it that some individuals are capable of staying very skinny or slim in this obesogenic environment? Are they equipped with a superhuman willpower? Or do they have genes that favor their preference for certain foods? Do they have a really sensitive satiety system? Meaning that they become extremely full or saturated quickly? Or do they have like a super powerful or hypersensitive reward system that makes them completely unreceptive to rewarding stimuli that are all around us? Right, so So those are I think those are fair question to, to ask. But the essence I think those are also good examples with this, the conundrum between these obesogenic environments and, and, and, and individuals that that remain slim. And conversely, you also have individuals that are very prone to develop excess adiposity in environments where there's perhaps not where there's relative food scarcity or where there's not a high abundance of energy dense and hyper palatable foods. So we see both ends of the spectrum. And I think that exemplifies the interaction between our genetic predisposition and the environment. So I think the genetic process predisposition we must not underestimate in the variability we see in weight phenotypes amongst us. And it seems as if most of us so we can say, like, estimate up to two thirds of us actually, into some extent predisposed to develop excess body fat. But but but the end of the day, it then depends on the environment that we were living in. And it's not only the food environment is also the the environment, the environment that we are brought up in, right, how we raised and, and and finally, it also adds to the complexity with the socio economic and educational aspects as well. Right. So So, so again, it's very vague answer, but I think it serves to underline the complexity of the of the biology also.


Nick Jikomes 17:13

So how much of this can we think of in evolutionary terms in the sense that, you know, for all of us, if you go back far enough in history in our evolutionary history, you know, we're descended from humans from animals that didn't have the kinds of food surplus that we have today that didn't have a choice oftentimes, as to, you know, when they could eat more or less, that was determined by the scarcity of the food in the environment. And it's sort of it makes evolutionary sense that you'd want to buy us an animal to accumulate fat in a natural environment where there's going to be, you know, periods of feasting and periods of famines that you can't always control. So, you know, it's sort of a safety, you could think of it I guess, as a safety mechanism, it's better to be biased to put on excess body fat, so that you can actually survive a period of famine or food scarcity than the opposite. And, you know, as far as I know, most animals, most mammals, at least, do often have that bias, right, I spent many years working with, with laboratory mice. And if you just leave them in the cage, and don't give them much to do, and they have all the food that they they can eat, provide it to them, you know, they will put on body fat, is that a reasonable way to think about it? Do we basically have that general bias in the population?


Christoffer Clemmensen 18:32

Yeah, I think that's, that's also that's a very interesting topic. So I generally agree to that the biological mechanisms that in prevent us from lowering our body weight, or from losing body fat, seems to be extremely powerful. So we talked about these homeostatic forces or homeostatic mechanisms, regulated by a region in the brain called the hypothalamus. They're very powerful in terms of preventing, basically missing a single meal mode for most people that that feels uncomfortable. I know it's been popularized with this intermittent fasting and alternate day fasting, etc. But most people will find it uncomfortable skipping a single meal, despite that they have storage levels of energy that can make them go for weeks, if not month, right. So there's no no stores danger with respect to skipping meals, nonetheless, we've evolved a system that immediately immediately somehow perceives this as a as an energy crisis or or organismal crisis if we start skipping meals. So so the system our defense system, against weight loss is extremely powerful, you can say, but then what about the other side of the spectrum and weight gain? So that's a topic that that we're actually also pursuing in in in I left and and there's some there's some I'm not saying there's some conflicting observations. So if we overfeed humans as well as animals meaning if we if we, if we make them go through exponential paradigm, where we introduce them to a controlled energetic surplus, so, we explore what are the energetic requirements for either human or an animal in order for them to stay weight stable and then we multiply this by a factor of 1.5 or two. So we introduce a laboratory control overfeeding experimental setting, then we can control a certain amount of weight gain, we can do this in rodents as well as humans. But at the moment, we then release or stop the overfeeding trial, we actually see the animals and humans lose weight back down again. So they found back find back to this homeostatic, oftentimes it's referred to as a setpoint. We can also discuss that that theory, but they seem to find back to the starting bodyweight level. And this is a little bit conflicting with this progression of obesity, we see it at at the more global scale. So why is it that we see as a species we seem to put on more more bodyweight fed fatness over years and decades, and but we still seem to be equipped with this biological defense system against control over overfeeding. So that is that is one of the things that we're trying to, to under understand that at the moment, but but I think it's, it's, it's fair to say that that mechanisms that prevent us from losing bodyweight, are more powerful or rigorous than the mechanisms that prevent us from gaining body weight. But we are equipped with mechanisms that actually prevent us from gaining excessive body weight and fat mass. I mean, there's nothing wrong in the modern environment, you'd easily be able to consume the double amount of energy in each meal. But there's mechanisms in place to prevent you from doing this. So you are, you do become saturated eventually. And if you always, for some reason go on eating frenzy on a holiday or something like this, you actually will most people will experience to come back climb back down again, even though they may have gained a few kilograms. But evolutionary to go back to your question. So there's I think, there's been some arguments against this sometimes referred to as the Thrifty Gene hypothesis that we've been our ancestors has been exposed to fair minds throughout our evolutionary history. And then this is push this selection, pressure genetic selection towards basically then eliminating genes that couldn't, couldn't survive in this condition. But But there's been some resources have made calculations based on this and have argued that if that was the case, then we should all be prone to be seen. If you calculate back how many fair minds we've been exposed to those, then we should have have out selected the genes. So we shouldn't, there shouldn't be 1/3 of the population that will be lean today, then. So that's one arguments against this Thrifty Gene hypothesis, at least.


Nick Jikomes 23:28

And so when we talk about these, these so called defense mechanisms that regulate satiety, that make us feel full and prevent us from eating, you know, even even more than than we do, you know, we could be eating even more than than we do. What are some of these mechanisms? What are some of the signals in the body that, that tell tell us to be satiated that prevent us from overeating? Even more than we do? And are they are these sort of motivational circuits in the brain? Is there stuff released from the gut into the bloodstream? What are some of these things?


Christoffer Clemmensen 24:02

So I think one of the most powerful signals is the most powerful signals are typically endocrine hormonal signals. And one of the most well known factors is a hormone called leptin, that is produced by the adipose tissue from dip asides in a in a quite tight relationship with the amount of adipocytes or size of adipose mass we have. And that signals serve to inform the brain about energy stores in the form of triglycerides and adipose tissue. So, that is quite a well characterized signal. And there are a few human individuals that are so unfortunate to have mutations in the gene that encodes for leptin or the receptor for which leptin interacts with in the hypothalamus of the brain and these in He has become morbidly obese unfortunately. So which also shows them the importance of this of this single single factor in the regulation of body fatness. So, one of the key functions of this hormone leptin is exemplified if you go on, if you've tried to calorie restrict to lose body weight, it seems as if the decline in circulating leptin is being perceived by the brain. And that will then promote excessive hunger but and also stimulate increased motivation. So it will also impact the mesolimbic system reward pathway to prioritize energy dense palatable foods. So you'd have some kind of food seeking behavior to replenish this energy deficit. And that's one of the reasons for why it's so difficult to to maintain them on certain dietary regimen independent of, of your diet, basically, because doesn't matter if you go in low, low carb or low fat or low whatever diet not to lose weight, eventually, a decrease in circulating leptin will be perceived by the brain as an energetic crisis. And that will then elicit a series of, of behaviors and programs towards basically eliminating this energetic crisis. So that's very powerful signal. But there's of course also a series of other endocrine signals including changes to thyroid hormone levels that are important for sustaining energy expenditure and we see also impacts on on a lot of, of the well known infrequent factors could be growth hormone excess, IGF catecholamines, and insulin, glucagon and some of the godparent peptides as well. But the God peptides peptides are generally more well known for the kind of effects in between meals. So they're more these kind of short term saturating factors that that works in the postprandial state or to eliminate meal meal alternative meals during during eating for example. And then, speaking about signals that prevent us from gaining excessive body weight those signals unfortunately or not, unfortunately, because it creates work for us but but those signals are not that well described. And this is actually what we're we're trying to solve right now are trying to understand what are the endocrine or hormone regulators of this overfed state that actually brings weight back down again, following a period of overfeeding. Typically, or many of these infrequent signals, then either coming from adipose tissue, the liver, the god, pancreas, and will typically signal in a subset of neuronal populations in the hypothalamus of the brain and or in the brainstem, and through feed forward mechanisms that will impact our behavior.


Nick Jikomes 28:09

So with Leptin is a hormone, so it's released into the blood by actual fat cells. And it sounds like it's, it's basically, you know, straightforwardly related to the fat levels in the body. So the more fat cells you have, the higher the leptin levels are. And it's assist satiety signals, so more leptin in the bloodstream means basically, your body is telling your brain and the rest of the body, we've got a lot of energy stored up, we don't need to be so worried about food seeking anymore. So we can, you know, put our resources towards other things we've got, we've got all this energy saved up in the bank, and it's released into the bloodstream, it traveled all the way to the brain, it is going to affect circuits that are involved in food seeking. And it's a hormone we use hormones all the time, we use exogenous hormones all the time, you know, human growth hormone, you know, any number of other things that people use for various purposes. So can't we just use leptin as as a treatment for obesity? Can't we just sort of inject people with leptin and there'll be less hungry?


Christoffer Clemmensen 29:12

So I'm pretty sure that that when the the group of researchers that discovered Lipson in 1994, they they they stumbled upon this discovery about well, it was actually decades of work, I'm pretty sure that that was their hope, or anticipation as well, that leptin would be as super powerful signal to imitate pharmacologically. But as it turned out, it seems as if the central leptin signaling is already to a large extent saturated, so it doesn't have much of an effect to add more leptin to the system because the receptor signaling is already at its max. And whereas it seems if the primary function of physiological function of leptin is actually in the lower end of the spectrum. So when you when your adipose tissue is, for some reason, the lack of perf anywhere about shrinking or if you somehow is in an energy deficit state. So the brain is more sensitive to sensitive to sensing lower circulating levels of leptin than it is to senses to perceive Higher, higher circulating levels of leptin. So I think that was perhaps a big disappointment at the time, but there was some early clinical trials with recombinant leptin in the late 1990s. But they were largely disappointing that it showed very little promise with respect to to to weight loss. So that was that was more or less discarded around the turn of the century.


Nick Jikomes 30:57

And is there an analogy here with something like insulin resistance, so you know, when you talk about diabetes, we talked about people being insulin resistant, so their bodies don't respond to insulin in the appropriate way. Because you know, something is metabolically broken, that prevents, prevents their cells from responding in in the way that they should, can something like that happen with these satiety signals like leptin, where the body is producing a lot because you've got high fat content, but it's just not getting where it needs to go, or the body loses its ability to actually sense it or something like that. There is


Christoffer Clemmensen 31:29

a large body of literature on that phenomenon, leptin resistance, but also resistance to a lot of other hunger satiety signals. I think it's still being debated whether that whether that's a scientific deep detour or not, given what I was, I guess, I was trying to explain to voice that it seems as if the leptin signaling is already saturated, and it doesn't, it's not because of resistance at the, at the central level, or the reception level, that it's not as if the hormone doesn't work. It just doesn't, it just doesn't help to add more. But there has been a lot of there's a large body of literature on leptin resistance. So and it's still, I think, an ongoing going topic for many, many investigators. So I'm not going to also disregard it as a whole. But I think this, I just subscribe to the notion that leptin This is more of a hunger than a satiety signal, meaning that it's the absence of leptin, that way, you see the most power of the logical effects effects, as opposed to the increase of normal levels of leptin, where you see very little physiological effects. So I think for me, that's at least the most rational explanation for the four first for that hormone at the time being, but there's a lot of interesting also, cellular and molecular work being done on leptin receptor signaling in the brain. And another research area that I think is interesting is the idea of empowering leptin signaling in the obese state. So, some people are trying to use poli pharmacology or combination therapy as a way of is there any way to empower enhanced leptin signaling, so you somehow can get more saturating benefit for for leptin signaling in in the in the obesity situation? I think that's still an interesting concept. But I think leptin resistance as an analogy to insulin resistance, I think it's it's not. It's not as clear cut as for insulin resistance and diabetes.


Nick Jikomes 33:42

I see. So instead of thinking about leptin as the signal, which just sort of linearly suppresses hunger, it's more like, it unleashes hunger when it's not around, you know, if you have some leptin, you don't need to be super hungry, but when it goes away, you better go find food. But if you've got some leptin around, and you just add more, that's not doing what we would hope it does.


Christoffer Clemmensen 34:05

Exactly. And that's supported by the genetic models both unfortunately, humans that suffer from leptin deficiency or animals have leptin deficiency these, they become extremely sick and and morbidly obese. So that shows the lack of the signal, this is really detrimental. But all the circumstances where we try and increase the signal, it doesn't seem to add much benefit.


Nick Jikomes 34:30

And so it sounds like there's thinking that there are other factors circulating in the blood, other endocrine factors, other hormones, potentially, that help regulate satiety and food seeking behavior, or weight gain itself. How do we what are some of these things or why do we suspect there are these other factors circulating in the bloodstream?


Christoffer Clemmensen 34:52

I think it's based on the work that has been done with this paradigm. I was I was trying to toggle it up pretty Stay with this over overfeeding experimental overfeeding paradigm. So, we've people have been been doing overfeeding studies from for many decades, a lot of studies in the 60s and 70s and 80s, where they've done prolonged overfeeding studies up 200 days of controlled overfeeding. You see in some extreme cases 15 Plus kilogram controlled body weight gain in these studies. But what is also apparent is that once you release, people from this control overfeeding studies again they lose body weight. And to my knowledge, it there's it has not been uncovered, what mediators of this post overfeeding weight loss what what the mediators of this response are. And I think there's evidence to suggest for especially from the road literature that it could be endocrine regulator. So it's a little it becomes a little bit technical, but some, there's these rodent studies that are termed parabiosis, where you basically join the circulation of two animals. So you make kind of a pair of cybernetic twin, red semis, so you stitch them together on the side. So they are, they're basically surgically connected in pairs, meaning that they share as blood circulation. So, all circulating hormones in animal a will travel to animal B and vice versa. And that system that enables you to examine if you do some type of intervention on animal A, and it affects animal B, this is likely due to some type of circulating component traveling from A to B. And those type of experiments has taught us a lot about endocrine regulation of bodyweight, and in context of overfeeding. It has been shown that if you overfit to overfeed one partner, you actually see the other partner lose a lot of body weight and fat mass in response to overfeeding of one partner again, suggesting that there's some factor released from from the overfed animal to the non overfed animal that then induces satiety and weight loss. And so in in my lab we've asked is, we study both this type of intragastric or exponential overfeeding in, in, in experimental animals as well as humans. So we, the way we go go about it is that we run these overfeeding trials, and then we kind of agnostically look at all tissues as well as circulating plasma. And then we expose it to these more kind of NOMID novel omics technologies that enable you to an unbiased and perhaps systematic fashion to characterize previously unknown signals that could be mediating this effect. So it's a combination of an old intervention with novel technologies that we hope can can help identify some of these circulating factors that we believe exist.


Nick Jikomes 38:13

I see so so one of the ways that we know that these circulating factors exist is you can literally surgically attached one mouse to another mouse almost like a siamese twin. And if you take mouse a and you overfeed it, and it starts to gain weight, the other mouse actually stops eating, which implies that something in the blood and the circulation is promoting satiety due to the overfeeding of the first mouse and then actually causes the second mouse to lose weight. Hmm, exactly. And so when we when you do experiments in mice, and you make them obese and you make them gain weight, you know, in the literature, you often read that, you know, mice mice were given a high fat diet. But I'm interested in a little bit more detail on what the diets are that drive weight gain most effectively in laboratory animals. Is it high fat, literally like high saturated fat or unsaturated fat? How does that compare to the protein and the carbohydrate levels? What you know, what macronutrients tend to cause mice are other lab animals to most readily gain weight.


Christoffer Clemmensen 39:15

So it's it's a it's a good question and and I think it's an important question. If you follow some of the oftentimes heated debates on social media such as Twitter, on macronutrient, compost composition or distribution and the effects on human health and body fatness. You see oftentimes the criticism of the rodent studies is that well they have completely different dietary preferences, genetic predisposition exam, which is also a postural and it is also true because the it seems if the the, the easiest way to get a mouse Fed is to is to end produce a, relatively a fairly high fat diet. So it's diet that oftentimes would have 50 to 60% of the energy coming from fat. Whereas I think for most humans, that would be probably too fatty of a diet, and it would not be the most palatable human diet. So to get an experimental animal fat, you'd give it a high fat diet of 55 to 60% fat, and the rest coming from a mixture of sucrose in turn, so that would constitute a carbohydrate and some some protein to to ensure that malnourished with respect to amino acids can still also grow. And then there's been done a very kind of rigorous study a few years back where some researchers basically did I think 20 Plus, if not more diets, where they basically did all these kind of micro adjustments to the to the macronutrient distribution and and concluded that it's a really high, high high fat diet that is the most kind of obesity promoting diet in experimental animals.


Nick Jikomes 41:11

I see. So it is literally a high fat diet that makes them obesogenic but there's also it sounds like there's enough protein for them to meet their minimum amino acid requirements, but it's not high protein beyond that. And there's also a sizeable proportion of that is carbohydrates, and in particular, sugar.


Christoffer Clemmensen 41:29

Yeah, so I think that the diet we use in my lab is called is oftentimes termed a high fat, high sucrose diet, it is hot, it is very high fat, it's 58%. Fat, but the carbohydrate in the diet is, it's comprised of sucrose. And in our hands, it's the diet that that is the most efficacious diet in order to render the animals obese as well as some of the other metabolic derangement that that follows obesity, including glucose intolerance, or pre status of diabetes, which we also like to study. So that is the most efficacious diet in our hands.


Nick Jikomes 42:23

Sorry, I was on mute. I want to hear more about your research to develop new tools to treat things like obesity and metabolic syndrome and things like this. But actually, before that, can you talk a little bit about what are the drugs that have been used or that are more more recently been developed? For things like obesity? I know I didn't look too much into it. But I know that there was something that was making a buzz recently about being a new anti obesity drug. Can you talk a little bit about what that was and how that drug works, and why we think that those mechanisms will be effective.


Christoffer Clemmensen 42:55

Yeah, so we talked about the failure of recombinant leptin to treat obesity around the year 2000 or so. And, and basically, up until very recently, we haven't had any effective weight loss therapies. But then it as it turned out, a subset of, of drugs that were originally developed for treatment of type two diabetes turned out also to have quite powerful effect on weight loss. And I think once the companies discovered that they started to optimize the weight loss and components of these compounds and and they are now being approved these years, I think they've one of them from a Danish company, Nordisk was approved in 2020, or 2021, by the FDA for obesity treatment, and we have Eli Lilly is coming out with a drug that's already approved for type two diabetes and now being fast tracked for obesity or weight loss. And these compounds are compared to what we've had previous extremely efficacious. So you see in a body weight loss of 15 to 20% is over one to two year treatment period, whereas previously, we had a difficulties to obtaining 10% weight loss with the drugs that we have available. And the adverse effects were also previously much more severe than what you see with this new class of compounds. So these new drugs, analogs of peptides that are coming from the gut, the gastrointestinal system. Typically they're built on a god peptide called glucagon like peptide one referred to as GLP. One we produce this endogenously in response and we secreted in response to meals but it's half life is extremely short, meaning that it's cleared by, by enzymes in its cleaved it by enzymes in the blood within a few minutes, meaning that we basically cleared following meals extremely rapidly. But the companies have succeeded in making really long lasting versions of these compounds by substituting some amino acids in the sequence. So they have half life that that makes them suitable for once weekly administration. So, peptides that are based on these peptide analogues of these gut hormones, GLP one, and then the Eli Lilly struck, it's a dual acting peptide on GLP one and another hormone called gastric inhibitory peptide, which is kind of accustomed to GLP one, so they may peptide that has dual acting effects on the receptors for both GLP one and tip, but there's a lot of resemblance between these these these compounds from these two companies. And this seems to really spreading also outside kind of academia and your normal practitioner, it seems as if it also goes into popular media. So you see a lot of celebrities praising these compounds now and and then I think that's an interesting topic to discuss, what are the implications of these apparently very efficacious compounds that are now entering the market?


Nick Jikomes 46:21

Yeah, so glucagon, like peptide, one, GLP. One, these drugs are similar to this peptide that's produced in the gut, what is the normal physiological function of GLP one,


Christoffer Clemmensen 46:33

so, the primary physiological function is glucose induced insulin secretion. So, in response to a meal, it fatigue it facilitates the ability of the body to, to, to absorb the nutrients or to to, to ensure that the nutrients are being are being taken up by the by the organs in relation to or are in agreement with insulin induced nutrient uptake. So insulin typically works on on liver fat and muscle cells. So an enhances the ability of insulin to act on these tissues basically, by by empowering insulin secretion. So its primary role is actually glucose induced insulin secretion. And its effect on satiety, then, I think it's debated how much effect endogenous GLP one has on satiety. But it's very, very clear that the pharmacological versions work in the hypothalamus and of the brain and the brainstem to elicit powerful satiety a lowering of food intake. So both rodent and human studies shows that these compounds, they just lower food intake tremendously. So so that's, I think, one of the one of I think one of the kind of happy, happy coincidences or the kind of the serendipity with this development is that, that the long acting versions are so powerful weight loss agents through their saturating effects in the brain.


Nick Jikomes 48:06

Okay, so, a major outcome these peptides and these drugs have is to cause more insulin release. So, okay, so, this is not my area. So this, this might be a very basic question. So these drugs cause more insulin release, and that leads to satiety doesn't just consuming more calories also cause more insulin release, and if so, that confuses me.


Christoffer Clemmensen 48:34

Yeah. So So these things are uncoupled. So the effects on glycemic control of glucose metabolism are through increased insulin secretion, that will then more rapidly remove the circulating substrates from the plasma and send them out to the respective tissues. But independent of the incident, the GLP, one directly works on GLP one receptors in the brain, which elicits powerful food intake suppressing effects through the same neurons that, for example, leptin work on these Pumpsie neurons in the hypothalamus and specific neurons in the nucleus of the solitary effect in the area. postrema. So GOP one in and of itself works on these appetite regulating neurons in the brain.


Nick Jikomes 49:20

I see. So GLP one goes all the way up to the brain works on circuits related to food seeking behavior and hunger in the brain and can satiety that way, in parallel to what it's doing sort of outside the brain and the rest of the body with respect to insulin and things like that. Exactly. Yeah. And so what I mean, what's your view on like, does the data for these drugs look as good as the internet buzz seemed to imply it was Do you have any, do you have any Are you cautious in any way about how well these drugs are going to work? Do you think that this is the type of peptide receptor interaction that's ideal? What Your basic thoughts on how well this could work.


Christoffer Clemmensen 50:04

I mean, they're working very well. And they've been tested quite rigorously over the last many years. So the predecessors for some of these drugs were developed by the same companies and have been around. The first one was approved in 2014. saxenda is directly tied, it's another GLP, one analogue. They work very well. And the adverse effects are I mean, they are for some individuals, on tolerable, but they are not, they're not severe as such. So the main adverse effects are nausea, and for some vomiting, and some reported this effect is trenchant whereas others have difficulties living with this, and then we'll have to discontinue the drug. But so far, they've been liberated from severe adverse effects such as development of, of, of other like, severe kind of disorder. So so so just, for example, some of the, the historical weight loss agents would have neuropsychiatric adverse effects or cardiovascular adverse effects. So that's a no go for new weight loss drugs. And these drugs seem to actually have positive effects on the cardiovascular system. So so they seem so bad, to be clear with that regards and weight loss of 15 to 20% is, is actually is quite sick, quite decent. One thing to keep in mind is that for these compounds, as well as other compounds, for example, drugs used to treat high cholesterol levels or blood pressure, etc, the moment you stop treatment, the weight will rebound again, so it's a lifelong treatment, it's not a cure, it's a treatment that will then counteract some of these homeostatic mechanisms to try to impose weight regain. So the body would somehow still be in a perceived energy deficit. But that is an activity being opposed by the drug. But once you then discontinue drug treatment, you will unleash this homeostatic defense system again, then the weight will rebound.


Nick Jikomes 52:23

One thing I want to ask you about so we've been talking about, you know, hormones and gut hormones that are relevant to metabolic health, and that have long been known to regulate hunger and satiety. I want to talk about a neurotransmitter that will help set us up to talk about some other stuff. And that's serotonin. So you know, people know serotonin first is a neurotransmitter in the brain. It's famous because of SSRIs, especially serotonin reuptake inhibitors that are used to treat depression. But as many people now know, there's a lot of serotonin in the gut. Serotonin does a lot more stuff than just, you know, regulate mood and aspects of brain function. It's doing stuff all over the body. And in fact, a lot of the side effects for many serotonergic drugs can include things like metabolic effects. And so can you give people just sort of a basic overview maybe of how serotonin starts to tie into things like metabolism and weight gain and feeding? I know that there's some relevance when it comes to things like nausea and appetite. And you know, how do you think about serotonin as a metabolism and, and obesity researcher?


Christoffer Clemmensen 53:28

Yeah, so it's, it's a good question. So it's not a topic that I have with activists will have access to assets, some of it but but it's, it's not. It's not a neurotransmitter that being that widely studied, there are some labs that are of course, focusing on this but I think one thing to be said is that there has been one drug on the market that have been working through serotonin to see receptors so one of the serotonin receptors and approve weight loss drops. So that clearly emphasizes that the serotonin system is important for weight homeostasis, and that isn't, I guess, that's has also been known for for decades. And I think another thing that I want to add in also, perhaps to discussion is the I think the clear interaction between oftentime psychiatric disorders or such as are drugs that you use, that we use to treat psychiatric disorders such as antidepressants or anti psychotic agents that they most often has quite powerful adverse effect on weight gain or weight loss. Most often it's weight gain, emphasizing the interaction between perhaps not deceived pathologies, but at least the drugs we we use to target. For example, the serotonin system seems to infant also energy homeostasis. So there's a lot of there's a lot of evidence for the involvement of the serotonin system in many aspects of, of energy metabolism. Yeah, so that there's at least some, some things to unpack there.


Nick Jikomes 55:18

And what kind of like Komori? What kind of psychiatric comorbidities do we see with obesity? So for example, we can think of obesity as purely a metabolic phenomenon, like there has something to do with satiety signals in the brain. And you know, the nuts and bolts of our cellular metabolism going off track somehow. But But I would imagine that there's a lot of overlap. On the psychiatric side, for example, someone might be overeating, not because their metabolism is broken in some basic way, but perhaps because it's a response to depression or anxiety or something like this. How do we start to think about tying those pieces together?


Christoffer Clemmensen 55:53

Yeah, and that's I think that's one of the important challenges in modern biomedical research is that we start to acknowledge that most of the diseases that we study is actually much more heterogeneous than we than we initially thought that that we that we're currently kind of acknowledging in the way we started them is that I think there are many origins of of obesity or weight gain. And for some individuals, it will have be a have a clear psychiatric origin, whereas for others, it will be a clear, clear cut kind of endocrine origin disruption in for example, leptin signaling, whereas other individuals that would have could have a mental mental underpinning that will lead to compulsive overeating or other kinds of behaviors that somehow is then driving some type of altered eating, eating phenotype. So I think that's one way of viewing it is that we need to be better to segregate the obesity etiologies, basically. And that's something that we're not very good at at the moment.


Nick Jikomes 57:01

I know that, you know, recently, you've started to look at things like psilocybin and tryptamine psychedelics, when it comes to their possible impact on feeding behavior and metabolism in mice. So can you describe what some of those results are? And why you even thought that that was a relevant thing to test? Like, why would I even gave you the idea to look at something like psilocybin when it comes to feeding behavior?


Christoffer Clemmensen 57:25

Yeah, so the I think the origin for this work, I'd have to go a little bit of detail, but I'll try and be be brief. And so we're really interested in trying to develop drugs or pharmacotherapies, that will have sustained or long lasting effects on bodyweight. So as opposed to the current therapies that once you stop treatment, you'll see weight regain, we'd like to develop some therapies where you kind of readjust this defendant level of body fat, we'd like to create therapies that enforces or renders the brain to defend a lower level of body fat and accept that as its new, quote unquote, setpoint. And how do we, how do we do this? So here, we kind of started to seek inspiration in developments within treatment of depression and addiction. And we noticed that some of the compounds that were emerging work, and antagonists of the NMDA receptors such as ketamine, and also serotonergic, psychedelics, and kind of commonality for this, it seems with very, not necessarily single administration, but with very infrequent Drug Administration, you'll see long lasting disease modifying benefits, suggesting that kind of synaptic changes to synaptic structure or newer structural components might be able to sustain these kind of changes over a longer period of time and a kind of our dream or vision was Imagine if we could do something similar to obesity or weight loss if we could impose new structural changes that will then materialize in the form of a kind of lower level of defended body fatness. So that was the starting point. And that, so we started extra exploring the NMDA receptor antagonist, and we saw some quite nice effects and we're continuing to develop this. So we've now actually use we've developed these peptides, small molecule conjugates, where we use discard peptides to target NMDA receptors specifically to brain regions of interests as a kind of Trojan horse strategy. So that's one of the key areas of work of the lab. But in parallel with that, we couldn't kind of let the idea go about serotonergic psychedelics. And and we were excited to think about kind of the the broad spread of blue traffic benefits of psychedelics for multitude of diseases and given some of the commonalities between a digital addiction like phenotypes and the Depression and obesity, we just went ahead and started to explore the effects of which is then selected psilocybin. And then we explored the effects of psilocybin on on eating behavior and Weight Loss Weight gain in mouse models of obesity basically.


Nick Jikomes 1:00:17

Okay, so the I guess the idea is, you know, if you, if you have an obese individual, you know, one way to think about what's kind of going on in the brain is, the brain has accepted one set point for what the body fat content of the body should be. And in this case, it's something that's too high, because it's going to have negative health consequences. So what you'd like to do ideally, is come up with an intervention that sort of resets the circuits in the brain, so to speak, so that the setpoint, for fat content is lower. And again, ideally, you'd want an intervention that makes that kind of reset in the brain, so that you don't need to chronically be administering a drug or something, and the person then just has a brain that can naturally regulate its own feeding behavior, without a continued intervention being necessary in the long term. So you know, the basic idea with these psychedelics. For many of the psychiatric applications, one of the remarkable things about them is that unlike other psychiatric drug treatments, they don't require chronic use, they're inducing some kind of neuroplastic change in the brain so that circuits are physically changing, then then you get effects that are persisting well beyond the administration of the drug. And so I think what you're basically saying is, you'd like to have a drug like that, with respect to obesity, because you don't want to be chronically administering something and you want the brain to be sort of reset so that it can then handle itself. Yeah,


Christoffer Clemmensen 1:01:43

exactly. So that's at least I think, ambitious goal or kind of holy grail within obg therapeutics to develop, it will be a cure basically. And, and it sounds a little bit maybe over ambitious, but I don't see why we shouldn't try and pursue this and, and I think the devils in the detail, I guess, also probably, you know better than me, but for the psychedelics, it's also not necessarily want one treatment, then your cure for life, it could be perhaps less frequent treatments over a period of time or some type of combinatorial therapy either with could be co administration of another drug, or it could be also psychological counseling. And I don't I think I think we must be open to these type of, of other interventions for each treatment. It's great that we have these new drugs in the market, but I I think we shouldn't stop innovating at this point, we must really continue to try and and and continue to develop more therapies also, in parallel with acknowledging the the heterogeneity in the disease origin, right. So there will not be one size fits all in terms of weight loss treatments. And I think the final argument for this could be a viable strategy is the effect of the bariatric surgery. So the obesity surgeries, we haven't talked about those, but they are remarkable in the sense that they seem to have this effect on readjusting the homeostatic level of of defended body fatness, or or the setpoint, if, if we should call it that. So that that's at least one type of inspiration and something to aspire to mimic that effect with a with a pharmacotherapy. So it's single intervention that will have the sustained effects on lowering on lowering this defendant level of body fat.


Nick Jikomes 1:03:36

Out of those surgeries work. Are you talking about the surgery where they basically go in and make someone's stomach smaller?


Christoffer Clemmensen 1:03:41

Yeah, so it's either the most well known or most widely applied surgeries or they ruin why gastric bypass is a rerouting of the gastrointestinal tract or vertical sleeve gastrectomy where you basically make the stomach smaller. So I think historically, the idea was that they work because it's a physical restriction. But nowadays, it's it's widely accepted that it's not the case, they actually work because they have influence on the secretion of some of these aforementioned God peptides. So they seek to influence a long list of, of signals that are rising from the gods. So in response to so basically, you have some type of readjustment of the gut brain axis and the communication between the gut and the brain. And that works basically, quote, unquote, miracles in terms of weight loss maintenance. So that's really exciting. And I think there's been work trying to really dive into the details of this over the last 1015 years and there's been made some headway but but I still think we need to fully understand how they work so effectively, but it's not by just the physical restriction of the God I think that's, that's clear that that is not the driver of the effect. It is probably the Through metabolic or endocrine mechanisms?


Nick Jikomes 1:05:03

And And do we know of any metabolic effects or effects on feeding behavior that that psychedelics like psilocybin have? Is it affecting in a setting when measured, you know, changes in gut hormone secretion or food intake? And what do we know about that?


Christoffer Clemmensen 1:05:19

Yeah, so we tried in, in our in one paper we published in 2022. And I think I believe that's the first paper of its kind, at least we couldn't find the other manuscript, we tried to do a very comprehensive and broad characterised characterization of at least psilocybin and its effect on animal physiology, and metabolic regulation. So we examined the effects of both micro dosing and single high dose administration in generic models of obesity, dietary models of obesity, models of pharmacology induced weight, regain diet induced weight regain palatable diet preference. And so we tried to basically create a whole bunch of behavioral and physiological tests and then do a broad kind of characterization of, of the effects of psilocybin on these parameters in the mice. And somewhat disappointingly, we didn't find much in the mice, we saw that it had, by convincing effect on lowering sucrose preference, which is sometimes used as a kind of


kind of hedonic feeling test. But I also have I mean, I don't know if it's very surprising. I mean, if we,


if we believe, I don't know if but what is the driver of the benefits of psychedelic therapy in humans? I mean, do we need the psychedelic experience? Or is it part of the we need this highly evolved prefrontal cortex to have the false full clinical benefit? If so then the rodents a really poor model for studying this. So I think, to my knowledge, there's been no data to find with respect to psychedelic therapy in humans and exploring, eating behavior, weight regulation, or anything like this. So I think it would be extremely exciting to do a human study, perhaps with a binge eating disorder type of setting and explore the effects of a psychedelic drug and that disorder.


Nick Jikomes 1:07:29

Yeah, interesting. So what kind of things are you guys working on today in the lab? What are some of the big questions that you're pursuing right now?


Christoffer Clemmensen 1:07:36

Yeah, so I've already touched upon a couple of those. So one of them is, is this targeting of the post synaptic plasticity in order to introduce sustained effects on bodyweight through pharmacological means, and we studied the molecular biology of neuroplasticity, in order to better understand what are the targets we want to go at pharmacologically? So we're really interested in studying kind of the nitty gritty of synaptic connectivity in these brain regions that are important for appetite control, hopefully trying to come up with kind of next generation weight lowering pharmacotherapies. And that is one big focus area. And then we really, we really excited about this overfeeding intervention. And we really believe that that whole, it could hold promise to identify unknown circulating factors or hormones that could be also mimic pharmacologically that we don't have to mimic them, but at least uncover aspects of energy metabolism or energy homeostasis that, that we don't that we don't know, as of now. So we really, we believe that the combination of these overfeeding intervention with new methodologies could really, yeah, unveil some some new insights into energy homeostasis. So those are two primary areas of focus that that we're really working on in the lab, and then we have a series of other side projects, but those are the the main focus areas.


Nick Jikomes 1:09:11

And so as someone who, you know, your whole career is studying obesity, and metabolic health and all this stuff, has, how has your work and your studies over the years influenced your own your own life in terms of you know, Have you have you changed your diet at all based on stuff that you've learned? Are you very particular or disciplined about about certain aspects of your own metabolic health? You know, how do you think about all this as as a scientific expert in this stuff?


Christoffer Clemmensen 1:09:41

Yeah, I don't I mean, of course, I'm the scientific guy. I mean, it's, I think about the science of obesity from when I wake up to when I go to bed, so of course, it somehow is also there in context of my own life. I think it actually, because I don't know if maybe it's an excuse, but because I believe in the role in, in the fact that genetic susceptibility and the environment and positioning plays such a big role in, in my food choices and my eating patterns and how I live my life, I acknowledge that I'm just kind of a slave to society that's, that I'm surrounded by so I think I eat completely, completely normal. And I, I tried to Pro to prioritize healthy eating, and I try to stay active, but I think that's what most people people do. But I think we, in general, I think we overstate the role of, of the individual and the individuals kind of idea about who you are, and how you want to impose self control or willpower over your own life, and underestimate the power of the biological mechanisms that, that come into play when, when we in terms of eating and weight regulation.


Nick Jikomes 1:11:14

One thing I want to ask you to is, so when you when you talk about experimental animals, so you're studying mice, or rats or something like this, if you give them that high fat, high sugar diet that we talked about before they will put on weight, they can become obese. What are the best ways in lab animals that they lose weight? To what extent can that be driven purely by giving them like an exercise wheel? or to what extent does another diet get them back to their starting weight? And if so, you know, what is the composition of that diet?


Christoffer Clemmensen 1:11:45

Yeah, it's good question. So, one thing we joke about quite often is we've cured mouse obesity, 1000s of times. So it's, it's quite easy to cure based in the mouse, because they actually extremely sensitive to these gut hormones we talked about before. So if you give them one of these modern drugs, you can more or less cure their obesity, but it's the same as with humans wants to stop treatment. And if you, if you maintain them on this high fat, high sugar diet, they will go back up again. But they're just a little bit more sensitive to the pharmacology, perhaps because we can dose higher. And if you give them an exercise, we'll you will see a change in body composition, you will see a decrease in fat mass, perhaps an increase in lean mass, but they will, you will not spread a lot of adipose mass. So So as for humans, exercise is good for more or less everything you can think of, except for lowering your bodyweight. So it has, I mean, there's so much evidence that exercise benefits, more or less, all types of chronic disorders, except it's very inefficient for weight loss. Same goes for lab animals, and you can maintain them on a high fat high sugar diet, and then you can switch them to this boring Chow road child either lose a lot of weight, because again, it's their genetic sensitivity in the environment, we position them in. And if you they just have access to one diet, they somehow they actually capable of, of lowering body weight compared to on the high fat diet. But if you then reintroduce a high fat diet, they will go back up again. So in some ways, they're quite good. The mice and rats are quite good model for for studying human energy metabolism. And they're at least they're much more predictive than for studying your typical brain disorders. So neuro psych, psychiatric disease, etc. With them, they have much less predictive value, right?


Nick Jikomes 1:13:41

So so you can make an obese mouse, you can give it one of these drugs that we've spoken about, and they're actually highly effective. So you will cure the obesity effectively meaning specifically that the weight of the mouse will go down. My question, my next question is, what if you just do that persistently. So for an extended period of time you take a formerly obese mouse, you give it the anti obesity drug, which mimics some of these gut peptides, and its weight goes down, but presumably, it has the same diet available to it. They might be eating less, but it's still eating that high fat, high sugar diet. In other words, the mouse can persist in its eating habits, maybe eating less overall, with this drug doing what it does, I would imagine that the mice still have maybe some metabolic issues that come from continuing with that high fat, high sugar diet. Has anyone looked at that and seen, you know, other aspects of metabolic health and what happens to them in the presence of of taking this drug?


Christoffer Clemmensen 1:14:40

Yeah, good point. I mean, if you wait match a group of animals on a healthy child diet versus a high fat high sugar diet, so the medicine bodyweight, I would assume that we'll be able to detect some metabolic defects in the animals that are maintaining the high fat high sucrose diet will probably be a little bit less instance sensitive, they may have hyper slight hypercholesterolemia and some other defects, I would, I would be pretty sure that we would see that effect I can, on top of my mind, we call someone having done this type of study, but I would be certain that that that would be the case. So there is an direct effect on a very unhealthy diet compared to a healthier diet, in the weight meds condition, at least in the road. And I think we'll be able to see that.


Nick Jikomes 1:15:30

Yeah, I mean, my concern with some of these new drugs would simply be that, you know, if they're very effective at the weight loss component of this specifically, you know, that's, that's great. But what if, you know, we're just sort of enabling people to persist in the eating habits that caused the obesity to begin with. And so now we're just sort of paper papering over the problem where they might eat less, and they might lose that weight, which is a good thing, but they're still eating the same diet composition that that caused the problem to begin with. Is there any concern about that?


Christoffer Clemmensen 1:16:02

So there's good point, I think, in general, the, there's some evidence that the compounds also effect macronutrient, or eating preferences to one healthier diet. But on the other hand, you can also imagine a circumstance where you introduce a compound to two individuals that live in an environment where they mostly have access to to fast food, restaurants, and then they'd have to eat less of that fast food as compared to what they've normally do. So you can imagine that you could see a state of malnourishment or malnutrition, insufficient intake of vitamins, minerals, etc. So that I think that's a fair kind of caveat to invasion. But I think in general, you there's the reports that people actually prefer healthier choices when they are on the drug.


Nick Jikomes 1:16:58

Have people are looking at food preference shifts in response to this GLP, one drug in rodents? And if so, what what are those?


Christoffer Clemmensen 1:17:05

And there are few studies, I think, in general, in rodents, you typically see changes in macronutrient preference from the top of my mind, I would, I'm pretty certain that you see a decrease in the preference for fat given that that is most preferred, macronutrient enrolls at a slight increase in protein and carbohydrates. But I'm not 100% Sure, but it has been done with with many of these drugs and these type of macronutrient preference essays in rodents,


Nick Jikomes 1:17:36

I see so so based on the information we have now, it's not simply that these drugs are decreasing the amount of calories consumed, they also seem to be inducing a shift in the macronutrient preference things that you want to eat.


Christoffer Clemmensen 1:17:49

Yeah, yeah, I mean, eventually, eating, I mean, to translate the sensation of hunger has to be, you have to go through motivation and actually locomotion in the end to realize this. So. So the hunger satiety circuits are heavily interconnected with motivation and reward. And, and and it's similar circuits, ex executive circuits in the brain, right? So there's interconnectedness between these circuits. So I think anything that would stimulate kind of canonical hunger in the hypothalamus would also have an impact on increasing the food motivation in an animal and the preference for energy dense, palatable foods as well. So that's typically highly interconnected. I suppose that when you if you suppress this, this pathway, you also likely to suppress kind of the preference for these type of hyper palatable foods,


Nick Jikomes 1:18:45

as well. We talked about a lot already. Is there anything that you want to reiterate or touch on? Before we go?


Christoffer Clemmensen 1:18:55

I'll probably come to think about a ton of things afterwards, but I guess it'll be too late. No, but their worst case or best case, we will have to do a follow up.


Nick Jikomes 1:19:03

Yeah, for sure. Uh, do you want to maybe just leave people with you know, what's, what's a really exciting question that your lab or other labs are pursuing right now with respect to obesity and metabolic health? That is a major question that we don't know the answer to right now, but you think we will understand in the next few years


Christoffer Clemmensen 1:19:22

Oh, wow. And I guess I'm most absorbed by how the brain defends these different levels of body fatness. What what what is it that that that makes the brain for Person A defend 150 kilogram body weight with I don't know 70 kilo grams of body fat. Whereas for Person B defends a very very lean phenotype and why is it so difficult to to readjust this defender level of body fat although it being pathological for for one individual I think that that, but that has I guess that has has been a topic of interest for many decades. So I probably probably won't be solved within a few years. But I think that that's still is the what fascinates me the most is this kind of homeostatic defensive of body weight and body fat.


Nick Jikomes 1:20:18

All right, well, Professor Clemmensen, thank you for your time. Thank you

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