GDF15, Morning Sickness & Mitochondrial Stress | Stephen O'Rahilly | Episode 311

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and Matter Podcast. We learned together from the best scientists and thinkers alive today about how your mind-body reacts to what you feed it. Before starting Mind and Matter, I spent 10 years in academia doing scientific research. I got a PhD in neuroscience from Harvard University where I focused on neuroendocrinology and the neuroscience of behavior. And before that, I specialized in molecular, developmental, and evolutionary genetics. I used my scientific background to parse and translate information guests share on the show. And in addition to the podcast, I write long-form content and send out a free weekly newsletter at the Mind and Matter Substack at mindandmatter.substack.com. I also offer private, science-based health consulting, where we work one-on-one and apply the same rigorous evidence-first approach you hear on the podcast, the personalized. We can obtain and analyze your biomarkers, work on diet and behavior strategies, review supplements, and drugs that you might, or anything else related to general metabolic health. So, if you'd like more tailored guidance on your personal health, head to nickjikomesomis.com and fill out a short form or book time with me there. A great way to support my content in all of its forms is simply to visit mindandmatter.substack.com. You'll find a link to that in the episode description, and you'll also find a link to my current affiliate partners through my support page. These are products that I use myself that relate to physical, metabolic, or mental health. For example, one product I use every day is the aquatru water filter, which removes heavy metals, microbes, and orcundisrupters. You name it so that you have higher quality drinking water. All of those links for health consulting for my affiliate partners and the substack page are all in the episode description, so thank you very much for listening and don't forget to check out mindandmatter.substack.com for all of my content. Hey everyone, today's show is supported by Brain Bean coffee. Brain Bean is my new go-to coffee every morning. It's clean, it's smooth, and you're going to feel good about drinking it. Coffee in general is one of the richest sources of polyphenols in the modern diet, especially something called chlorogenic acids. Research has linked chlorogenic acids to brain and metabolic health in different ways, but the problem is that conventional roasting burns most of them off before the beans reach your cup. Brain Bean solve this with smart roasting, which is a proprietary process they design and implement to preserve the coffee's delicate balance of polyphenols. So in Brain Bean, you get something like 447 milligrams of chlorogenic acids in every cup, which is two to five times higher than other coffees on the market. Brain Bean is USDA organic and comes from a sustainably farmed single estate. Every lot is third party tested for molds, micatoxins, heavy metals, and pesticides. They sent me a bunch of their testing literature, so I've looked at it myself and they do a lot of testing, which I like. If you're looking for an enhanced version, they also have a Zen blend coffee, which is the same smart roasted beans infused with things like L-thienine, alpha-GPC, which has coline and MCT, medium chain triglycerides. It helps keep you calm so you can carry on with your day. Head to brainbean.com and use the code Mind Matter 15 for 15% off your order. They've also got other stuff too, so check that out. I like their grass-fed colostrum product. I actually put it right into my coffee. They've got collagen peptides and lots of other good stuff as well. So check out the link in the episode description or go to brainbean.com, which you can also find on my support page at mindandmatter.substack.com and use that code Mind Matter 15 for your 15% off discount today. O'Rahilly, not O'Rahilly. Thank you for joining me. Do I have the time to chat? Do you want to take a moment and just introduce yourself to everyone and talk a little bit about who you are and what your lab studies?
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Sure. So my name is Stephen or Steve O'Rahilly. I'm a physician scientist and endocrinologist by training and instinct. I've been at the University of Cambridge running my own labs since 1991 and indeed as well as running my own lab, I helped to build up a group of scientists here in Cambridge studying disorders like obesity and diabetes. I'm built the Institute of Metabolic Science, which is now one of the world's largest institutes studying these diseases. If you ask me what I do, I suppose my scientific career has been a tale of three hormones. I've worked on why what insulin does and where it goes wrong and why some people are resistant to insulin and we still work on that. I've worked on the control of body weight by leptin and its downstream mediators and why that leads to obesity. And in the last seven or eight years, I've developed a new interest in this hormone, which wasn't really recognized as a hormone until about seven years ago, GDF15. So there might kind of three babies that have kept me going for decades now
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in the lab. And so I just have to ask because I don't really know how this works and I believe you're the first night on the podcast. But, sure, Stephen O'Rahilly, why did you get knighted and how does that process work if we take just a minute to tell us? You kind of never know. It's a
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classic British, it's a quiet British phenomenon. You never know why, but you do get a letter from the cabinet office and from the prime minister's office saying that at the time the monarch, it was the queen then, is minded to give you an honor and would you accept one? And you have to say you would accept one and you wouldn't. As an Irishman, it's a bit unusual because I didn't even have an English citizenship at the time. I guess you get these things for contributions to general, I mentioned I built the Institute of Medical Science. I did quite a lot of stuff for young physician scientists around the countries supporting the development and career trajectories of young physician scientists. You know, it's hard to say because these things take behind the type of place behind closed doors and I don't think they become open to public scrutiny for 50 years. So, who knows? You know, people, whoever was on the panel like me, and thought I might deserve some recognition for the work I've done in the UK. It's rare to get it purely for science alone. I mean, I think if you win the Nobel Prize, you almost pretty much definitely get knighted even if you've never done anything. I think in general, it's kind of a mark of somebody's done some good around the place for a lot of people in the public domain. And I'm very grateful for the great work of the National Island. So, three hormones will probably we'll talk about at least one
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and potentially all three to some extent today, GDF15, which is probably going to be newer and less familiar to most people. Sure. And then insulin and leptin before we dig into some of that biology, I want to have just a general discussion with you for a little bit about what turns hunger off in animals. When do animals stop feeding? Now, the one thing that clearly turns off feeding sometimes is when you have a big meal. If you eat enough, you feel full, you stop eating, we know that from direct experience, we know we've all seen the documentaries where the lions kill the water buffalo, they eat pounds and pounds of buffalo, and then they rest and digest. So a full stomach tends to give animals a feeling of satiety, and they stop eating for some time. What else? When we think naturalistically about animals out in the wild, natural circumstances, natural signals, natural stimuli, besides eating a lot, what are the types of stimuli, the types of environmental contexts that turn down hunger in animals and cause them to stop eating for some time? Well, I mean, the classic is the illness response generally. I mean, there's a
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stereotype set of neuroendocrine actions that occur if cytokines go up, for example, or if my favorite hormone GDF15 goes up which happens in similar, but not entirely overlapping circumstances. And so we have an inbuilt circuitry, which basically says, hey, you're sick, you may just have ingested the thing that made you sick. The last thing you want to do is keep eating more of that stuff that you made you sick. And those signals come up through the hind brain into the parabrachial nucleus, and then it tends to be that center in the parabrachial nucleus that really coordinates the the aversive response to eating. So all of those signals coming through the area post-trainer, that bit of the hind brain that's open to the bloodstream. And as I say, the cytokines that do infection, they're not entirely the same as what happens with GDF15 with the cytokines you get fever. And that's almost certainly to help you shake off the bugs that are causing the
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tend to have a particular temperature preference. So there's a circuit in the brain for the non-neural scientists. We're talking about circuitry that's largely in the brainstem and the hypothalamus. So this is sort of an old ancient very hardwired circuit meant to detect aversive stimuli and
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regulate feeding appropriately. Yeah, absolutely. And it's not just the parabrachial nucleus, which is in between the hind brain and the hypothalamus, is... It's increasingly seen as really the critical place that makes you go, if that's the sort of center of nausea behavior and it's a relay center to things like a vomiting, for example, that can actually happen with much more local circuitry within the hind brain, but it certainly sends the adverse signals upstream. You know, GDF15 doesn't make you fever, for example, but it does give you the same sort of sickness behavior as the lying down, the reduction in physical activity, the inability, the lack of desire to ingest any food, even increasing peak cuts, you know, the phenomena when you eat soil rather than food, with the idea that that actually helps clear any toxins that have been ingested.
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Yeah, yeah. And I guess so, you know, you can eat a lot and get a full stomach, that'll make you less hungry, that'll make you eat less. It almost can get sick, basically. You ingest something, a poison, a toxin, something, and it's gonna make you sick. We've all been nauseous, we've all had a fever, had an infection. Obviously, you get nauseous, you don't want to eat. In fact, sometimes the opposite is happening, you're spitting up what you recently ate. This is tie-in two to why we see sometimes just animals like pets, house cats, and stuff. Sometimes it's like they go eat grass or plant or something, and it seems like they're trying to throw up on purpose.
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Absolutely. Well, I mean, there are certain animals in rodents, for example, can't vomit. So you peak out, this is eating of non-food stuffs to clear things through the circulate, through the gastrointestinal tract, is the equivalent of vomiting in species that can't vomit. And then what about
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what about just like fear and predation? So if I'm a rodent, say out in the wild, I might be out foraging for food, but then all of a sudden, I've got to run for my life and hide.
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Yeah, well, there are some things that are more dominant for survival. Being eaten is the most immediate threat to your survival. Being a bit calorically deprived, you can cope with that for a few days. So there's a hierarchy of responses to those competing ethanol. And of course, that business of eating versus... You just see it in any wildlife movie you've ever watched to blinds and antelopes on the savannah. I mean, you can just see that the antelopes are calculating. The relative importance of continuing to chew on grass versus keeping away from the circulating predators around them. So that calculation must be deeply ingrained in the evolutionary biology of animals that are essentially prey. They have to constantly do that equation.
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Yeah, and that equation, there's some kind of balance of variables here. Some of them are tied to the external world. What do I see around me? Do I see a lion approaching? Do I see danger coming? And some of those variables are internal. So the brain is literally reading hormone levels,
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the levels of things that we'll probably talk about today to sort of read out, how hungry am I? How much do I need the calories and how do I balance that again, stall of these potential, competing demands out in the external world? Yeah, and it's much more complex than we've used to thought. We had a very one-sided and easy, simple view that leptin stimulated propolyomelic cordon suppressed. It's counter-regulated HRP. And that was all nice and simple and would tell you whether you were hungry or we now know that HRP neurons are incredibly sensitive. And they even increase at the visual appearance of food. So these stimuli, in this particular part of the arqueot nucleus, are hugely sensitive to external stimuli like visual stimuli or the smell of food. Far more, making that computational aspect of the arqueot far more complicated than we ever thought it was. Because it's taking the sort of vegetative signals if you like the leptin, the propolyomelic cordon, those sort of simple things of how much fat do you have, how much leptin do you have, you know, have you got adequate calories on board. But then you're getting the moment to moment flipping of these neurons with things like vision, things like the side of food, proximity to food, smell of food, all having profound influences on those neurons.
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Yeah, so you mentioned these circuits and the hypothalamus. These are actually some of the neurons that I worked on as a graduate student. They are responding and doing based on slowly changing signals like hormones that are basically telling the hypothalamus how much fat reserve do we have, you know, how recently did we eat things like that. But they can also respond very, very quickly. They can, you know, you're retina can see something relay that into the brain, you can smell something and so forth. And so these neurons can respond to fast and slow signals. And there are some kind of like integration that happens that ultimately informs the decision about do I keep looking for food, do I run for shelter and so on and so forth. Well, one of the nicest papers I think we ever
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published worked myself. My colleague said after Farooqi was my graduate student at the time of the fellow and then my colleagues, Paul Fletcher and Ed Bullmore neuroscientist. We took some humans in teenagers who had never seen leptin. He's a very rare at the time. There are hardly any of the people found in the world, but we had two kids, not kids, I had a lessons who had never seen leptin. And we took them and we showed them pictures in the FMRI scanner. And then we showed them we put them
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in the brain effectively, they volunteered to be in a scanner. What do you mean they never saw leptin? They were congenitally deficient in leptin. They were usually the body could not produce it.
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Yeah, and they had homozygous mutations completely obliterating them. So they never seen leptin and they were in 1560. They were enormously obese. But we managed to find a scanner big enough that they would take them. We put them in the scanner. They agreed to it. They were wonderful, wonderful kids. They were fantastically cooperative and really wanted to help us with the science. And we showed them pictures of things like money and footballers and things that should excite. And I looked at the various bits of the brain that normally get excited in kids but with and not much excitement happened. We showed them pictures of food and the areas of addiction and reward just went absolutely screaming in terms of blood flow activity. And even with things like cauliflower or broccoli or something that would normally cause a great deal of excitement. And then we gave them their first dose of leptin and we gave it for a couple of days. And there were still enormously obese but like five days later there was no change in their body weight. But within just those few days of giving leptin and then we put them back in the scanner. They had completely normalized their brain responses to so they were just as interested in money and football as they were in food and they weren't that interested in broccoli and they were more interested in ice cream. And so you could just see this amazing don't give me that this brain is how we are visually interpreting the stimulant, the excitement where is being influenced by this little hormone coming from adipose tissue. It sort of made me think that the Cartesian dualism of brain versus body was complete nonsense. I mean this is this beautiful integration of these vegetative signals with something as sophisticated as interpreting a visual image, you know, all integrating together in the kind of addiction areas of
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the brain. And that was that. Yeah so we're talking about leptin and the hormone. It's based, it's released from fat tissue. It's basically a signal that's telling your brain, it goes to the brain and it's telling the brain how much fat we have, how much stored up energy we have essentially. And so what you're saying is, you know, these patients, these boys that you were working with, they could respond to leptin, their brain was sensitive to it but their body could not produce it. Their fat cells were releasing it or whatever. And so it's illustrating how this hormonal signal from the body, from the fat tissue literally gets into the brain and it is changing how the brain responds to reward and ultimately sort of what motivates us and what we care about. Yeah absolutely.
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And you know, I think we in the era of the now the GLP ones and obesity we kind of slightly forgotten the 20-year ago era of leptin and what a transformative piece of work it was from Jeff Friedman who discovered it and that our contributions came along with the human. You know, this was really the first example of showing very clearly how a hormonal signal was absolutely essential to how our brain's regulated body weight. And both in mice and in humans, if you lack leptin, you are enormously obese. There's no question, there's no question, there's never an answer, that's an
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absolute not given. And that is because leptin is a crucial signal from the body telling the brain
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what the state of nutrient stores is and if it goes down, you know, we could debate whether it's what is real biology, is it more important in normal biology in the context of starvation? Because certainly when you starve, leptin drops below threshold levels and then you get all that you get all those messages to go on fine food, et cetera. Because when you get obese, leptin goes up but there is some flattening of the response and you don't, it doesn't totally prevent the onset of obesity. So there's debates, you know, philosophical debates about whether it's a starvation hormone or an obesity hormone, you know, that two ways of looking at it.
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When we think about and we think about hunger and satiety, generally, people often talk about insulin, in the context of fat storage, and how it's affected by diet. And it's often become insulin resistant. There's a very close correlation between metabolic dysfunction and insulin resistance, including an obesity. So even in people that don't have the rare genetic condition, or they're not producing leptin, we talk about insulin resistance, but there's also leptin resistance. So normal people can become resistant to the effects of leptin.
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I mean, that's almost by definition, if you're fat and you have high circulating levels of leptin, then by definition, in some ways, you're leptin resistant because you're not suppressing your food intake to go back down to a normal body weight.
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I mean, there are lots of people who debate
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the term leptin resistance, Martin Myers, for example, experts in the University of Michigan thinks it's a terrible term, we should never use it. It makes us blind to what, to the range of, it thinks it's just a range of normal biology. But I mean, there's no doubt that there are individuals who are truly leptin resistant. I mean, there are plenty of people now who are defined with leptin receptor mutations and homozygous, and they look like people who are totally deficient, and they don't respond to injected leptin. But I think that it's not unreasonable
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to think about leptin resistance,
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and then if you think it's, could we be smart enough to come up with drugs that overcome leptin resistance and become leptin sensitizers? It might be possible to develop something
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that could be a leptin sensitizer.
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And that's not crazy. I'm aware of several biotech companies looking for leptin sensitizers. Yeah, but in some ways are the GLP-1 agents leptin sensitive, they are, because they make you get less, obese your leptin levels drop. And my guess would be if you took people who had been rendered normal weight by giving them GLP-1 and you gave them a shot of leptin, they probably respond better to that leptin. So almost anything that makes you thinner within some way leptin sensitizes you. So leptin, it's a, it's cytosatiety and hunger.
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It's literally like a fat, it's a fat to rise, it's telling your brain how much body fat you have in essence. Yeah, I mean, it's more,
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it's broader than that and more important than that in some ways, because basically you can imagine, I do see it more as a starvation hormone, and it's like the Sherlock Holmes dog that didn't bark at the night, you know, the famous story where it was, it gave more information by not barking than barking. So leptin does, when leptin drops to become undetectable, that's when it's doing its real work, because A, it makes you go and say, geez, I've got to really find some food. B, it switches off your sex hormones and your reproduction and says, forget it, it's not a time to reproduce. It turns down your immune system activity to save calories, so that you're, you're in the large amount of calories you're expending normally on turning over immune cells, it's shut right down. So it does a whole range of things to help you survive a period of starvation. So that's what it does in its dropping. It turns on the glucocorticoids and stress hormone, again, to help you get through this period of stressful lack of calories. So that's, I guess, what leptin really does in its role as a starvation hormone.
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So when you're starving, your body fat goes down,
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it gets lower and lower. Eventually, you're truly starving, and now you're at risk. Leptin will be very low in that case,
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so it's a Glee starvation. It's a kind of stress response. The other hormone that goes up under conditions of stress, basically, and that's what you mentioned before, GDF15. What does GDF15 stand for? And what are the basics of what that is?
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Oh, Lord, it was christened by a group of scientists. Who thought it was part of a, I'm gonna have, I'm so embarrassed to have,
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I've forgotten what the GDF15 is. Isn't it growth differentiation factor?
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We've got one of which group, which group it was. Yeah, yeah. Because the guy who discovered it, Sam Breit hates the name. I think it shouldn't be, so Sam Breit discovered it. Right, it's an example of one of those things where... I'll tell you how it actually really happened, is that Sam was an Australian who came back to set up his own lab in Sydney back in the late 1990s. And he did expression cloning, and he expression cloned it from activated macrophages and called it MIC, macrobate with a microfagion, hipetry cytokine, MIC. And then it is discovered that it looked like a bit like members of the TGFB to super family. And that's when an international committee gave it its GDF15 growth differentiation factor, Monica, so we've kind of... It's not that meaningful a term. What Sam really found out was that if you transgenically overexpressed it in mice, they lost weight. And then he also discovered that it acted through the hind brain because if he's lesioned various bits
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of the brain, nothing happened,
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but if he lesioned the hind brain, the minds didn't lose any weight when given GDF15. So Sam kind of interpreted this, that the GDF15 may have been a leptin-like signal, something that comes from the body, because GDF15 is produced in many cells
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throughout the body, and then an ax on the brain.
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And it was in 2017 that four different pharmaceutical companies simultaneously identified the receptor. And there's a couple of interesting things about the receptor. One is that it's a hetero dimer of something called GFRAL and the tyrosine kind is ret. But the amazing thing about it is it literally is nowhere in the body apart from the area postrema and the immediately adjacent nucleus tractus solitarius. But there's only in those brain regions. I mean, you'll hear people argue, and you'll hear some things going around, but basically the strong papers and my own work that we have been used on published using techniques that can measure a single mRNA species of... We never see a single mRNA species of this. Anywhere other than in these two nuclei in the hind brain. And when I heard that work presented, I went to... I discovered this that when I went to a scientific advisory board meeting at Novo Nordisk, this is all unpublished.
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But I just got one of those hairs on the back of the neck
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moments of this is back in 2016, 2017, thinking, oh my word, we've got another hormone on... We've got another hormone on the block.
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We've got something that is going from the body to the brain.
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This has got to be doing interesting and exciting things. And we must start, our lab must start working on it. So we started working on it. Some of it in collaboration with Pfizer and my colleagues at Pfizer. And we were the first to show that this was an aversive signal that if you gave GDF15 to mice and get paired them with a flavor, they didn't like the flavor you paired it to.
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So we can see that it was truly aversive.
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And my... So that was one of our earliest pieces of work to show that it was aversive. We showed that it caused an increase in stress hormone levels when you gave it. And basically I came up with the idea and I wrote this in a brief editorial in 2017. I called this the central hormone. I said, you know, infection is well covered in humans and mammals. We've got loads of cytokines. We know what happens when you get lots of response to infection. But threats are not just infectious when we were evolving. There are lots of noxious foods, lots of poisons. We need something that is responsive to a wide range of such stimuli.
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And that was one thing we knew about GDF15 is that it went up
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no matter what type of toxin you gave to a cell or what type of... Whether the toxin might have connoisseur toxin, whether it was ER stress. It just went up in response to all those sorts of stress. So I suggested that it was essentially a warning hormone to basically say, hey guys, that you've just come across something quite nasty. Throw it up, lie down, get better, don't do it again. And we've recently shown you some unpublished work that if you give mice some tiny dose of alkaloid flavor and a bit of flavor, and they don't taste it if they're a wild-type mice. But if you give them a tiny dose of GDF15, we can enhance their ability to spot nasty chemicals. So GDF15 actually changes the taste thresholds for alkaloid chemicals. So high GDF15 levels make animals eat less, ultimately lose weight. But it's not simply tied to eating food. It's actually tied to detecting averse of stimuli such as toxins. Absolutely, yes. We show in our first paper, back in 2019, we, with my colleague David Satt. and Satish Patel, we re-showed this was not consistent with a leptin-like signal which went up with food and down with stuff. It was much more consistent with a toxin detecting a system. And then, so we've continued on that since and it's working cancer cachexia because cancers are very stressed and cancers produce a lot of GDF15 and quite a bit of the weight loss associated with cancer is due to high GDF15. Pfizer have a phase 3 study now going on in cancer cachexia and phase 2 showed for the first time. No one has ever been able to reverse weight loss during cancer cachexia and there are phase 2A study. They did show some reversal of weight loss in people who had high GDF15 levels. So I think this is little doubt that GDF15 is playing a role in the weight loss you see with cancer and that may end up having some genuine therapeutic benefits. I mean GDF15 is certainly driving. I don't know if you've ever had a friend or a colleague or a patient or whatever but who gets this platinum treatment and how awful that makes you feel when the nausea and vomiting of cancer chemotherapy. That is entirely GDF15 driven. So, this platinum drives lots of GDF15 production. She goes up rapidly and hits the hind brain and makes people throw up. So I think this blocking GDF15 again should in the future have real therapeutic benefit in the nausea and vomiting of chemotherapy. But the thing that we got me most excited was when I suddenly started reading again, Sam Breit's old work on GDF15 being very high in human pregnancy. Just even normal pregnancy. And then you may be familiar with the fact that quite a few mean at least 80% of women feel a bit sick in pregnancy, 2% are hospitalized with severe recurrent, and about 20% of women lose about 16 weeks of work due to intolerable nausea and vomiting. So it's a big problem. It's an understudied and unbig problem. And basically we that's me and my collaborator in California, Marlena Fejzo, between us basically figured this out and sorted out the role of GDF15 in nausea and vomiting and pregnancy very recently. And I think that's going to rapidly turn into treatments and prevention. And so that's been a very exciting journey into something I never thought I'd work on. But that's what we've been doing for the last couple of years. So GDF15 can go up if someone is sick with you know, in infection. GDF15 can go up if you're ill from a disease like cancer and cause you to eat much less. It can go up if you're eating something that has a toxic chemical in it, plant alkaloid or something like that. What about what I'll just call normal food? What if an animal has a normal meal of a normal size? Does GDF15 go up or down when you're eating normal food? It really doesn't because and we have done we have done major studies of overfeeding and underfeeding and collaborating collaboration with colleagues in Louisiana who had the I have done overfeeding studies in humans and underfeeding studies it barely shifts. So so it's it's not doing that sensing of caloric amount through it really isn't I mean we showed very very strikingly I mean amazingly stable in fact in these individuals who have been systematically overfed over a six week period amazingly hardly shifted at all and these were and these are people really putting on substantially amounts of weight and they said now the one thing that might it can happen if you've got food allergy that there's there's there's there's a Ruslan medicine for doing some nice work saying that you know if you get food allergy the nausea and sudden vomiting and feeling feeling crap that people get when they're truly food allergic and they develop an intense cellar GDF15 is partly responsible for the symptoms they get with food allergy but it's not you know I think you know that's a very nice point you allowed me to make the contrast between it and leptin in terms of it being it's not a nutritional amount sensor that's that's not what it's what it's
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what it's yeah it's not it's not telling the brain how much food you just ate or how much calories around either either based on what you just ingested or leptin by how much fat you have it's somehow tied to distress or aversion something going wrong is there you said overfeeding doesn't trigger it can you is there any type of meal that you can give an animal that will cause GDF15
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to go up that let me let me correct myself slightly from one of them if we take mice and we give them a hive 60% fat diet really and we keep giving them for weeks and weeks we start getting put fat in their liver and we start giving them fatty liver disease
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then the GDF15 goes up big but what's going up it's going up because the liver is diseased right right you know it's you know what we've got is a fat induced disease so if you feed an animal a diet chronically such that it starts getting fatty liver disease the GDF15 will go up when the
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liver starts getting filled with fat and probably becomes dysfunctional the stomachs yeah and because of the and what we can do is we can do the same to to GDF15 knockout animals who don't have GDF15 and give them the same amount of thing and actually they end up putting on more weight because it's the ones who are getting sick are getting put off their food and this brings us to
00:35:23.000 --> 00:36:04.000
I think an interesting point which is so GDF15 knockout they gain more weight they are not producing this kind of distress signal or they're not responding to it and so the I guess the idea here that we can talk about is something is happening to cause distress or dysfunction in tissues and presumably GDF15 is tied to eating less in this case in order to prevent more of that dysfunction from coming up that's right that's right yeah yeah so where so we said it's made in the body it's made across tissues let's zoom in a little bit further where is it made within the cells where
00:36:04.000 --> 00:38:18.000
were all deluretl exams pt not like a hormone which is stored in little different stimuli can put it up. I mean I'll give you two examples of who are the people who have the highest levels of GDF15 in the world that we know of and they have it correctly. The first group are people with thalassemia. Now thalassemia is a blood disorder. It's a blood disorder due to a mutation in the alpha globin and in some cases this is alpha thalassemia, the other globin chain and sorry that there are other repeated lobin. Either of the globin chains which means that they have a very dysregulated production of hemoglobin in their reticular site and their red blood cell precursor such that the protein stress, the unfolded protein stress is immense. So and of course your red blood cell precursors are all over your body all in the bone marrow so there's many many cells in your body and every one of those cells is highly stressed and those people with thalassemia have levels just as high as you see when you give people chemotherapy or give them they have it lifelong. And similarly people with primary mitochondrial disorders people with mitochondrial mutations also have extremely high because the mitochondria stresses through to the through to the so there are seem to be multiple arrows down to the transcription on regulates the regulation happens at the transcriptional level as the M-R&A goes
00:38:18.000 --> 00:38:22.000
up and then the protein goes up so it is it is largely a transcriptional
00:38:22.000 --> 00:38:58.000
regulation and so it's it's it's quite remarkable there are very few proteins which seem to have so many levers to turn them up either levers through P53 or other other stress related integrated the inter-stress bond they just seem to be every form of stress in the cell has come down into the promoters of GDF15 and made it possible to turn it on so yeah so lots of
00:38:58.000 --> 00:39:02.000
different forms of stress can turn on GDF15 GDF15 is produced throughout the body
00:39:02.000 --> 00:39:21.000
you know the M-R&A is located inside us all of cells so when some kind of stressor is applied GDF15 can go up it can go up how how specific are these signals both in terms of their production and their readout in the brain so for example if we take the case where you're giving this egregious diet to mice for
00:39:21.000 --> 00:39:30.000
weeks on end and they start getting fatty liver disease is the liver specifically cranking out GDF15 or does the rest of the body crank it out too and
00:39:30.000 --> 00:40:40.000
can the brain even tell where that signal's coming from first of all let me turn to the brain first the brain can't be a power is coming from because it's just it's blood delivered in all in all circumstances it's blood delivered however what the brain can detect and does seem to be able to detect is the rate of change of increase of GDF15 not just its absolute amount and the response that the neural circuitry of the brain has is very much dependent on the rate of change. So I've just told you about kids with thalassemia. They have levels that are astronomical. If we gave you that fusion, you'd be throwing up for a week. And these kids are not throwing up with thalassemia. They have desensitized the system. So the system is capable of a over time desensitization. And so what's often being detected is a rate of change. Right. So if you're one of those kids, you've got high GDF15, but if it's consistently high, the brain is paying attention to how consistent that level is.
00:40:40.000 --> 00:40:42.000
Now what I would say is that we rarely,
00:40:42.000 --> 00:41:11.000
and we've looked at this in some day, we rarely see any obese people with thalassemia. So it may be that that very high level is maintaining some tonic reduction in food intake. Because that's a kind of guess, because we don't have the epidemiology strong enough to prove that. But it's just striking that you don't see many obese, even in cities and things where there's plenty of obese people. If you have thalassemia of that level, you don't seem to get that.
00:41:11.000 --> 00:41:12.000
And so that was as well.
00:41:12.000 --> 00:42:04.000
Now returning to the site of where it's being produced, you're absolutely right. The site depends entirely on where the cellular stress is taking place. Now one nice example of that is the commonly administered drug metformin. And we showed a few years ago that if you give metformin to people, they increase their GDF15 levels by two to threefold in the circulation. And actually what we showed by working in mice and knock out, that's entire, that's why metformin causes it to lose two or three percent of your body weight. It's not a very strong and body weight. But it's the GDF15 that's doing the body weight. So in such a case, you give metformin is used for different reasons. It's sort of been touted as a longevity drug, perhaps,
00:42:04.000 --> 00:42:08.000
some people. But when you give metformin, GDF15 goes up.
00:42:08.000 --> 00:42:42.000
And based on what you've told us so far, when GDF15 goes up, it's not telling your body's not telling your brain just eat less. We've got enough calories. You're telling your brain something stressful is happening. We are in distress and therefore let's eat a little bit less to maybe fix the problem or something like that. Yeah, and the question is, that brings up the question. Is that a healthy way of doing metformin is giving you. But what I would point out is that GDF15 almost certainly also has some stress. So if you give GDF15 to animals paired with a color,
00:42:42.000 --> 00:42:44.000
they don't want to go back to that, that's a lot of stuff.
00:42:44.000 --> 00:42:51.000
So there is a diverse element to one of the commonest obesity, anti-obesity drugs that we're now using. It's...
00:42:51.000 --> 00:43:02.000
Do we know... Do we know if elevated GLP-1 or the use of GLP-1 therapies elevates GDF15?
00:43:02.000 --> 00:43:38.000
We don't, but I have no reason to think that it would. Although what I can say is that a subpopulation of GLP-1 receptor expressing neurons in the hind brain also co-express the GDF15 receptor. And it may well be that the nausea and vomiting that you get with GLP-1 is because it's hitting GFRAL, those expressing the same pathways in the hind brain. So there may well be a relationship between GLP-1 and use nausea
00:43:38.000 --> 00:43:51.000
and the GDF15 signaling pathway. Yeah. So GDF15 is... When it goes up, it's aversive. Presumably animals don't feel good when GDF15 is going up,
00:43:51.000 --> 00:43:57.000
meaning it's rising and the change in concentration is becoming elevated.
00:43:57.000 --> 00:44:16.000
It's sort of a general distress signal of some kind. I want to talk about mitochondrial stress in particular. What are some examples that have been studied of say mitochondrial diseases where GDF15 goes up? And what's happening there? What is the actual disease and what's going wrong under the hood? Yeah.
00:44:16.000 --> 00:44:57.000
So mitochondrial disease is a few areas where GDF15 is actually come into clinical practice. So doctors who practice mitochondrial medicine will use measures of GDF15 to help them confirm a diagnosis of mitochondrial primary mitochondrial. So it's so closely related to the pathophysiology of disease that it's being used as a clinical marker.
00:44:57.000 --> 00:45:06.000
GDF15 is sufficiently elevated. You're saying it's basically used to diagnose mitochondrial disease. Yeah. I mean, it's an FGF 21.
00:45:06.000 --> 00:45:49.000
They're together. They are used to help people. You know, if the So, sorry, I'm, I'm sorry, blanking there. I'm not sure not sure where I'm going with that point sorry.
00:45:49.000 --> 00:46:20.000
Okay, so it Marker of mitochondrial distress and disease it can be used ase as a, marker of those things. So it's used to clinically for that reason. So, so basically if someone were
00:46:20.000 --> 00:46:35.000
So' it is actually strongly associated with, if if you correct for other factors, and you have high GDF in it is saying something's going wrong. somewhere.
00:46:35.000 --> 00:46:39.000
It has been used as a mortality
00:46:39.000 --> 00:46:42.000
predictor in some large scale, population studies.
00:46:42.000 --> 00:47:15.000
So it's a mortality predictor in general people with higher GDF15 are more and
00:47:15.000 --> 00:47:20.000
that's right, that's right I mean they feed in exactly
00:47:20.000 --> 00:47:22.000
how the mitochondrial distress feeds into the
00:47:22.000 --> 00:47:34.000
integrated stress response is not... entirely clearly something to me but but it is it is one of the most of robust associations between a type of a stress
00:47:34.000 --> 00:48:10.000
and a high level of, and we made the distinction earlier, between acute and chronic overfeeding. So you can have a meal of a. normal size, you can even have a big meal today. You know, you give an animal a big meal once, and it doesn't really make GDF15 go up. But if you give them an egregious diet where they're over eating, you you know, bad stuff for a long period of time, you give them one of these egregious high fat diets that that lab mice are often given for weeks on end, and it will start to go up, presumably because there's some kind of mitochondrial distress starting to happen. What about other stimuli that we can make
00:48:10.000 --> 00:51:00.000
the What about physical activity, which brings us to the idea of exercise and training versus over training. Are there physical physical insults that can become chronic or too high that will, intense rugby matches in France among professional French rugby players. And showing that level is about doubled after having participated in a pretty heavy judy rugby game. So yes, there has been quite a bit of interest in whether GDF15 is a physiological signal after exercise, whether it's responsible. is you give a a DNA damage cis-pl to and this is been. a colleague my my colleagues the fiser to to prime its. you give a single dose of a DNA damage reagent like cisplatinum you inevitably get a massive surge in gdf 15 coming both from the liver and and the kidney cells, predominantly the cells that responsible for the production. And that is why these so-called highly-hylometic hematomic hematopropiasis, cisplatnam and a few others, that correlates very much with their abilities to acutely put GDF15 up. If you ask me chronically, then I'd go back to thalassemia and say, if you were born with a little abnormal factory of hem-heemidloban production in your red blood cell precursors, and that is causing immense amounts of intuitive stress response, you will have massive amounts of GDF15 in your plasma all your life. But that's not really fizzyome, that's pathology. So another thing that you mentioned, which is also a very common, a very natural form of distress and metabolic stress for some people is pregnancy and women.
00:51:00.000 --> 00:51:21.000
Obviously, the whole body has to accommodate another body that's growing inside of it. There's lots of tissue and metabolic rewiring that's happening. And a very common experience for women at different phases of pregnancy is nausea, vomiting, sickness, just not feeling good in various ways. What does GDF15 and its dynamics look like in pregnant women?
00:51:21.000 --> 00:52:27.000
Yeah, you've asked that question in a very interesting way because we kind of asked the two in that way, who's making the GDF? Is it the mother's stress body making the GDF15? What's going on? So it took us about, the body of work we published, we published it in nature a couple of years ago, myself and the same I call it Marlena Fejzo. And one of the things we found out was it's not the mother's body making the GDF15. It's actually entirely made by the fetus. Every middle, every million whole, every molecule of GDF15 that's in the mother's body is coming out of the placenta and is encoded in the fetal genome. So it's the fetal genome and alone that's making 99% or more of the GDF15. And we were able to do that because we had some genetically discordant fetuses and mothers who had different, therefore protein sequences of the GDF15 and we used mass spec to pull apart the two differences. So that was a very nice bit of elegant work to be used to
00:52:27.000 --> 00:52:32.000
show. That was perhaps a little bit surprising, right, because you might think, oh GDF15 ,
00:52:32.000 --> 00:53:35.000
it's a distress signal, obviously the mother's going to be distressed because it's a stressful change, but it's actually coming from the developing, it came from the fetus and 100% of it pretty much came from the fetus. So that was one mind, nothing. And then we started thinking back and of course what's fascinating is GDF15 evolved in George Fish, but actually GDF15 in the placenta and at high levels is humans and catarine primates only, not even spider monkeys, not even other monkeys. It's the highest level primates in the only group in which you get this high levels of GDF15 being made. So again, we can come back and that can help you think about the evolutionary basis and maybe I'll return to that moment, but to briefly say what we discovered, we discovered it's made all entirely by the fetus and the reasons why some women are sick and some women are not are twofold. One relates to the amount of GDF15 that the fetus is making,
00:53:35.000 --> 00:53:39.000
so if you make the fetus is making more, then you're more likely to be very sick, but
00:53:39.000 --> 00:54:16.000
more importantly actually was the mother's own biology. And if she had low, low, GDF15 in her plasma before she was pregnant, then she was at much higher risk of getting sick. If she had higher levels, she was at much lower level risk. So, okay, that's interesting. So I'm just going to think out loud here. So I can imagine two pregnant women and all other things being equal. One of them has low GDF15, which would seem to indicate low distress in her body overall. Maybe better might accundral function overall. Another woman is sitting at a higher
00:54:16.000 --> 00:54:36.000
baseline going into the pregnancy. She's got more of this GDF15 distress signal going on. So the woman listed with the lower GDF15 levels who become as is more likely, sensitive to the GDF15 produced by the fetus. It's totally unfair. And there's old data and there's
00:54:36.000 --> 00:54:46.000
old data that no one talks about because it's kind of dangerous to talk about, but it's there and it's real. And it says basically it says if you're a smoker before you're before you have your risk
00:54:46.000 --> 00:54:57.000
of having hyperamesis. So is it fair to say that women who get sicker during pregnancy, that could be an indication that they're actually healthier?
00:54:57.000 --> 00:55:31.000
I mean, there's certainly a correlation between this. It's not the total determinants. And much of the determinants are genetic and not to do with their illness. So the women, there's very strong genetic influences around levels of GDF15. So you're a level of GDF and you talk about these two women. Yes, their levels of GDF15 might relate to how good their diet is or how they smoke or don't. But they're also very strongly influenced by genetics, which they have no control over. So it wouldn't underest
00:55:31.000 --> 00:55:56.000
to the genetic. Right. Well, I mean, it's a little counter-intuitive to me because naturally, I would think if a woman becomes pregnant and she's pretty unhealthy and she's more distressed, then her metabolism's not working that well, this might be bad for the fetus and therefore, the fetus would produce more in that environment compared to the healthier woman. So next, I want to ask you like, how much variability is there between pregnancies? Why would one
00:55:56.000 --> 00:57:37.000
fetus produce, say, more than another? What's causing the production in the fetus? I mean, the fetal production, again, has genetic influences. We have a paper we're producing at the moment, being able to show that the fetal genotype influences the levels in the mother, whereas the maternal genotype has no influence. So we can see that what the fetus has is doing. There are other fetal influences. The size of the fetal percent, twin pregnancies are more female fetuses produced about 10% more, GDF15, so there are multiple influences. And of course, the fetus gets half as genetics from the mother, but also half from the father. So the father will be influencing what the amounts of GDF15. You ask about recurrence. If a woman has had hyperemesis in one pregnancy, she, she's much more likely to have it in a second and third. she's announced herself as someone who is effectively susceptible to those conditions. I go back to your obese woman going into pregnancy, and she's definitely going to have more risk of pre-atlampsia and low-small-fredation. Lots of complications, but not necessarily of the hyperemesis. So there are very good reasons to go into pregnancy healthy and not in terms of very important maternal and fetal health issues. So I wouldn wouldn't want to give the impression that it's a good idea to go into pregnancy unhealthy, because it might reduce your risk of hyperemesis. Yeah. I want to ask you next about. So GDF, so a woman gets pregnant. GD-DF 15 goes up
00:57:37.000 --> 00:58:07.000
by some amount and it's coming from the fetus. You would
00:58:07.000 --> 00:58:31.000
from things, actually. We have pretty rare almost all singleton pregnancies, so they're very precious. So each pregnancy is an extremely precious event. We don't have that many of them, and they're singleton. Secondly, we are serious omnivores when we're during our hunter gatherer. We ate everything. We were dependent for survival on eating a huge range of food,
00:58:31.000 --> 00:58:32.000
and we ate a huge
00:58:32.000 --> 01:00:07.000
and we ate a huge range of stuff and 3rdly we were highly we're highly migratio, so we kept on coming kans different to environments that we had to explore as we migrated the I the idea- so here's the idea of the cleverness of GDF15 and cleverness of taking that let's take the mother's placenta in the first trimester and send out a signal during the first trimester that makes her very wary of eating any stuff that might be too retogenic and damaging during the first thing. That's that's that's send out that signal because actually in the first trimester you're only trying to grow a kind of sesame seed into a plum. You don't need you know you don't need that much listen and by the way by the time you become pregnant you must have had enough left that fat stores to get pregnant so you're gonna have enough fat stores to keep a first trimester pregnancy. You you know. Got it. But when you start getting to the second and third trimester yeah that's when you need to start growing that baby. I see. So but there's the because the beauty of GDF15 is that you get on the desensitization so the vast majority of women get some nausea in the first trimester and then you gradually less nausea and less the second and second. Of course the only the only you know I've been focusing focusing on the hyper-emphasis but that's only 2% of the population they're like they're like the friendly fire and casualties of an evolutionary mechanism. Yeah. overall because it keeps the women from being exposed to bad stuff in the first trimester. You know, the husband goes back to the cave.
01:00:07.000 --> 01:00:11.000
What do you bring in that cave?
01:00:11.000 --> 01:00:24.000
What kind of rotten limb? Wow. So, yeah, there's a couple interesting things here. So, you only see this in so-called higher primates, this higher expression of GDF15 by the fetus.
01:00:24.000 --> 01:00:52.000
As you said, we mostly have one child at a time. We certainly don't have large, large litters, and many other mammals. They're very precious. The pregnancy takes a long time. Development is long and human and higher primate. So they're very precious. And at the same time in the first trimester, even though you're eating for two, that second person is a little tiny thing at first. So, you don't actually need absolutely huge amount of calories early on.
01:00:52.000 --> 01:01:56.000
You're going to need more and more as development proceeds. So, one way to think about this is that perhaps this is related to the woman being very selective, very picky about what she's eating, so as to avoid things that might be compromising the pregnancy early on. Yeah, and of course, that's when the pregnancy, you know, during, when I say to rapid genesis, it means malinformation. That's the time when even a single molecule can make your foot turn into a head. Right. You can make your foot turn into a head. Right. You can make your foot turn into a head. You can make your foot turn into a head. Right.
01:01:56.000 --> 01:02:07.000
Yeah. And perhaps these things are related. Yes. You want to be very, very careful, especially early on in pregnancy, and maybe biology has actually evolved to favor that tendency.
01:02:07.000 --> 01:02:19.000
Absolutely right. Absolutely right. Yeah. Yeah. It's the most dangerous 12 weeks of our lives. Yeah. Does nausea and vomiting during pregnancy? So tends to happen earlyed pregnancy, that makes perfect sense.
01:02:19.000 --> 01:02:25.000
How has that changed over time? Are more and more women have they started to get more nauseous and more sick
01:02:25.000 --> 01:03:56.000
earlier on over time? Or is that changed? It's pretty it's not it's pretty stable and and you know, the sometimes we us talk to colleagues they are is really isn't it just you know we're all a bit sensitive these days. I'm a bit privileged and isn't this the privilege person is kind of whining about the this is nonsense this condition of course across countries across time you know and a few years ago there was a survey of mortality in Botswana and it was the fourth common sense of maternal death in Botswana. It actually calls death because in rural Botswana you couldn't get access to intervene it's fluid rehydration. So you know and recently we did the study in Sri Lanka where we looked at thalassemia women we give questionnaires to them and their friends who recently had pregnancies and these were not a wealthy area of Sri Lanka this is not a well 10% of the control women had had hospitalizations because of nausea and vomiting and that's in a you know in a relatively impoverished part of South Asia. So it,, it's, it's ubiquitous. It's happening all the,
01:03:56.000 --> 01:04:13.000
you know eat a huge variety of foods eat as many different types of foods as possible you know have a very very diverse diet is that perhaps not necessarily the wisest approach for a woman in her first trimester I mean I think nowadays when we know we're not eating
01:04:13.000 --> 01:04:42.000
pathogens and harmful food and infected food we're probably all right we can probably still stick with a nice different a nice diverse of uninfected untoxic non-toxic food is I mean they're the you know just to remember back in our past how much our food was infected and how much of a food did contain you know microbial toxins and fungal toxins and other things not uncommon in period before we regulated our foods supply the extent we now
01:04:42.000 --> 01:04:57.000
wow wow so I want to talk a little bit about weight loss and weight loss therapies and things like that so we said already GDF15 is a distress signal so if you increase GDF15 the brandall
01:04:57.000 --> 01:05:00.000
detect that and you'll eat less and you might if you only knew that you
01:05:00.000 --> 01:05:05.000
you might think oh great this could be you know a weight loss hormone that we can start playing with
01:05:05.000 --> 01:05:15.000
you you know similar to other therapies that people are developing and and it looks like people have done experiments with dual GLP-1 GDF15 agonists and indeed they
01:05:15.000 --> 01:05:32.000
you can stimulate weight loss. Now, something like a GDF15 ag. here, because even though it's going to stimulate a less feeding, it, it is a distress signal, and therefore there might be some negative consequences to stimulating that receptor.
01:05:32.000 --> 01:06:45.000
There's a couple of issues. One is theoretical. Yes, in my own mind, if you want to lose weight, You probably wouldn't, of hormone whose job it is to make you feel terrible and so so that would be just one theoretical at least and then but in practical terms two companies Merck and Lilly at least two maybe basically there's a third I'm trying to remember the but have you have have gone as far as using making longt long acting GDF15 and uh and uh uh and despite in some cases having had quite promising results in primates have gone into humans and shown not only I mean the the nausea that you would expect in the acute administration but if they slow titration they have very very disappointing effects on weight on weight loss so that may be the tacky phylaxis that I mentioned the fact that it is a hormone that seems to downregulate its its responses to to sustained administration so at least as I say three companies have gone down the route of trying this and
01:06:45.000 --> 01:06:57.000
all have dropped out so yeah interesting so um a different so instead of agonizing the GDF15
01:06:57.000 --> 01:09:46.000
receptor instead of stimulating that pathway you could also think about doing something something in in the opposite direction so say you wanted to treat something like cancer cachexia and a cancer patient or maybe develop something that helped women that are very very nauseous and sick early in pregnancy be less so you might you might go in that direction is that a viable approach. Antigone is extremely viable and very active right now there are at least four companies developing a blockade of either G and or to G from the receptor in the treatment of cancer catexia Fisor did have a trial in heart in on people lost weight with heart failure But they had adverse results results in phase 2A so Adverse events so yes in cancer cachexia certainly multiple companies to say Pfizer in phase three blocking it to to result in a treatment for hyper-emesis would be a boon fantastic boon one company biotech company NGM is in phase 2b of their trials and and myself and colleagues that we are trying to we've just started a company we're trying to have our own ideas about how we might improve an antibody um correctly try to find funding uh to to allow us to do that what we do with funding from the british government is we are doing a lot of work for women who you know many women who have had hyper-emesis are very distressed because they love their baby and they's love to have a second child but they can't bear the idea of have going through the through the nasty experience they had in through the nasty experience they had in the previous one and as I mentioned to you you get this desensitization phenomenon which we can exploit and so we have got a grant to to randomize women to metformin which I mentioned to you increases your gdfd in by two or three fold and they what the idea would be that we would give that to the women three to four months before they're planning and ex-pregnancy before a planned pregnancy, and then see if the women so even in developing countries and in poor rich countries you know women who who had had hyper-emesis could could use this in there in their next pregnancy
01:09:46.000 --> 01:09:59.000
pregnancy how does um obviously a major part of pregnancy is your body changes you have to you have to put on weight you have to eat for two again um how does lefted signaling change across
01:09:59.000 --> 01:10:13.000
pregnant pregnancy Yeah, it's fascinating and its biology is almost unexplored because the placenta makes a ton of leptin And why on earth does it do that?
01:10:13.000 --> 01:10:15.000
Now that is that is a real
01:10:15.000 --> 01:12:44.000
Now I have my own ideas is purely speculative Leptin is really important to maintain the immune system. It signals is one of the few things that doesn't the peripheral blood is maintaining immune systems So you can a vision during our evolution if we had if you had a nutritional ease stressed pregnancy where the woman was eating up her fat and her and the leptin coming from her fat tissue was getting less and less. If you lost leptin completely then she would become an immunocom That's a hand wavy but I've never seen anything better than that suggested. My reason was why leptin is produced by such an extent by the by the presenter. Yeah, the question is what you could do that you could do to do that It's tough, I mean, yeah, because some people will be determined by your genomics and you won't be able to do much about that. Another another part will be department by you. The other thing I should have, it goes up inexurably and so the next thing will be determined by I can imagine a horrific explosive increase in investigation of people who are just having a high GDF15 and then they have and they can come from absolutely anywhere. It would potentially be quite an expensive addition to the ethical. Yeah, but just add a more basic level if I got a GDF15 blood test say I would probably like to see that number be little bit more.
01:12:44.000 --> 01:13:06.000
I want to shift gears a little bit and talk about obesity more generally in particular talk about things like certain aspects of adipose tissue biology and how that varies between people and maybe why some people are more prone to weight gain and obesity than others.
01:13:06.000 --> 01:16:02.000
, we think about adip post-t you it self and the but it's very difficult I'm not sure if you're able to give you data on that because it's really really it's a hard thing. Your potential fat storage capacity of any one individual is hard thing to measure. What I would say is if you, if you, you measure how metabolically healthy or sick they are, what do you think that the nutrients that they're eating are being healthily stored in the body and not causing any damage or their nutrients are causing them to be insulin resistant and a high triglycerides and low H. If you take the difference between those two people and then you do a high-pult. It's a normal piece of work as we do. We don't take any sort of a priori view of whether this is something in the brain or the liver or muscle or ________. We just ask what's the difference between these individuals and the fat cells screams out of the data. It really screams. There's almost no tissue other than fat and adipose tissue that comes out that says the genetic variance that me put you in one group or the other all most entirely being expressed in fat cells and an adipose tissue. And that what this looks like is that there are a group of individuals who can overeat but are abundantly k.a. producing particularly subcutaneous fats under the skin and particularly fat in the bottom and high hips and thighs and those kind of safe protective regions. Those individuals are fine with And it is the if you like the health of the adipose depot that is the biggest determinant of who's who's going to cope with over eating and who's not going to cope with over eating.
01:16:02.000 --> 01:16:47.000
This is the basic idea here is you've got this several fat that accumulate you know in your gut and around your or and then you've got subcutaneous fat that under the skin and this tends to accumulate you know in certain areas of the body. And one of them is generally seen as being
01:16:47.000 --> 01:18:02.000
that it's the absence of the fat in your subcutaneous tissues and that's really the main one because if we take genetic variance that that select, the absence of subcutaneous fat and the lack of. be.
01:18:02.000 --> 01:18:17.000
Making insulin lower, not having it too high to often what is your general view on insulin signaling and how critical it is as an area of focus when we think about preventing or reversing things like the idea be a city.
01:18:17.000 --> 01:19:46.000
I've been very careful of this because it's a controversial area one that generates a lot. It's some light sometimes more heat and I mean what I would say say broadly is that the causation of obesity, where where there's somebody is a obese or not has too much body fat stored or not. The differences between those two individuals are largely in the brain and they're large in the biology of it is largely to do with biology of appetite hypothesis for e-genomics, of simply looking at obese versus non obese. get a screaming brain signal, you, you know that the principal, the principal determinant of who's obese and who's not obese is a central nervous system, phenomenon. Now insulin can signal the central nervous system, but Ask when you get obese, who gets obese and sick and who doesn't who doesn't get sick now there the insulin does come in in a major way.
01:19:46.000 --> 01:20:00.000
And what do you say sick? What do you mean by sick?
01:20:00.000 --> 01:20:09.000
multiple where you're right, which are and ask what the question and in a and polycystic over is syndrome Things associated with having become obese
01:20:09.000 --> 01:20:12.000
So when you become metabolic
01:20:12.000 --> 01:21:10.000
obesity then the link to insulin action insulin resistance is is pretty strong there and you know, we could debate how how is it is it is an attempt at protective mechanism is it path of is it you know is it part of the path of physiology But I think it comes into the second order problem whereas a lot of people Put it into the first order problem and say that that the difference between being obese and not being obese is largely driven by your insulin and drop driven by foods you eat and if you have hyper insulinemia then you can become obese as a result of insulin Access and I think the evidence for that is less strong unless I'm less convinced that that is that is that that's a major driver of the differences in who's between who's obese and who's not obese
01:21:10.000 --> 01:21:20.000
What are some of the things that you guys are going to your lab today that you're particularly excited about that maybe we'll will start to hear about before too long. Yeah, okay, so
01:21:20.000 --> 01:22:46.000
We' we have a nice paper coming out in a month's time in a few weeks time in cell where we found that nearly a third of humans at least a third of British Europeans We haven't got quite the prevalence of other distributes to to test this yet but have got a Genetic variant in the ketone body receptor HCAR2 Which has has been hiding in plain sight. I mean it's been a nice story because it's something that's been The never-spotted because it was because of a genetic quirk And we essentially have found that this that The people have this he keep on body receptor variant and that Carrying that variant predisposes you to the metabolic syndrome and we have that don't our work with colleagues advisor and and The people The The there are two-thirds reduction in receptor expression because of the presence of this
01:22:46.000 --> 01:23:01.000
misence barrier. So that would imply that different sub-populations would be more or less well equipped to deal with ket, potentially use them for energy. Yeah. Or the normal physiological flip
01:23:01.000 --> 01:23:31.000
and the normal role of ketone bodies in suppressing it is abnormal in those kind
01:23:31.000 --> 01:23:40.000
like this type of variation among humans would imply that you know things like a ketogenic diet might work better or worse for some populations. Exactly. It'll be a lot of
01:23:40.000 --> 01:23:45.000
interest to the ketone community to realize that actually outed out there a third of people who've got
01:23:45.000 --> 01:23:51.000
a different way of responding to ketone. Interesting. Oh, what else? What else are you working on?
01:23:51.000 --> 01:26:29.000
And the next thing is something that really surprised me and I didn't really think you could be as important as this but we found a sink, we simply to lead a single family with two sisters with severe lipodystrophy, which is being a bad very, in a basement membrane protein, uh, lamina, um, and then we found some in Brazil in the same thing. So we proved that it's multiple families with, with, so it's a real, it's a thing. And my brilliant, uh, fellow colleague, you know, Sam Lockhart, thought that's quite interesting. It's an extra cellular, maybe, let's look more generally at ECM proteins and adipose tissue and how they link with waistip ratio and metabolic, and, sound found, an astonishingly common, uh, a number of rare variants. And if you go to UK biobank and all of us, about the million people are, so start looking at these genes and finding people who have heterosigas, luscious function mutations, and then looking at their body composition, there is an astonishing amount of genetic variation in genes that are expressed in adipose tissue, but, but, they're extra cellular, like collagen proteins and, uh, atoms, uh, metalloprotonazers, and, uh, look together as if they represent quite a, what a bit of the variation in health or, or absence of health of adipose tissue. So we're, we're, we're having to move basically, more. If you take an average gene in the the genome. just take them extra cellular membrane, you get up to 12% 10, at least 10 times more, uh, in terms of that, uh, uh, metformin, uh, I'm trying to start the company, uh, going. And so yeah, keeping going, hopefully continue to get enough money to do any, to do some work. Yeah.
01:26:29.000 --> 01:26:40.000
Yeah. Is there anything you want to reiterate from our conversation today about GDF15 and metabolic stress about hormones or B city, or, or anything that we talked about before we sign off?
01:26:40.000 --> 01:27:31.000
Um, I don't, I'm sure, I think so. I mean, I just think, um, you know, hormones are, are amazing. I mean, I, I, they've always led or everything that I've, that I've done them. I think, you know, that, they're made in, in one part of the body. And then they, they go out into the, the royaling sea of the bloodstream and they, they're, they're present in picomolar concentrations and they have to act like as if going out in a little rowing boat across the Atlantic from Ireland to America and send a signal in that distance. So if something is doing that, then it's got to be really important. So I, I guess what I've always tried to do is stick with hormones because they're, they're designed to be really crucial inter organ, uh, communicators. Uh, and they've got to be telling us some things that are really important.
01:27:31.000 --> 01:27:35.000
All right. Well, Professor Stephen O'Rahilly, thank you very much for your time.
01:27:35.000 --> 01:27:37.000
Okay. Thank you.
01:27:37.000 --> 01:29:27.466
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