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GLP-1, Weight Loss Drugs, Ozempic, Obesity, NMDA Receptors, Metabolism & Brain Health | Christoffer Clemmensen | #161

GLP-1, Weight Loss Drugs, Ozempic, Obesity, NMDA Receptors, Metabolism & Brain Health | Christoffer Clemmensen | #161

Download, watch or listen to M&M episode #161

About the guest: Christoffer Clemmensen, PhD is scientist running the Metabolism & Molecular Pharmacology group at the University of Copenhagen in Denmark. His lab studies the biological basis of obesity & other metabolic disorders.

Episode summary: Nick and Dr. Clemmensen discuss: GLP-1 & gut hormones; obesity & metabolic disease; GLP-1 agonists and weight loss drugs (e.g. Ozempic); novel, dual-action weight loss drugs his lab has created; and more.

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

*This content is never meant to serve as medical advice.


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

Christoffer Clemmensen 2:25

Thank you for having me on once more.

Nick Jikomes 2:27

Can you just remind everyone, especially those that did not already listen to our first conversation from last year, who you are and what your lab studies and what you guys are interested in?

Christoffer Clemmensen 2:39

Yeah, so I run a lab at the University of Copenhagen in Denmark at the so called no Nordisk Foundation Center for basic metabolic research. And we can already kind of

And my lab is currently I think, comprised of 14 or so individuals, some mixture between bedstraw master's students, PhD candidates and, and postdocs.

And next to that, I have a small biotech company, where we also try and develop further develop or commercialize some of the things that we worked on in the academic lab in collaboration with the University of Copenhagen and the kind of this technology transfer unit at the university. So a lot of lot of stuff going on.

Nick Jikomes 4:25

In your view, what causes obesity? Is it all about energy balance? Is it is it exposure to contaminants in the environment? What are the major drivers of obesity?

Christoffer Clemmensen 4:39

That's a tough opening question. And I think the best the safest short answer is we we have no clue right now. I think that's and that's kind of interesting. If you look at also some of the the kind of summarizing review work that is coming out these years. I think the As researchers are more and more open to newer theories, as opposed to just 510 years ago, where it was kind of oftentimes more clearly stated that the modern environment with its readily available, highly palatable, energy dense, cheap. Food is the primary driver of the modern obesity epidemic, it must be right. But then there's evidence coming in kind of suggesting that it may be more complicated than that. In which includes, I mean, there's a variety of different work here. And you've also had I think, John Speakman on your podcast, who has done work in on basal metabolic rate, using doubly labeled water over decades to show that there seems to have been a quite weird but interesting, sudden decline in in basal metabolic rate over the last 30 years or so. But actually no decrease in in energy expenditure from physical activity, which is a little bit counterintuitive. What we oftentimes say like that, it's the decrease in physical activity. And at the same time, they've done work showing that it's, there's no obvious correlation between the density of fast food, full service restaurants and obesity numbers. So there's kind of these pervasive ideas that it's the it's fast food and its lack of physical activity that is driving the epidemic that is not necessarily 100% supported by evidence. So I think I mean, we must acknowledge that something in the modern environment, but but it's not necessarily I think, exclusively something to the food environment, but a combination of factors at least. And that's the safest answer, right? Something in the modern environment. So it's the same kind of teen environment interaction, right. But there's definitely something with the modern environment that is very, that has very negative consequences in the interaction with our genome that elicits that many of us develop excess body fat mass. Yeah, like narrowing it, yeah, narrowing it down further than that is really, really, it's really difficult. Yeah,

Nick Jikomes 7:08

I think, you know, from talking to John Speakman, and Robert Lustig and a bunch of other people on the podcast and thinking about this, you know, to sort of re summarize and build on what you just said, you know, the naive, the naive assumption or explanation for what causes obesity is, well, we live in the modern world, we have a surplus of highly palatable, cheap foods, people are simply eating more calories, and they're moving less, right. So we're lazier and we're more indulgent. Therefore we're getting bigger. But as you pointed out, and as others have pointed out in different ways, that can't be the full picture. Because actually, we're not moving less than we were a few years ago, we're actually moving a little bit more, and our metabolic rate is going down. And no one really knows why. And we're actually not, you know, we're not all eating more than we were 510 1520 years ago. So the eating more moving less hypothesis can't be the explanation. Certainly the amount of calories we eat, the types of calories we eat, and other things in our environment have to feed into the explanation for why obesity is moving in the direction that it has been. But the simplistic answer that most people would think of from a common sense perspective, we're just eating more moving less is known the explanation we know that for sure.

Christoffer Clemmensen 8:27

Yeah, and at the same time, it also kind of conflicts with this notion of that body fat mass and body weight is homeostatic ly regulated right? So if we, if we trust that we are equipped with these homeostatic systems that ensures a stable body temperature, stable blood pressure, water salt balance, they actually also similar mechanisms in play right to ensure that we have stable body fat mass and bodyweight so most of us are some of us go through our lives, decades without counting calories or worrying about how much we exercise. But our body weight is remarkably stable, right? So many of us can rely on this kind of on these homeostatic mechanisms to ensure that we match our intake with expenditure. But still, then there are now individuals then that develop obesity. So there's something what is it that the environment that triggers this sudden imbalance that overtime develops to become a quite large expansion of body fat mass? I think that's still a mystery, right?

Nick Jikomes 9:23

Yeah. I mean, so so, you know, as you said, body weight and food intake, these systems in the body, just like other systems in the body are homeostatic, ly regulated. So we normally normal animals, most people for much of their lives, don't have to think about this. Right? The the sort of, sort of cartoon model I think the average person has in their head is, oh, well, you're metabolically healthy when you're young and then at some point, you become quote unquote, old and your metabolism quote unquote, slows down and then you start gaining weight. And that does in fact happen for a lot of people but a it doesn't happen for everyone, be it have different people at different times. See, it's starting to happen even for children more and more. So it's not like you just get old and magically, you're supposed to just start gaining weight at some point, it's that these homeostatic mechanisms are becoming broken at some point. Due to, you know, XY and Z, and we don't know exactly what is breaking them, or what causes them to break when you're 40 years old, or five years old. No,

Christoffer Clemmensen 10:25

and then adding to the complexity is something that we oftentimes put in different books that by apology, and that's the socio economic status. So if there's one predictor, if I, if I were to ask people about one thing, in order to predict their body, my body weight or BMI, I could only ask one question I would ask about this, their socioeconomic status, basically, I guess that's two questions, education and income. And that is by far the best or worst if you want predictor for your bodyweight. So there is again, something with our income and education that predicts whether we have a higher risk for developing obesity. And then again, how does that fit with this idea of homeostatic regulation. And then even in the, in the areas of the world where we have the highest prevalence of obesity, you still have individuals, despite the lift surrounded by by people in their family and the friends have a BMI of plus 35, there are individuals that are completely lean, without worrying about or thinking about their body weight. So they have they're wired differently, right in terms of homeostatic protection or defense against their weight. So yeah, their complexity is, is, is very large.

Nick Jikomes 11:40

We're going to spend a lot of time talking today about some recent research that relates to these new and very popular weight loss drugs, these anti obesity drugs like ozempic. And these are GLP. One, drugs. And I want to start out by giving people a sense for some of the basic biology around GLP. One here. So to start, can you just describe what is GLP? One? And what is it doing endogenously in our bodies? Yeah.

Christoffer Clemmensen 12:06

So GLP one is one out of several hormones that are produced by our guests, gastrointestinal system. So it's produced by a cell type called the L cell in the in the gut. And, and typically, these hormones, they are peptide hormones, meaning that they're a specific size in terms of the they have a specific number of amino acids. They're produced in response to ingestion of meals, right, and they are sensitive with respect to macronutrient, and even macronutrient micronutrient distribution. So we know that historically, they were discovered for glucose ingestion, you see secretion of this glucagon like peptide, one GLP. One, and it was then identified that this would affect them be the cells of the pancreas to stimulate insulin release. So the first kind of loop discovered in the middle of the of the of the 80s was that glucose ingestion elicits GLP, one release from the God that signals in the pancreas to potentiate insulin secretion, so we can remove the glucose from the plasma. So it's a part of kind of this glucose regulating endocrine system. And so this was referred to as the incretin effect. So that means if you give the same bolus of glucose orally, versus intravenously, you'd have a much, much more pronounced insulin response to the oil load, because you get the effect of an increase in hormones. And by the increase in hormones are comprised of the GLP. One, and it's closest gap. So So these hormones were identified in the 70s, and 80s. And in addition to GOP one tip, the most well known cloud hormones are peptide yy, PY y or this hormone called neurotensin, CCK. And a few other more well known peptide hormone secreted from the gut in some type of mixture in response to ingested meals, right. And so the endogenous function is typically referred to as this incretin effect, to potentiate insulin secretion so we can remove nutrients from the bloodstream and get deposited into a muscle and fat and liver tissue typically.

Nick Jikomes 14:34

So every time we eat, basically a cocktail, different hormones get secreted, and they're meant to affect different tissues in the body so that our body can effectively utilize whatever it is we've we've put into it. So if you eat a meal with one nutrient composition, and then a meal with a different nutrient composition that might necessitate higher or lower levels of glucose uptake. ache or other nutrient absorption. And so when everything's working properly, these gut hormones get secreted in some combination that's suited to enable our bodies to uptake what we've actually ingested.

Christoffer Clemmensen 15:11

Exactly, yeah.

Nick Jikomes 15:13

And so, so GLP, one has to get secreted, and then it has to activate GLP one receptors, where I'm assuming that these things are located on many different cell types and tissues throughout the body, what are the major tissue systems that respond to GLP? One that express the receptor.

Christoffer Clemmensen 15:30

So initially, we were we were building we've been focusing on the on the endocrine pancreas that have these in they have these islands of endocrine producing cells that produces insulin, the betta cells are glucagon the Alpha cell, and they are decorated with these GLP one receptors. So that's also why this well known effect on insulin secretion, it has been been early characterized, then there are also local neurons sitting in the proximity or vicinity of actually where the where the peptide is produced in the gut. So for example, vagal nerve, projecting to the to the brainstem, probably picking up locally produced GLP one signals and transmitted through nerve signal directly to the brain. And then this GLP one receptor is pretty densely expressed in the hypothalamus of the bottom of the sitting just around the third ventricle of the brain and the bottom of the brain, and also in the brainstem, where the vagal nerves predicting around these two nuclei called the area postrema, and the nucleus of the solitary tract. So So, especially specifically, in the context of obesity and diabetes, it's the GLP one receptor is expressed in the hypothalamus and the brainstem, we're interested in and in the pancreatic beta cells for the insulin secretion. And then it's expressed to a lesser extent, in in, in other in other tissues, and we continuously try to kind of discover kind of smaller, or more subtle levels of expression on other facsimile, immune, immune, a type of cells, etc, to try and understand what effect the peptide can have on other cell types and systems. But mostly, it's expressed in the beta cells of the pancreas in these two areas of the brain,

Nick Jikomes 17:19

I see. So it makes sense that it's expressed in the pancreas because of GLP. One is related to food uptake and nutrient acquisition and the insulin response, it makes perfect sense that you would find it in the insulin, which is where in the pancreas where the insulin is secreted. It's also found in the nervous system. So it sounds like you've got the vagus nerve, which reaches down into the gut, so it can sense the GLP one there, really that information back up to the brainstem? It's, you also have these GLP one receptors, you said in the brainstem and the hypothalamus, how are they sensing that GLP? One? Is it crossing the blood brain barrier and getting into the brain? Or is it getting to those areas in some other way?

Christoffer Clemmensen 17:59

Yeah. So, so yeah, so this is the intriguing part. So these areas often referred to as kind of circumvent regular organs or sites. So they are, they are kind of the just surrounding the third and the fourth ventricular system, the blood brain barrier, this is often referred to as being less fenestrated, or more leaky. So and that system is, is, is quite advantageous in this sense that this is where the brain is capable of communicating in your endocrine in an integrated fashion with the rest of the body. So especially in the hypothalamus, the the most lowest region called the arcuate nucleus is decorated with receptors for circulating hormones, peptides and proteins, including insulin, but also leptin produced from the adipocytes. So that area of the brain can actually see peptides and proteins in circulation and is less protected than the rest of the brain. So it's a kind of a neat design in terms of brain body communication, right? So the brain can pick up on what's happening in terms of nutrient status, and endocrine kind of factors that signal also nutrient status. I

Nick Jikomes 19:19

see. So most of the brain is protected by the blood brain barrier. So there's tight regulation of what goes into the brain. We don't want bacteria getting in we don't want toxins getting in we want to control exactly what's going in because the brain is sort of the master controller of everything. So we've got this blood brain barrier that's that's tightly regulating what gets into the brain. It's preventing a lot of things from getting into the brain. But a couple parts of the brain special pieces including the hypothalamus, they are in direct contact with the blood. So they are the hypothalamus is basically directly sampling what's in the bloodstream.

Christoffer Clemmensen 19:50

Exactly. So if there's been if you do labeling studies in rodents, you put a floor for something on on a peptide GLP one peptide, you can see that dig up concentrates in those regions of the brain, but it doesn't get further into the brain typically.

Nick Jikomes 20:04

So for a neuron in the hypothalamus say, what happens when GLP one binds to its receptor? Does the neuron become more excitable, less excitable? What actually happens to neurons when GLP one gets released? Yeah, that's,

Christoffer Clemmensen 20:22

that's a good question. And at the neuronal level, you see increased excitability, but it is a G protein coupled receptor. So you don't have this kind of immediate depolarization, necessarily with a, so it's perhaps more sensitization of the neuron in those cells. So one of the neurons that expresses the GOP one receptor is called the pumc, or the Pumpsie neurons, which is kind of the primary is is kind of saturating or satiety hormone in the bottom of the hypothalamus. We talked about this ying yang hormones a little bit simplified fashion where the AgRP neurons and these are because they produce these neuro peptides Express AgRP upon c. So the ADRP neuron is the hunger promoting neuron and Pumpsie known as the satiety promoting neuron. And the Pumpsie neuron respond to two 1/3 of them expresses the GLP one receptor and will then signal or at least sensitize in response to GLP one and we'll have a little bit be excited, have increased his excitability. And same goes for some of the neurons in the brainstem. I see

Nick Jikomes 21:33

So so the neurons in the hypothalamus and elsewhere that have the GLP one receptor, they're sensitive to GLP. One, GOP one is basically making them more excitable, which may or may not translate into causing those neurons to fire more directly, but will make them more sensitive to their inputs. So yeah, so you've got these two populations in the hypothalamus in one nucleus, you've AgRP neurons which promote hunger basically, and see neurons po MC, which promotes is tidy basically. So the palm see satiety neurons have GLP one receptors and GLP, one goes up, you would expect the you would expect to promote satiety, more, or satiation less hunger.

Christoffer Clemmensen 22:13

Exactly. And they also then a lot of indirect communication. So there's a recent work where they were they using a method called fiber photometry. So you can actually in the vivo, in the live mouse, you can read the activity of neurons, once they fire, they get your you get like a calcium signal that you can pick up on with the optic sensor, the fiber. And then you can see if you give these analogs GLP, one hormones that you also can see a suppression of the AgRP neurons, it's not direct, because it doesn't have the receptor. So there is a lot of cross communication going on between these neuronal systems, right, so So, so again, and we can talk about this later. Also, we see also that activity deeper in the brain with some of the these type of gut based hormones, but it's not because they we just talked about, they don't reach deep into the brain, but they will have feed forward or they will have activate neuronal signals that will then kind of signal further into the brain and kind of promote even affect, for example, the mesolimbic hedonic reward pathway, but those are not because the peptide is direct signaling there, but it's through feed forward pathways.

Nick Jikomes 23:21

I see. So so the the hormone GLP, one can promote satiety at the level of the brain by acting on specific neurons in the hypothalamus.

Christoffer Clemmensen 23:30

Exactly, yeah. And probably in combination with the, with its effects in the in the brainstem, right. So there's been, there's a study from 2018, where they did, where they made a GLP, one receptor knockout animal where they only upgraded or knocked out the GLP, one receptor in glutamatergic neurons. So they use the marker for glutamatergic neurons called the V glute Cree mouse, and then they crossed it with GLP, one receptor flux mouse, so you only lock out the receptor in neurons that expresses expresses this marker for glutamatergic neurons. And then they tested one of the earlier long acting versions of the GLP one drug and they saw that in mice that didn't have GLP one receptors in the glutamatergic system, the drug didn't work on on body weight going and food intake lowering. So based on that study, for example, you can pinpoint that the pharmacological benefits on body weight and food intake is mediated, at least through glutamatergic system in the brain, they did the same for the GABAergic is system and they didn't see any, any loss of effect of the drugs. So those type of combination of these mouse genetic works with the pharmacology can then teach us more about the central motor function. And

Nick Jikomes 24:47

so because we've got these circum ventricular organs that can directly sample the bloodstream, the brain, the hypothet, in parts of the brainstem, the hypothalamus, that means these GLP one agonist drugs, the exemplar x and the related drugs, they are actually acting on those areas of the brain directly.

Christoffer Clemmensen 25:04

Exactly. And we haven't this is something we should probably touch upon now, because the endogenous hormone is very, very short lived less than two minutes. So it's debatable whether the endogenous produced GLP one ever reaches the brain in a sufficient concentration to signal satiety. I see. So it's, so we exploit the system with the pharmacology because we can make create these super long left versions of the hormone that are protected from in somatic cleavages in the bloodstream, and through liquidation of fatty acid Sidechain. They also bind to albumin, so they stay in blood circulation for many, many, many days. And that way, we kind of they've been engineered to signal in the brain, as opposed to the endogenously produced GLP. One.

Nick Jikomes 25:49

I see. So that was actually going to be my next question is how these GLP one drugs differ from endogenous GLP one sounds like one major way is they've been engineered so that they last longer, they're in circulation for longer, and therefore they can promote satiety with a longer time course.

Christoffer Clemmensen 26:05

Yeah, and that is the primary difference from the endogenous one, so is the substitution of a few amino acids to prevent them from being degraded by an enzyme called DPP four. So they don't have this in somatic breakdown. And then through this limitation of this fatty acid side chain that is kind of a well known modification in medicinal chemistry now, because it then enables your peptide to bind to albumin that circulates in large quantities of the body. And that is, then again, you you retain the peptide, longer time in circulation. So this is also why a significant breakthrough in this area by the pharmaceutical companies was from going through the ones daily to the ones weekly version that that is now on the market. So the the predecessor to some macro type was called liraglutide. And it was a once daily GLP, one receptor agonist and through further refinement of this side chain, it was made into a once weekly drug basically. Yeah,

Nick Jikomes 27:09

so through these kinds of modifications, it's a once weekly drug, because it's been engineered to basically stay in circulation for longer, the body can't break it down as quickly as it can break down the natural GLP. One hormone

Christoffer Clemmensen 27:21

Exactly. But other than that, they stick them in the same way bind to the same receptor that signals the same this G protein coupled GS pathway. So So other than that, they work the same way as the endogenous hormone.

Nick Jikomes 27:32

And so when GLP one or these GLP one drugs like as Empik are working when they're doing their thing, what are the effects on the GI system that are related to the satiety signals so that the brain is being signaled satiety? But what's what's happening to the GI tract? Is food moving through the GI tract less are other things being secreted like other gut hormones, what is the GI system basically doing in response to this hormone.

Christoffer Clemmensen 28:01

So So one of the world's most well described effects is a slowing of gastric emptying. And whether that contributes to the weight loss, I think, is not 100% Clear. But to my knowledge, some of them have the earlier versions that has was more or less efficacious. And bodyweight also had the same storing of gastric emptying that maybe speaks against this as a major contributor to the to the weight loss, but in general, they slow they slow gastric emptying, so So basically, food moves slower through the GI system. If the drugs affect secretion of other endocrine factors from the god, i think i To my knowledge, I don't know, I wouldn't think so. There's also in many, in many hormone system, it's well known that when you kind of introduced some hormone replacement type of therapy, that you kind of shut down the endogenous production and to my knowledge that's not reported for the GLP one system, which is also quite fascinating. So then I don't believe you shut down the endogenous production with the drugs. Okay,

Nick Jikomes 29:08

interesting. How well do these GLP one drugs work? Can you give us a sense of that in terms of the magnitude of the weight loss that people are seeing when it works, as well as the percentage of people that it actually works for?

Christoffer Clemmensen 29:23

Yes, so the first generation of these drugs were approved by the American authorities the FDA in 2014, and marketed under the name SEC sender. And this is the drug we just talked about called liraglutide. This was a once daily injectable, and it had approximately 8% weight loss over one year in individuals with a BMI above 30. So what we classified as individuals with obesity and then there was the development with going from the director type to the same actor type with the one stage to once weekly, and I think it was a little bit And I mean, it was just I think it was unexpected that the weight loss was so much potentiate it with that modification so the the once weekly drug in individuals with BMI above 31 year trial, you see weight loss of 15%, approximately plus minus there's not been so many trials but up to 70% with this type of Best in Class GLP, one receptor mono agonist and typically then we talk about De Novo Nordisk compounds electrotype, which is kind of the leading one when we talk about the mono agonist drug, but there's also then the dual agonists that are now entering the market, and maybe we can also talk about them later. Yeah,

Nick Jikomes 30:40

we'll get to that later. So so. So the drugs that are out there, the ones weekly injectables, the Novo Nordisk version, we're talking on the order of 15% loss of body weight, on average,

Christoffer Clemmensen 30:54

in individuals with obesity, BMI above 30. And then out of those 15%, average, there's, of course, a large variability in how people respond to these drugs. So typically, around 15%, we classify as non responders, meaning they have get less than 5% weight loss. But it also means that of course, there are people in the other side that lose a lot of body weight up to 30% weight loss on these drugs. And that's still it's something we don't know why that is people respond so differently to these compounds. Why is yes?

Nick Jikomes 31:27

Is there a relationship between how obese they are in the magnitude of the effect three, the most obese people tend to lose the most? Yeah,

Christoffer Clemmensen 31:34

good question. I believe so. So most of these trials are done in in, in rather homogeneous populations. So typically in in obese in individuals with obesity. So I haven't seen any trials with with individuals that are rather more lean. So So that's more anecdotally, right, that you see, people with less obesity respond less. And then there's also the another kind of complexity is that people with CO morbid obesity and type two diabetes, they also actually have less of a weight loss response. So there's something with the type two diabetes that we can see effect on the weight loss that we also don't know why I

Nick Jikomes 32:12

see. So people with obesity and type two diabetes tend to lose less weight with these drugs and people who have obesity, but not type two diabetes.

Christoffer Clemmensen 32:20

Exactly. So the most beautiful data from the phase three trials is typically in, in obese patients with obesity without type two diabetes, because that's where you get most most weight loss, typically, I

Nick Jikomes 32:32

see. And so. So when you say earlier, you said about 15% of people about one or two out of every 10 people that's obese, that takes this drug is not going to see a significant response, it'll be 5% or less body weight loss. Does that include those people type two diabetes, potentially? Is that one of the things feeding into that? 15%? They should?

Christoffer Clemmensen 32:52

Probably not. I think that they've already been been selected out of these type of trials. So it shouldn't be. So

Nick Jikomes 33:00

about 50% of non diabetic obese people will not see a lot of weight loss from these drugs. Yeah. Okay. But still, that means a vast majority do see some, and many of those see quite substantial weight loss.

Christoffer Clemmensen 33:12

Yeah. And that's also why we see they're so popular. Right. So I think finally, probably it's the first safe and efficacious weight loss that has entered the market. I mean, up until now, right? And this is also why they've been so popularized. Yes.

Nick Jikomes 33:29

And I want to come back to the safety question in a minute. First, I want to ask you about the weight that they're losing. So for people that lose weight on a sim picking similar drugs, what are they losing? Is it primarily fat? Is it primarily muscle? Is it a mixture of both?

Christoffer Clemmensen 33:44

Yes, I was actually just trying to look up on these data, because in the first many of the clinical trials is not they haven't done body composition on all of the patients, which I think is also it's just doesn't, it's just too difficult of a measure to as compared to bodyweight to participate on on subset of patients and then some of the follow up trials. So typically, its data suggests that 25 to 40% of the weight loss stems from loss of, of lean mass or of fat free mass, so to say, and then, again, how much of the fat free mass is muscle mass is then probably 50%. And the rest is comprised of the rest of the orange right? But if we just talk about fat free mass, because if you do DEXA scanning that cannot differentiate necessarily between muscle and so it will just say let's just say fat free mass, non fat mass, and then up to 40% of the lost weight. In some of the studies from with the GLP, one agonist is coming from fat free mass, and Ms. Historically, if we look at dietary or diet restriction, I think typically the numbers around 25% with kind of normal, low calorie weight loss type above studies I

Nick Jikomes 35:00

see. So with these drugs, you're seeing a higher loss of fat free mass than you would with just raw food restriction. Is that what you

Christoffer Clemmensen 35:08

think we we don't have the data yet. And at least so I've seen ranges from 25 to 40%. And I also looked at Eli Lilly struck, which is we can toggle this dual GOP one chip agonist, it seems as if it's also around 25%, in that one study that they reported. So I think the jury's still out. But of course, it's a very hot topic. It's something that is being discussed widely. Now. Is this kind of risk with the loss of muscle mass?

Nick Jikomes 35:35

Yes. So what So regardless of what the numbers actually are, there's some loss of fat free mass. Is that okay? Is that not ideal? Is that dangerous? How do How should people think about that? Should they want to preserve that fat free mass? Or is it okay to lose it?

Christoffer Clemmensen 35:53

So I think there's two ways to view this, the first of all, this, this will be very individual, right, both depending on on your sex or gender, and your age. And starting points. I think if you're old and somewhat frail, you want to, at any cost, you want to preserve your lean mass, because we know that's directly correlated with how long and how well you live, right, you'd want to be able to walk up the stairs and grocery shopping, etc. And so I think once you've acquired fat free mass at all, he wants to preserve it at any costs. A, but for some individuals, I think it's expected if you know, if you have a higher body weight, with elevated body fat mass also comes elevated fat free mass. So typically, individuals with obesity will have more fat free mass also, compared to the absolute.

Nick Jikomes 36:44

So if you go from being lean to being obese, you're not just purely gaining fat mass you're gaining some amount of everything might disproportionately be fat mass, but you're also gonna be gaining fat free mass. Exactly.

Christoffer Clemmensen 36:55

So that's also what we what if we kind of acknowledged this 25% loss of fat free mass from the diet restriction studies, maybe that's expected, right? But maybe we want to make sure that with the drugs, we don't accept, or we don't go beyond, for example, those 25% Maybe that's a target to begin with, right. But that being said, Why not preserve the lean mass we already have acquired. So I think that's the ideal future, right, that we come up with interventions or strategies, that that ensures that we can preserve as much as the lean mass that we've acquired as possible and exclusively lose body fat mass. And this is, of course, something that the pharma industry, but also academics are working on on right now to come up with ways to ensure we can preserve lean mass, they can be lifestyle interventions, or they can be kind of drug poor administration type of interventions.

Nick Jikomes 37:47

And when we look at the clinical data in humans in conjunction with the preclinical data that would have been done to justify those clinical studies, and we look at the weight loss, how much of that weight loss can be explained by a reduction in food intake? Or in other words, is there also a change in things like basal metabolic rate that feed into this?

Christoffer Clemmensen 38:09

So this is also a frequently debated question. So the rodent data is less clear some of the road and study suggests that there is an effect on energy expenditure with this increase in hormones that use you'll see increased thermogenesis. But the human data suggests that it's exclusively driven by a reduction in food intake. Maybe there's an effect on preservation of energy expenditure. So we see with a severe calorie restriction, if we go on a diet, we see that energy expenditure drops in order to kind of protect body fat mass. So it's, that's what contributes to prevent us from successful weight loss is a decline in expenditure as maybe the drugs can alleviate that a little bit.

Nick Jikomes 38:54

I see. So So sort of the natural condition is that when an animal is faced with starvation, or calorie restriction conditions, there's less food coming in, to supply and to fuel the body. And so there's a compensatory drop in baseline metabolism, so that the animals using up what it has less

Christoffer Clemmensen 39:12

expected we see a quite pronounced metabolic adaptation in order to protect its body weight and fat mass. So that's, that's just well described, both in humans and in animals, and then some of the drugs can maybe offset that reduction in energy expenditure. Slightly, that's least a hypothesis by direct effect on energy expenditure, I think in humans is probably not one of the mechanisms.

Nick Jikomes 39:36

Okay. Okay. So the weight loss that many people see is largely coming from a decrease in food intake. Exactly. And so when people take these drugs subjectively, what do they report does? Are they simply less interested in eating? Do they feel full sort of more of the time do they feel sick or nauseous or anything like that? What is the subject have a feeling of these drugs and dues

Christoffer Clemmensen 40:02

combination of all these, all these things you just listed right. So it's less interest in food, kind of inability to finish portions, they'd kind of pile up on their plate. Some background nausea for some individuals, that's also one of the main side effects is nausea and vomiting. Right? So I've heard one one individual, an older woman say that it kind of she, she had the sensation as as, as she recalled from being pregnant when you're 30 years ago, like this background nausea all the time. And that's exaggerated when she was eating. So that's why you then you want to eat less if you so that. So it's a it's a variety of these kinds of experiences that we hear from from individuals taking the drugs, but in general, just less drive towards eating basically.

Nick Jikomes 40:58

So with that in mind, so there are at least anecdotal reports that people are quitting drinking, quitting smoking, they're they're having, they're having help with substance abuse that might be that they might have. And that sounds like a good thing. But I want to, you know, think about that through the lens of another weight loss drug that we saw come and go historically, and that is remounted bombs. Do you remember the case of Vermont, Vermont? Can you give people just just a very short summary of what that was? What happened there?

Christoffer Clemmensen 41:31

Yes, so we thought about was a very good idea, because it was kind of blocking this cannabinoid receptor that we know is related to or for most people, it's something they relate to, kind of consumption of marijuana or, or similar products that contains this THC that will elicit this receptor in the brain that we know kind of promotes hedonic food consumption. So overeating basically. So this kind of links with Murata consumption and over eating was a good idea to come up with that, why don't we block this receptor, this cannabinoid receptor in the brain, and then we can suppress satiety, or we can increase the tiny but maybe even suppress kind of this hedonic drive to eat palatable foods. And it actually this was developed this drug cannabinoid, I think, one receptor inhibitor, and it worked quite quite well. But it also had a lot of, as it turned out, quite severe adverse effects. Probably because it was targeting systems deeper in the brain than what we normally refer to as these kind of homeostatic systems. We talked about the circle matricula sites, I believe we might have been might have been reaching deeper into the brain and then playing around with other other other brain systems, right? I

Nick Jikomes 42:49

see. So so the the problem with Ramana bond is that, although it did help people lose weight, it was basically making them there were psychiatric side effects, people were feeling depressed, there was even suicidal ideation. So it was helping people were less interested in the rewarding properties of food. But they also became less interested, the rewarding properties of basically life itself, everything was less rewarding. And the problems associated that were greater than the benefits from from the weight loss side of it. And so that was pulled from the market. Now, the fear would be that with the Olympics and the new weight loss drugs, we're just going to sort of replay that episode. And so the way that one way to interpret the anecdotal reports of substance use people quitting substance use of alcohol and other things is that well, we're just seeing another amount of money, it's tapping into the reward system, generally speaking, and so food is less rewarding when people are eating less, which is good, because that's what we want here. But it's also making drugs and alcohol less rewarding. And by extension, perhaps other things which which could lead to bad outcomes. Do you think that's likely or it sounds like maybe you think that's less likely because the drug is sort of restricted to the circuit ventricular organs, and it doesn't get into these deeper parts of the Muse Olympic reward system and other places?

Christoffer Clemmensen 44:09

I mean, we know it influences dopaminergic signaling from rodent studies. So we actually coincidentally did is published a study last year in cell reports where we showed that we were interested in the interplay between nicotine and GLP, one receptor system, and then we teamed up with a group of researchers that had again this fiber photometry set up where they could record dopaminergic signaling in the nucleus accumbens of the reward pathway. So every time the dopamine receptor is being activated, the reward pathway will get like a response in the recording. So if you give the animals nicotine, we see that this dopaminergic pathways sliding up basically, and then we co administered with a GLP, one receptor agonist and we saw that the GLP one receptor in itself didn't do anything to dopamine signal But once we gave it together with nicotine, we suppress the nicotine induced dopamine signal quite potently. And this must be indirect. So again, this is how is it that probably through the brainstem circuits, how is these circuits are tapping into the dopaminergic system to, to kind of fine tune it in a way that then suppresses the dopaminergic response, we get to nicotine. And I think at least I think this is some of them mechanistic underpinnings of, of the potential effects of these drugs on substance abuse, right? That, that they are kind of playing with the dopaminergic system. But maybe we're fortunate in this case, that it's the indirect indirect effects that renders it, quote, unquote, safer than what we saw with rimonabant. I think one thing we already know is that so many 1000s and 1000s and 1000s of large trials have been done, there's now the longest one where patients have been for years on treatment. And to my knowledge, there's, there's not a very frequent reported side effect any of these kinds of anhedonia, these type of kind of more more kind of depressive type of states, for example. So I don't know, but it seems like

Nick Jikomes 46:12

they will attack it sounds like a pretty informative experiment to do an animal's would be to repeat what you guys did with a GLP. One plus nicotine experiment, for a reward a healthy reward, something that we don't want people to get sick of and to quit. Yeah, like, you know, exposure to conspecifics exposure to littermates. Exposure to, you know, water, I don't know something, something of the animal likes that is healthy for it, rather than something that it likes that it gets addicted to. Yeah,

Christoffer Clemmensen 46:43

so I actually had a journalist calling me up last week said that she's talked to this kind of a very, very kind of what you call not kind of a little bit of a tablet type of press. Let's talk to a woman that reported that she lost her sex drive with the, with these new kinds of drugs. And she asked me, Is there any kind of scientific foundation to support this? And again, I could speculate like we do now is that, well, we know that probably the sexiest one out of several natural rewards, right. So I think we can envision a way in which these drugs could influence these types of natural rewards as well. But it's at least again, to my knowledge, not a very common side effect reported. So it may be for some individuals, right, but but we'll we'll have to see. Yes.

Nick Jikomes 47:33

So the next area I want to ask about these drugs is long term effects and side effects. How long lasting are the primary effects on food intake? Are there any side effects and sort of wrapped around this whole question is, you know, how long have people actually looked? Has there been enough time to truly know what the long term effects are?

Christoffer Clemmensen 47:56

So as I just mentioned, I think there was just two weeks ago published a study on some magnetite with four years on treatment, where they show I think, I was a little bit surprised to see they actually show no weight rebound, because I think even for the bariatric surgeries, that works extremely well, you see, eventually some weight rebound over the years, right. But at least in the four years on treatment that they saw preserved, weight loss, stable weight loss throughout the years, it was only which one was a little bit surprised. It was only a 10% in this study. So again, it's not the magnitude that we oftentimes report or want to write but still it was quite interesting. And then regarding the long term adverse events, for some of them, we will have to see right but I think you can also flip it around right? So the reason why the the stock for these drug companies, most notably Novo Nordisk, and Eli Lilly is going up these days is that they continue to come up with report showing benefits on cardiovascular disease benefits on kidney disease benefits and osteoarthritis benefits on what not they're now doing phase three studies with Alzheimer's disease. So I think it's more the opposite, right, that they continue to show benefits on extreme inputs that are very important to human health. So I think one could also envision a future where we see next generations like imagine this is your kind of iPhone three, right? Imagine once we've developed these compounds even more in 20 years, you can envision a future where everyone are taking these drugs because they are directly linked to human health span. So I'm not a proponent or I'm not selling the drugs right now. But I think if at least if we continue to see benefits with no no surprise, adverse effects coming up with us, it's right. I think we'll see. Yeah, maybe it's the other direction, right that they will see more and more people want to take these type of drugs and it probably not for some people we go we or Manjaro what they call we'll see next generation compounds A being developed.

Nick Jikomes 50:02

You recently did a study where you basically created a new version of these drugs. And can you set up that study for us? What was the rationale for this? And how exactly did that drug work? And why? Why did you even think to look at this? Yeah,

Christoffer Clemmensen 50:17

so there's out find it somewhat short. So we were we became interested in the glutamatergic NMDA receptor that is typically something you associate with memory ratios, cognition and kind of this long term potentiation. That's something that synaptic neuroplasticity the reason why we became interested in the first place was that there was these studies with ketamine showing the effects in treatment resistant depression 20 years ago, and then there's been more and more research uncovering the mechanism for this, why is it that ketamine seems to have long lasting benefits in depression, and then some of the data coming out in the molecular mechanisms pointed to a role for BDNF brain derived neurotrophic factor some of the mTOR signaling pathways, and a lot of these pathways were quite interested in in appetite regulation as well. So BDNF is a very common pop up in all the genetic studies of bodyweight variability. And if you give BDNF into the ventricles of the brains of mice, they lose weight also. So the link between ketamine, which is an NMDA receptor blocker, its benefits and synaptic plasticity and depression. And its mechanisms involving these pathways that we know is also interested in interest interesting in satiety control was the first kind of the first kind of gave the first stimulate the first ideas to think about the uses of these type of channel modulators for obesity. And then we could see in the literature that there were already sporadic studies, actually a few human studies, testing NMDA receptor antagonism for binge eating disorder. And we found studies in rats and monkeys also suggesting that it could have effects on on hedonic food intake, but they're like, there's not many of them. And then at the same time, the human genetic studies of bodyweight variability clearly point to a role for neuroplasticity and glutamatergic signaling also. So these different pieces of evidence increased our interest in NMDA receptor channel blocking for weight management. So we started to do experiments with commercially available compounds, including ketamine, and the approved Alzheimer's drug called memoryten. And then a drug that's not on the market called MK two one, but it's a very potent channel blocker. So we we exposed obese animals for these drugs and looked at food intake and bodyweight and saw consistently that they actually lowered food intake and bodyweight when we gave these drugs systemically. So

Nick Jikomes 52:56

an NMDA receptor antagonists drugs that block this receptor that's important for plasticity and learning memory, they tend to help with obesity animals tend to eat less and lose weight. Yes,

Christoffer Clemmensen 53:09

but it's not. It's not like it's not. It's not very consolidated evidence that you find in in the obesity literature, it's kind of you have to search for it to see it previous. So there's like a handful of previous studies that are spread across decades of work, basically.

Nick Jikomes 53:27

Yeah, I see. So we had some indications that NMDA receptors blocking them might help in obesity. Obviously, these GLP one drugs, you're very familiar with them yourself. They've they're out there, they're working in humans approved, causing weight loss and some people. So what was what was this new drug? There's like a twist on this drug, right? You did something kind of clever to make it work in an interesting way compared to the other GLP one drugs?

Christoffer Clemmensen 53:52

Yeah, so the NMDA receptor antagonist as small molecules so like rimonabant, they will basically penetrate the blood brain barrier and signal throughout the brain. So we saw when we give high doses of these drugs, the animal also started to move more, they became hyper Lokomotiv, that body temperature increased, we saw a lot of adverse effects. That's it's not it's just not a useful drug for obesity treatment, you cannot have it weight loss drug that have these adverse effects. But we thought we want to just exclusively harvest the benefits of these drugs in this circuit ventricular size. So how do we ensure that they don't penetrate deeper into the brain, and this is where we start to make these peptide drug conjugates. So we took the small molecule, and then through a chemical linker, we attached it to the peptide. So we basically created a single molecule with the small NMDA receptor chemlok attached to the GLP, one peptide, and then through the GLP, one, peptide not being able to penetrate deeper into the brain, but homing into its GLP one receptor and when the peptide interacts with its G protein coupled receptor, it is being internalized as a complex, and then you can sneak in the small molecule into those same neurons that internalizes that GLP one receptor and suddenly you have cell specific delivery of that small molecule only in GLP, one receptor expressing cells.

Nick Jikomes 55:14

Okay, so you've, you've essentially taken the GLP, one peptide, and you've stapled it to an NMDA receptor blocker. And you've done that in a way that it can't get through the blood brain barrier. So this drug can't penetrate into all of the brain. But it can get into parts of the brain like the hypothalamus and the brainstem that are directly touching the the bloodstream that don't have blood brain barrier, they're protecting them. And, and so it because it's GLP, one connected to the small molecule drug, it binds to the GLP, one receptor on the neurons that have like the satiety neurons, the pumps, neurons we talked about before, and then it goes inside the cell, and then the small molecule drug is cut off of that, and then then it blocks the NMDA receptor.

Christoffer Clemmensen 56:00

Exactly so so and I'm not a chemist, but fortunately, the first author on our paper and has been working on the project for long time is a very smart chemist. So there's from the antibody drug conjugates space in cancer treatment, that's been developed a lot of different linker chemistries in order to kind of facilitate delivery of a of a toxic agent only to cancer cells. So you want only delivery of, of kind of this payload to specific cells. So they've been developed a linker type of chemistry that is sensitive to the intracellular environment. So it will only be cleaved once it's inside the cell. So it can be for example, pH sensitive or sensitive to other intracellular aspects that will ensure the cleavage is only happening intracellularly, but it stays stable in in circulation,

Nick Jikomes 56:49

I see. So from a chemistry perspective, this thing can be engineered so that the the sort of double molecule, the peptide plus the drug can't be broken, it's stable unless it goes inside of a cell. And it can only get inside of the GLP one receptor expressing cells. Exactly,

Christoffer Clemmensen 57:08

yep. So that is the idea. And then you have liberation of the small molecule within those cells. And then you need them to block the NMDA receptor in that those same cells. Okay,

Nick Jikomes 57:19

so So sort of the end effect physiologically of this novel compound, is that you're able to block NMDA receptors in GLP, one expressing cells only.

Christoffer Clemmensen 57:31

Exactly. So it's a very, very specific delivery of that small molecule in but we believe the idea is that that's perhaps the cell type, we want them the signaling of those molecule molecules the most anyway, so why deliver them through the whole brain when we can get them only to those specific neurons? Okay,

Nick Jikomes 57:50

so my next question would be, what is the neural effect so of the neurons that have the GLP, one receptor that are sensitive to this drug? What is the effect on neural activity that this drug has because on the one hand, we said before that GLP one renders neurons more sensitive to their inputs, so it should make them more excitable, but the NMDA receptor blocker is going to prevent NMDA receptors from opening and depolarizing the cell so what's the net effect here?

Christoffer Clemmensen 58:17

Yeah, so temporarily so so the idea is that the NMDA receptors is in interaction with the AMPA receptor being recruited once the glutamatergic drive is sufficiently high, you get the NMDA receptor, you remove this block bind and punishment, you get signaling through the NMDA receptor. So the idea is, I think in terms of plasticity, that continuous blockage of the receptor might increase the glutamate in the synaptic cleft, and then subsequently, it might elicit some of these adaptive responses to to strengthen the neuronal connectivity. But all of these details, the short answer is we don't know what is happening for all these details at this point. But what some of the things we did was that we teamed up with a group of researchers at the University of Texas that is doing a slice electrophysiology, so they take out slices of the hypothalamus, and they can bait them in this kind of specific buffer and then they can patch on to individual neurons, and then they have labeled the GOP one receptor positive neurons. So these mice come with a labeling of neuron so they know that they're recording from a GOP one neuron in this artificial setup. And then, once they put NMDA or glutamate on these neurons, you see a depolarization and an inward current. And then if you put these channel blockers on that have been developed to block the channel, you see that this blockage is complete, you prevent completely this inward flux of ions. And if you put GLP one on, nothing happens, you see, again, this NMDA receptor, NMDA induced, in what current but with the conjugate we see that we can mimic what we see with the Small molecules, this is one way of showing that we have retained the effect of the channel blocker in this type of ex vivo setup. In addition to those type of experiments, we also treat it, we took out hypothalamus and brainstem from mice that have been treated with the drugs. And then we use these modern omics technologies, where we look at all the transcripts and proteins that are changed in these brains of these animals. So all the mRNAs and all the proteins, and then we see that with the conjugate, we see a ton of pathways related to neuroplasticity, glutamatergic signaling, so proteins are being upregulated that is involved in synaptic plasticity, that's an indirect measure, but still, it's a quite quite clear signature that we see changes in synaptic plasticity with the conjugate. So we did these different types of experiments to to strengthen that concept works, as we have hypothesized, right, but we still work. I mean, we're still doing this type of studies setting up studies now to verify this specific neuronal modulation in vivo, through both the GLP one receptor and the NMDA receptor. Alright,

Nick Jikomes 1:01:11

so then, in essence, a lot of the experiments you did, were in rodents, you're comparing, you're comparing NMDA receptor blockers, like mk 81, to semaglutide, the GLP one drugs, so the normal GLP one drugs that are out there on the market already, NMDA receptor blockers, you can compare those to that and you can compare both of those conditions to the new dual action GLP, one plus NMDA receptor blocker drug that you just described? Yeah. How did the, you know on the terms of the basic effects on weight loss and metabolism? How do these drugs compare in your hands? Yeah, so

Christoffer Clemmensen 1:01:48

this is, normally we say the, the predictability or translatability of of drugs, weight loss drugs in rodents is quite good. This, they translate quite well to humans. But there's one caveat, and that is, once the drugs become very potent, such as the magnetite or some of the lilies precipitate, etc. They in in rodents, they're so potent, that they can basically clear the animal for excess body fat. But we can do studies where we can kind of tease apart what is the contribution from the NMDA receptor component. And that's, of course, what we're interested in to show that there is room for maximizing the weight loss benefits. So one study we did is that we pre treated animals, obese animals with some magnetite, the we go with oil, simply basically for two weeks, once they start to plateau, then we randomize them to stay on on some magnetite plus additional GOP one on top, or we put added our conjugate on top of the magnetite. And then we saw we could push, by the way, put down eight or so percent further, again, suggesting that that additional weight loss when you have maxed out on GLP, one that we can get additional 8% or so on top with the NMDA receptor channel blocker. So it's those type of experiments we tried to, to do in order to to show how much we could gain from the channel blot assay.

Nick Jikomes 1:03:15

So you actually gave rodents semaglutide, the GLP one drug, and additionally, at the same time gave him this new dual action drug, which is also a GLP, one drug plus the NMDA receptor blocker. And you're saying that you saw additional weight loss, so you sort of maxed out what you can do through GLP one by itself. And that if you add the NMDA receptor blocker in specific cells, you're getting an additional quite substantial amount of weight loss. Exactly.

Christoffer Clemmensen 1:03:41

So those type of studies we did and we did direct comparisons where we infused the molecule in the directly into the brains of rodents. So in the in the ventricular system, and then molar mass dose to some magnetite single infusion, and we saw even, I think, a doubling of the initial weight loss compared to some magnetite directly in the brain, we saw a little bit more preserved or slow rebound also compared to some magnetite and in that specific study. So but but because our drug in the paper we reported doesn't have this limitation, the fatty acid side chain is difficult to directly compared to the market of drugs,

Nick Jikomes 1:04:19

I say. But But in these experiments, when you when you compare semaglutide, the GLP one drug to the new dual action drug, not not giving them at the same time, but giving them separately to different cohorts of mice, the new drug is causing more weight loss.

Christoffer Clemmensen 1:04:35

So so that is yes, I think that is the point I was trying to make before so there is a handful of drugs now that if you dose them high enough in rodents, they will basically plateau at the same point, right so you can clear that body fat. So that's where you have to come up with you have to either dose dose a little bit lower to see where the how they differentiate, or you have to kind of do this as we did on top to see There's additional benefits that can be harvested. But

Nick Jikomes 1:05:04

But I guess the point of these experiments is there is additional fat mass that can be lost through adding the dual action of the drug, the NMDA receptor component on top of the GOP one component. Exactly, yeah. What about other effects, physiological effects that are relevant to metabolic health, I know that you guys looked at things like glucose homeostasis and and insulin. You looked at other things, what are some of the other effects that you saw with this drug. So

Christoffer Clemmensen 1:05:32

importantly, we saw across the board, like markers for metabolic health improved, like circulating markers for lipid metabolism, lowering of circulating cholesterol, triglycerides, and improvement in in also glucose metabolism. And so those are the things you need to see nowadays, with a new drug, right, you need to show benefits on several metabolic parameters. Then we showed at least in rodents, again, we didn't see any adverse effects on blood pressure or heart rate, which I think is important, again, to demonstrate you don't have any cardiovascular adverse effects. And then we saw some tendency also to this effect on energy expenditure signals quite interesting. So we actually saw quite a substantial protection of this Metabolic adaptation. So even though the animals in this experiment has lost 30% of the body weight, their energy expenditure was as high as the control animals that was still obese.

Nick Jikomes 1:06:31

I see. So that's interesting. So So earlier, we talked about this, when animals start eating less, there tends to be a compensatory Inc, or decrease in their energy expenditure. You're saying that's absent with this drug. So animals are eating less, but their energy expenditure is staying where it started up?

Christoffer Clemmensen 1:06:47

Exactly in this study, we had a control group that the calorie restricted to match the weight loss of the drug and they didn't slow, the metabolism was substantially slower. So they just basically decreased their energy metabolism dramatically. And we didn't see that with the treatment, they completely retained the the index pension throughout despite losing 30% body weight. So that could be 111. important aspect. Same goes for actually lean mass, we do see a little bit of lean mass loss. But again, compared to calorie restriction, we actually see a preservation of lean mass in the rodents again, so we don't see exaggerated lean mass loss either, because

Nick Jikomes 1:07:23

this new dual action drug has more specificity, I would imagine that inherently there's less chance or less likelihood of side effects because you're you're only affecting NMDA receptors, and only in these neurons. Is that did you guys look at that at all, like like any negative side effects? Is that true? Is that like a likely way that it would work because it is has that higher level of specificity. So

Christoffer Clemmensen 1:07:48

we did some of the most obvious tests for side effects that are very, that are very apparent when you use this NMDA receptor channel blocker on its own. So we use like this open field arena, where you will just video record the animal after drug exposure, and then with those very high, so we could see that the Mk 212, the group they basically it's they just ran around like crazy hyper locomotive, but in the conjugate dose equally high, we saw absolutely no effect on hyper locomotion against showing that we don't have this broad central delivery of the drug, we saw that we did the same for hyperthermia, like the elevated body temperature, we didn't see any, any adverse effects on body temperature either. So we did this kind of tip of the iceberg experiments to show that we don't have the adverse profile of the of the NMDA receptor channel blocker. So I think it's quite fair to to to to say that we do have this specific delivery, and we don't have systemic liberation of the of the small molecule.

Nick Jikomes 1:08:49

And what effects did you see in the brain what's going on to neurons in the hypothalamus and elsewhere when you give this drug,

Christoffer Clemmensen 1:08:57

so in the paper, we, quote, unquote, only did these type of omics experiments where we looked at the whole transcriptome, all the mRNAs, all the proteins in the hypothalamus we did in the brainstem, we also looked in the nucleus accumbens, then we did the whole brain 3d imaging with where we image the protein called C FOS, which is a indirect marker for neuronal activity. So when a neuron is activated, C FOS is being expressed. And then if you stay in for c FOS, it will indicate that that region has been activated.

Nick Jikomes 1:09:31

So basically, you can do an experiment where across the entire brain, you can look to see which neurons have recently been quite active.

Christoffer Clemmensen 1:09:39

Exactly. So the brain is it's a very neat technique the brain is is completely made clear, made completely transparent. And then you you can basically visualize 3d A whole brain when your hands have been activated. So it's very fascinating method and what we see is that we see activation of the same regions, we did the control against the magnetite and, and the mono agonists, etc, we see the same regions, as we know are being activated the brainstem, the hypothalamus, but we also actually saw some activity in the nucleus accumbens with the conjugate, which were quite interesting. Again, the molecule is unlikely to go there. So it must be some type of feed forward segment from possibly brainstem, that, that that activates this region of the brain.

Nick Jikomes 1:10:28

Okay, so you've seen neurons become quite active in the hypothalamus and the brainstem, as you would expect, because this is where the the neurons live, that we are affected by these drugs. But you see additional neurons elsewhere in the brain, in particular, the Museo limbic dopamine reward system that also become active. Do you know the specific neurons that became active are these dopamine neurons themselves? We don't

Christoffer Clemmensen 1:10:49

know at this point, this is just only see for us in regions that we know quite well defined, right? So we have no idea what the specific neurons are.

Nick Jikomes 1:11:00

So you sort of see the same areas lighting up, as with semaglutide. But then you see these additional areas lighting up, and we don't really know much about what that means yet. It sounds like no,

Christoffer Clemmensen 1:11:10

yeah. And some of the areas that we see with semaglutide, we also see an example of an exaggerated response again, which perhaps can be explained by part of the mechanism is that somehow you potentiate, the GLP, one receptor signal with the channel block and those neurons, again, this is speculative, right, but how it's working, it might be that we're kind of boosting the GLP, one receptor signaling in some way for the NMDA receptor channel blocking.

Nick Jikomes 1:11:35

And are these drugs affecting other aspects of metabolism in any way like lipid oxidation and sort of how the calories are being used?

Christoffer Clemmensen 1:11:43

I mean, they should they should be, I mean, they shouldn't be too much beyond what we see with the GLP one risks because we have this exclusive delivery and the NMDA receptor is is predominant expressed in the central nervous system. There is an interesting paper published quite some years ago, nature medicines showing that NMDA receptors in the pancreatic beta cells is involved in insulin secretion. And we've had many questions presenting this at conferences where people have suggested us to look more into this. So it could actually be beneficial also, for even further potentiate an insulin secretion, at least based on the literature, but we haven't again, we haven't spent much time on this as we're mostly interested in the brain, but it's something that we should look more into.

Nick Jikomes 1:12:30

So one of the one of the things you mentioned about NMDA receptor antagonists is they have a number of side effects, including hyper locomotion. But actually for something like obesity, you know, you could you could argue that that's an effect rather than a side effect. How are these drugs affecting baseline locomotor levels? Did you look at anything like voluntary wheel running or something that we might think of as akin to exercise and rodents? Yeah, we actually did. So

Christoffer Clemmensen 1:12:56

in this colorimetry system, where we measured the animal's energy expenditure over 10 or 1212 days of treatment we can also pick up on on locomotor behavior. And here, we actually don't see any differences compared to to vehicle treated animals. But we see that animals that are exposed to calorie restriction, they reduce the locomotion, which is a way to preserve energy. And in wheel running studies, we use an x we use we've established wheel running Model S as as kind of model for a version in rodents. So we see when we give an aversive substance, the animals, they don't like to run in the wheels, which so for us, we've tried to establish this as a model for predicting aversive aversion, or avoidance behaviors, or they avoid to run the wheel. So we compared the wheel running experiments next to some magnetite to see how this affected their willingness to run. And we saw similar profile, the first time they see that rock, it is aversive as any other GOP one, they don't like to run in the wheels, but on the subsequent days, they start running again. So I think diversity effects are quite trenches in rodents.

Nick Jikomes 1:14:07

I see. I see. So there's there's an aversive they stopped doing things they normally like doing for a little bit, but then they get used to it basically. And they start doing them we

Christoffer Clemmensen 1:14:15

we see this with all these weight loss drugs that hits the brainstem, that they they have an effect on the willingness of the animals to go in the running wheels, which is quite an interesting model, I think.

Nick Jikomes 1:14:27

Interesting. Is anything known there about like in humans, are there any looked at are there any reports about people's physical activity, so they're feeling less hungry? Partially, by just probably not feeling interested in food partially through nausea and malaise? So it's kind of an aversive state, maybe that's being induced? Are people reporting that they are exercising more or less or the same amount or anything like that?

Christoffer Clemmensen 1:14:54

Good question. I don't know. So I think in clinical trials, there's always Just like this drug is always being prescribed on top of lifestyle therapy, like recommendation to eat healthy, live healthy. But I actually don't know what is being reported back how much the subjects are increasing or decreasing activities, that's something that would be very interesting to look, look into. In the future. Also, I think you can, for some individuals, you can imagine that if they alleviate some of the issues with moving around, you know, if you lose a lot of, of body weight, you are able to move more like due to your physical size, but but I don't know, centrally if it's going to be affected by your kind of kind of predisposition or willingness to move that that I don't know. So

Nick Jikomes 1:15:41

where so given the experiments that you did, that you just described, where you've, you've made the drug more specific by basically making it a dual action drug, it's affecting only GLP, one receptor expressing cells, and it is then blocking NMDA receptors in the neurons that have GLP. One. It's, you know, everything that in your paper that sort of looks good, it's sort of improves everything, there's more weight loss, everything's as good or better than then what you see with the GLP. One only drugs. There's there wasn't a lot of negativity to report. In terms of how I read your paper. Do you think that these types of drugs will just sort of supplant the existing GLP one drugs where do you see things going in the next few years?

Christoffer Clemmensen 1:16:25

Yeah, I know that. So here we have to have a look at the current kind of landscape and pipeline that is going to the clinic right. So already now we can say that the GLP one mono agonist semaglutide is being heavily challenged by the dual and triple agonists that are either on the market or coming on the market. So there is the GLP, one tip co agonist developed and marketed by Eli Lilly. It's marketed as Manjaro for obese for diabetes and set bound for obesity. The clinical data shows that it has a few percent more weight loss benefits than GLP one alone. So this is the first kind of dual agonist that shows additional benefits. And then there's also a triple peptide agonist in clinical development. AWS from Eli Lilly targeting glucagon GLP tip also show very promising data. The same time the other companies are developing coadministration version versions with a long acting version of a hormone called M Yulin that has been developed also for weight loss. So you give a GLP, one together with Emelyn. So there is like an endless number of combinatorial waste, that are being attempted right now to potentiate weight loss to go from 15 to 25%, basically. So that's, that's ongoing. And next to that there is also then the lean mass preservation initiatives where people start to tap into this myostatin system. So targeting skeletal muscle inhibiting muscle atrophy pathways in order to preserve muscle mass while giving an appetite suppressant. So there's many different initiatives. And then coming back to our initiative is, of course, how's that going to fit into this competitive space? So there's the we'll have to see right. But we think that this never plus at the targeting the neuroplasticity could be a might show some benefits that we don't see with the other other drugs. And here we were dreaming about our vision is to develop therapies that will have more sustained effects. So if you kind of rewire some of the appetite or hunger pathways in the brain, you may be able to actually create a drug with more sustained way effects and less rebound. So again, it's it's the beast team, drug market is increasingly competitive. But there's also room for many new new types of therapies. But it's very exciting field right now. I

Nick Jikomes 1:18:59

see so so. We've got these weight loss drugs that everybody's talking about that many people are using been, there's room to improve them in the sense of making them cause more weight loss, there's room to improve them in the sense of preserving the nonfat mass with the fat loss. There's there's sort of all of these different ways you can make them more specific, so they're less likely to have side effects and remains to be determined what the long term effects will be. But it sounds like you're pretty optimistic about these drugs.

Christoffer Clemmensen 1:19:33

I'm pretty optimistic right now. I think it's a so far so good, right? But again, we will have to see but but in parallel, there's also there's been production issues. They're very costly to make these peptides but right now we also see development of of small molecule GLP, one receptor activators. So there's so many interesting things happening right now. So So, so in order to get weight loss drugs to Do as many individuals as possible, you also have to be able to to produce it easily and at low cost. Right. So those are some of the issues that we don't talk about that often. But we also need to, to talk about right because right now you're kind of catering to, to the part of the population that that has a quite high income, right? Because they they are not, they're pretty costly. But eventually, they will also go off patent, and the competition will be bigger. So,

Nick Jikomes 1:20:26

so So insurance doesn't cover these drugs for everyone, like, does it cover them? If you're a type two diabetic, does it? I mean, does it not cover it? Does insurance not pay for these drugs? If you're merely obese? It's

Christoffer Clemmensen 1:20:37

very country specific. So I can only it's tough for me to answer specific, I guess I should know, for the US. But to my knowledge, it's very expensive to get in the US. And I don't know how much insurance is covering in Denmark right now. It's, it's also somewhere between three to $400 a month to get the drugs, which is again, depending on your income level, it's it's, it's quite a bit of money, right? Especially if you're in the lower socioeconomic classes where obesity prevalence is highest. Yes.

Nick Jikomes 1:21:08

What about? What about Do we know anything about? So people are losing weight? Because they're eating less when they take these drugs for, you know, the roughly 85% that we'll see that effect? Are they eating different foods? Are they eating better? Are they merely eating less of what they ate before? Is it having an effect on the palatability of food and what they have a taste for, and you know, their propensity to eat healthy versus junk food?

Christoffer Clemmensen 1:21:39

So I think in the rodents, these type of studies have been done, and they show convincingly there's a change in macronutrient preference in humans. Again, I think that individual variability is quite vast right? Again, you anecdotally you have reports saying that I never touch dessert anymore, or I have been drinking alcohol since I started on the drugs. I don't like coffee anymore. I don't I can't I used to buy a whole pizza. I still buy one, but I finished half of it. And so it's so it seems to be there's a huge variability at least anecdotally, right. I'm not aware of any scientific,

Nick Jikomes 1:22:14

what are the road results in terms of the macronutrient shift? I

Christoffer Clemmensen 1:22:18

believe so I think ranges see that one of the first studies basically just showing that the change from less fat preference to more carbohydrate preference, typically, I mean, it's a little bit of a of a setup has limitations, right? Because you give animals access to like, pretty boring versions of casein protein, some lot fat, and then some, whatever carbohydrate source and then you basically see, how does it kind of prefer this type of these three different macronutrients in an untreated condition. And then what happens to this preference once you treat them with a variety of drugs, so it's, it's a kind of a limited buffet type of, of intervention. But it's saying I think, as far as I recall, the chase preference from from fat towards carbohydrate, and keep protein at the same level?

Nick Jikomes 1:23:10

I guess a little bit more of like a philosophical or societal level. If we just sort of extrapolate forward, where do you see things going in terms of development of these types of drugs and therapies? And the way that sort of we we interact with all of the things that we consume in our society, like, you know, 10 2050 years from now, are we all gonna be waking up and, you know, taking a shot of the GLP, one agonist in the morning and some testosterone? Are we are we just going to start injecting ourselves with, you know, five different drugs that have been engineered with such specificity that we all just sort of create the body that we all desire without having to do anything else about it?

Christoffer Clemmensen 1:23:55

Yeah, I mean, I'm, I'm happy to try and speculate, but then again, you know, if there's some adverse effects with this drug class being reported in two or three years from now, we'll have I mean, it can be completely scrapped. Right, and we'll have to start from scratch. But let's, let's imagine that we don't see this adverse effects with the increase in drug class. Then I think, as I speculated earlier, I have a hard time envisioning a future where we were this is not a type of drug that many people will take SDH specifically, I mean, we'll see the data from the phase three trial on Alzheimer's disease in 25 or 26. If it has benefits on preventing the progression of neurodegenerative disease, if it has benefits on cardiovascular kidney disease. I don't I mean, you can view it as kind of healthspan type of enhancing drug and again, let's it will not be some appetite or we go we it will be next Next, the next iteration of these types of molecules that are being refined, and maybe again, there'll be more individualized or personalized. Catering to different needs, I think most important is that the biggest fear is that we create a large separation between between socio economic classes, right. So you, you basically see the rich get healthier, and the poor gets no access to these types of molecules. And you'll see even further separation in inequity and inequality.

Nick Jikomes 1:25:29

Yeah, I mean, yeah, I mean, you can easily imagine that happening, because you know, if these things are expensive, and the work, that only certain people are gonna be able to afford them every month. Well, so one question I have, too. So related to just the general topic of hormone replacement therapy, you know, a lot of people do, you know, you see more and more people using growth hormone or testosterone replacement therapy and things later in life. And we know that a lot of those hormones, you know, generally go down with age. And so you're sort of just you're sort of just compensating for this age related decline that we naturally see with a lot of these hormones. But what about GLP? One's natural time course? Do we know anything about how that evolves over the lifespan?

Christoffer Clemmensen 1:26:08

Good question. No, actually, I don't I would be interested, interesting, interested in seeing like meal responses in very old individuals to see if they have impaired to Pawan secretion? I don't I don't think so. I haven't heard about it before. So I actually don't think it's changing with age. I wouldn't think so. But it's a good question. But I think, for the hormone replacement therapy with age, I think, and this is outside my field. But I'm always worried that if there is a meaning with the decline with age that pertains to the risk for developing cancer, basically, is that maybe what is the risk for, for for cellular kind of uncontrolled growth increases as we age, maybe you want less growth factors to promote that risk? I don't know. It's it's speculation, right. So I think that that could be one risk. But as we again become better with medicinal chemistry and targeted delivery, I mean, again, testosterone is a steroid hormone. And if we can think about ways to deliver it using peptides to tissues, where we actually want it, and then prevent it from going to the tissues where we don't want the testosterone signaling. I think those are more the strategies that I'm interested in, right. So one can easily envision a muscle targeted delivery of, let's say, testosterone, where you're probably not too worried about having having that delivered. But you don't want it to the to the cardiomyocytes to the heart muscle, right? So there's these these things you need to figure out how to how to how to do interesting.

Nick Jikomes 1:27:45

Well, so here's what I hope will be a fun but instructive question. Let's just hypothetically, let's just say you wake up tomorrow, you look like you're a lean fit guy. But let's say you wake up tomorrow and you've got a BMI of 30. So now Christopher is obese and you're not diabetic, but you are obese. Walk us through the thought process that you would have for you know, thinking about should you take one of these drugs, which one should you take? How would you think about it if you were obese?

Christoffer Clemmensen 1:28:16

I think I would, I would go ahead and start with testing either there's two on the market there is it's it's assembly gets married as we go. We is so magnetite and the dual GOP one chip Coronavirus. Medallia is marketed as set bound. So those are the two drugs that are available from this class right now. I guess I will Yeah, I think I would, I wouldn't hesitate with trying to put starting on one of these therapies. If I have failed in all other attempts, as most individuals with ADHD have for decades, right? They've tried all the diets out there and continue to to experience failure upon failure and you have the stigmatization, why not for once kind of get help with with pharmacotherapy? If, if that's now available. And if you respond well to the drug, you won't get the I'll be worried about the adverse response in terms of nausea and vomiting. And then I would hope I would respond well, right. So I think those are others, my kind of thinking about these considerations, but in

Nick Jikomes 1:29:25

with respect to those drugs that are on the market right now. Is this the lifelong commitment? Do you need to stay on these drugs? Or, you know, what do we know about weight regain coming off the drugs?

Christoffer Clemmensen 1:29:36

Yeah, so the few studies that have been done on this are very clear is the moment you stop treatment, the patients will regain weight as we know from all other interventions at lower body weight right. And

Nick Jikomes 1:29:47

when they regained the weight is that the same distribution of fat and fat free mass as before, that

Christoffer Clemmensen 1:29:53

has yet to be determined? And again, that will be very individual. So you can envision a scenario where you You've lost whatever kind of proportion of fat and lean mass. And then you condition two individuals one is going off to therapy and staying on the couch and the other one is being very active. So as you are in a positive energy balance, anabolic state, and if you're at the same time stimulate muscle protein synthesis, you'll have some of the excess energy go into muscle building, basically. And if you have absolutely no muscle protein synthesis going on, you can imagine that most of the excess energy will be going into your fat depots. So I think the devils in the detail with respect to how the weight regain will will affect body composition.

Nick Jikomes 1:30:39

What? So with respect to your lab and the research you guys are doing, what are some of the next steps for you guys in terms of these weight loss drugs? What are you working on now and what's on the horizon?

Christoffer Clemmensen 1:30:49

So we're continuing, we're excited about this peptide directed targeting of small molecules. We're excited about neuroplasticity in obesity, very excited. So we continue to think about other ways of targeting neuroplasticity for sustained weight loss. That's kind of our long term kind of dream project to be able to better understand weight homeostasis to create a therapy that will have sustained effects with very infrequent treatments. And at the same time, we continue to add on modes of action. So we have of course, started to develop this dual incretin with a small molecule. So we have kind of triple acting peptide, small molecules. And then we started to look at other indications also, especially in neurodegenerative disease. So if we, if the increase in hormones turns out to have a benefit on preventing progression of Alzheimer's disease, maybe attaching some of these NMDA receptor modulators to the inheritance will actually even benefit those type of indications more so we're looking at other indications also, right now. So many, many different directions, but we're excited about the targeted delivery, neuroplasticity and, and other indications for these molecules.

Nick Jikomes 1:32:07

All right, well, Professor Christophe Clement Clemmensen, thank you for your time, fascinating stuff. I was happy that you decided to come back on and talk about some of the newest work, and I look forward to seeing what you come up with next.

Christoffer Clemmensen 1:32:20

Thank you, and thank you for the invitation. It was a pleasure.

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Mind & Matter
Mind & Matter
Whether food, drugs or ideas, what you consume influences who you become. Learn directly from the best scientists & thinkers about how your body & mind react to what they're fed. New episodes weekly. Not medical advice.