The Real Reason You Can't Lose Weight - And How To Fix It | Dr. Simon Cork

0:00Dr Karan Raj: Our bodies seem to pull us to be a certain weight, and sometimes that's overweight. GLP-1 medications are helping, but what happens when we come off them? And can we permanently shift our bodies to help us stay thin and healthy, even off the drugs? That's what I'm finding out today with Dr. Simon Cork. He's an associate professor of physiology at Anglia Ruskin University.

0:19Dr. Simon Cork: If you are losing 5 % weight loss, you're probably not going to see an awful lot in the mirror, but it's going to have a huge impact on your health. Your blood pressure will decrease. Your inflammatory markers will decrease. Your risk of cancer will decrease dramatically. So keep at it.

0:34Dr Karan Raj: I'm Dr. Curran. And in this podcast, I speak to the world's foremost experts in science and medicine to cut through the BS of modern health advice. Thanks as always to Loam Science for sponsoring the show, the world's first invisible fiber blend with clinical trials. Simon Cork, you're an expert in appetite and gut hormone physiology. And I think we're beginning to understand more and pass out how big a role the brain has in coordinating with the gut and its role in appetite, in addiction, and so many things, you know, that's relating, especially to GLP-1s these days. Just talking about weight specifically, because weight is a conversation that people have been obsessed with for decades and probably even beyond that as well.

1:17Dr Karan Raj: What do we know about how weight is controlled? And specifically, why is it so difficult for us to change our weight from baseline?

1:25Dr. Simon Cork: I often, I think about weight a lot about in kind of how we think about how your heating at home is regulated around a thermostat. Lots of processes in the body are regulated around what we call a set point. So things like your blood pressure, your body weight being one, that we have this genetically defined set body weight that our body tries to protect at all costs. And so anyone who's dieted or fasted for religious purposes or tried to lose weight through diet and exercise knows that when you start to lose weight, you start to feel really hungry. We get this, what we term food noise, like the cheese starts talking to you in the fridge and the biscuits start talking to you.

2:08Dr. Simon Cork: You get tired. Your motivation to move starts to decrease. You get really grumpy. So your wife starts to dislike you because you're grumpy all the time. I mean, this is a physiological response to weight loss and it's protective. If we think about, you know, the 100 ,000 years of human evolution, we've not had 24-hour supermarkets and takeaways. So if we started to lose weight, then those physiological drivers kick in to essentially move you to the next part of the...

2:40Dr Karan Raj: So it seems our environment has evolved more rapidly than our physiology. So we're in a place of abundance of calories now versus a feast and famine.

2:49Dr. Simon Cork: But the opposite is also true. You know, if we, I've just come back from a week long, all inclusive holiday and my appetite has decreased, right? Because that's my body trying to get it back down to where it should be. So that balance of where your body weight settles is a relationship between when you put too much weight or try to lose weight. But the reason why it's so hard to lose weight is because you're fighting this biological battle.

3:13Dr Karan Raj: Now, obviously that makes sense mechanistically, how homeostasis is the priority of the body, that it wants to keep things in equilibrium. You mentioned blood pressure, the pH levels of our blood, it fights to maintain a boundary or a threshold. but if we look at what's happened epidemiologically our environment has obviously changed over the last few decades from a food perspective but our average body weight has consistently crept up how much damage does that do to this set point theory and is there some wiggle room there is it a settling point theory versus a set point theory because you know if it was very strict on that we shouldn't have been seeing an increase in body weight for everyone over these last few decades.

4:00Dr. Simon Cork: I think it's a, we have to, there's a lot of reasons, I think, why we've seen this drift in body weight and the food environment is certainly one of those areas, not only the abundance of food, but the types of food as well. And there's lots of research outside of my expertise, you know, in the nutrition, the dietetics area around, you know, the composition of food that we're eating our ultra processed foods and actually what that does to our guts, to our inflammatory responses, to our microbiome, all of that stuff, which can drive changes in how gut hormones and how appetite is regulated and secreted.

4:33Dr. Simon Cork: So there's lots of drivers for that, but also we're human, right? So although we might have this drive, certainly when we're looking at the overweight side of things, the eating more and the body weight increasing, we have the capacity to ignore those signals. And if you've been out for dinner and you've had two courses of a meal, there's no reason why you need to eat the third course. But we're human and we have areas of our brains that respond to those high calorie foods that can mean we're slightly more driven towards the higher end of eating than maybe under eating. And again, part of that is protective.

5:14Dr. Simon Cork: 100 ,000 years ago, we didn't know when the next meal was coming. And so having some capacity, some reserve for energy is protective.

5:22Dr Karan Raj: When we look at just appetite regulation, a huge component of that is hormones and it's biologically dictated. And I think a lot of people are aware of the hunger hormones, you know, the ghrelin, which goes up to drive the hunger. And then a lot of people assume that we've got the leptin hormone as well as other hormones, which drives the satiety. However, I guess it's maybe more useful to think of leptin as less of a fullness hormone or an anti-obesity hormone, which stops us overfilling the tank, but more as something which tells us the tank is empty. Would that be appropriate?

5:57Dr. Simon Cork: Leptin is more of a long-term regulator. It does have some short-term regulators, but it's more of a long-term regulator of your energy balance, your body weight. So most people, unless they're taking some certain medications or unless they have certain illnesses, most people are weight stable from sort of one month to the next year without having to spend, you know, loads of cognitive space thinking about how much calories they're intaking. And that is largely a manifestation of leptin. So leptin is, for those who don't know, leptin is predominantly secreted by fat cells. And the levels of leptin in your blood correlate very nicely with the amount of adiposity so those with bigger body weights with greater levels of adiposity will have higher levels of leptin than those with lower and when we talk about that set point that fine tuning of your body weight around what your settling point leptin plays a huge role in that so when i've come back from my nice week-long all-inclusive holiday and i've gorged for seven days my adiposity will go up slightly my leptin levels will rise ever so slightly and And that's my body's way of telling my brain that my adiposity, my fat levels have gone up ever so slightly.

7:12Dr Karan Raj: This only works within normal physiology. Once you break the bounds of normal physiology and we look at obesity states and there's maybe resistance or an ignorance of some of those leptin signals, this doesn't correlate so linearly. So someone who's obese can have high leptin levels, but they're resistant to leptin so the body won't respond to those satiety signals.

7:35Dr. Simon Cork: Exactly. So there's a few reasons why. So people with obesity do tend to generally have leptin resistance. And there's a few reasons why that might be. It has to get into the brain. And we think that it saturates those transporters that gets it into the brain. And the receptors that are signaling for it get downregulated. Now, what's interesting in obesity is that because the leptin, the signals from leptin are suppressed, you can think about it as someone who might be, let's say, 150 kilos or 175 kilos, for example, the level of leptin sensing in their brain means that as far as their brain's concerned, they may be a hundred kilos because that's the level of stimulation that leptin is giving.

8:17Dr. Simon Cork: And so when someone who's 150 kilos tries to lose weight, all of a sudden their brain is thinking, well, this guy's going into starvation mode and we need to protect it and get it back up to where it needs to be because the leptin levels have gone down.

8:30Dr Karan Raj: So you obviously focus a lot on the interplay between the gut and brain. It's probably still in its nascency, the kind of research of the gut brain when we're appreciating the role of the microbiome, its role in the gut brain signaling, the vagus nerve, the sort of big highway that connects both neurochemically microbiome metabolites, you know, using that as signaling pathways. is you've also done some research looking at a certain type of satiety hormone, PYY, in how that can suppress appetite as well, and specifically how the vagus nerve has a role to play there. Just talk me through the gut-brain axis in relation to hunger, appetite, and food noise.

9:09Dr Karan Raj: Sure.

9:10Dr. Simon Cork: So the main conduit of this gut-brain, what we call the gut-brain axis, which is this communication between our gastrointestinal system and our brain, is what we call the vagus nerve. it's my favorite nerve we all have same yeah yeah uh the word vegas comes from the latin for wanderer which kind of gives you an understanding of of what this does it's the one of the longest nerves in the body it's the longest what we call the cranial nerve so most most nerves come out of your spinal cord there's about 12 there are 12 nerves that come out of your brain stem this is one of them and it come it transverses all the way down your body so it innervates your lungs it innervates your heart and it also innervates your gastrointestinal system about 80 of the fibers because the vagus nerve is bidirectional.

9:49Dr. Simon Cork: You think of it like a motorway where it's got two lanes. About 80 % of those signals are going from the gut up to the brain. About 20 % are going in the opposite direction. So the vagus nerve is essentially what is in relation to the gastrointestinal tract is what's telling your brain what's going on in your stomach and in your intestines. So the first kind of manifestation that we see of this is when you start eating, your stomach expands. And in the lining of your stomach, we've got these really sensitive, what we call mechanoreceptors, which are stretch-sensitive receptors. So as you start to expand your stomach, these stretch-sensitive sensors on the vagus nerve start to fire, and they start to send signals to the brain to say that you're eating and you're getting fuller and fuller.

10:32Dr Karan Raj: How long is the response time from initial mechanical stretch from food or liquid to then that being registered as a conscious feedback by your brain that, okay, I'm starting to get full?

10:44Dr. Simon Cork: I think that varies depending on the person. And actually, so the signal is immediate. As soon as you start to stretch your stomach, those signals start to go. But our response to that as a satiety signal is very variable.

10:58Dr Karan Raj: Is there a threshold? Because this relates to this time lag, which a lot of people, maybe there's like this old wives tale that goes around being like, you should eat and then give yourself 15 minutes to register that because a lot of people may be overeating to some degree and not allowing that gut brain signal to land. Yeah, I think so.

11:17Dr. Simon Cork: I think there's a lot of factors that increase the sensitivity of this signal, right? So we talk about gut hormones. So gut hormones are those hormones that are released by their intestines in response to food intake. So things like GLP-1, which everyone's kind of heard of these days with the weight loss, but also things like PYY and CCK and leptin as well. those hormones take a little bit of time to get released because they respond to food in the stomach and you need a little bit of food entering it they respond to food in the intestine sorry they need a little bit of food to go in there but what studies have shown that those hormones do is they sensitize those those stretch sensitive nerve endings and so they lower the threshold at which they fire so as we start to eat these these signals the stomach starts to stretch these signals start to get off a little bit of food might enter the intestine release some of these hormones, which take a little bit of time to travel in the bloodstream, get to these vagus nerve endings, and then suddenly lower the threshold so they can start spiking and firing action potentials and signals much stronger.

12:21Dr. Simon Cork: So that's probably where that lag is coming from, that we need those hormones to be released to act in concert with stretching of the stomach to tell your brain, this is what's happening. But I think that the satiety response to that, at what point you feel full differs from person to person. And there's some interesting evidence, certainly from in animal studies where rats, for example, have been made obese, that the sensitivity of those nerve endings is lower. And so in animal studies of obesity, we see that you need greater volumes of food in order to start spiking those signals in the vagus nerve.

12:58Dr. Simon Cork: And that's also related to reductions in the release of those gut hormones as well. So the two things are probably happening in concert.

13:06Dr Karan Raj: So whilst we can't directly translate those animal findings to humans, that at least gives us a framework that we are obviously aware that in obesity, there are various subtypes of obesity, but broadly speaking in obesity, that's chronic, we know that there's dysregulated appetite pathways. And this animal model may mechanistically show us the path forwards where there's desensitization of those nerve endings. And there's also maybe a further delay in some of those stretch signals, which means that the appetite cues or the satiety cues are not powerful enough to get to the brain and we can overeat in obesity states.

13:45Dr. Simon Cork: Yeah, absolutely. And the vagus nerve, we're only just really being able to fully technically examine the physiology of the vagus nerve in any model. Certainly in humans, it's incredibly difficult to find out really what's going on there mechanistically. So yeah, we have to.

14:01Dr Karan Raj: Okay. So let's assume hypothetically that this was one of the causative factors in dysregulated appetite pathways in obesity, and it's worsened and more desensitized because of increasing adiposity. If someone were to reverse obesity and lose weight, whether through diet, exercise, or GLP-1 therapies, can you resensitize it? Do we know any of that based on animal models?

14:26Dr. Simon Cork: So resensitizing to leptin has shown some mixed results. I think it's in some ways, yes, but it takes a long time. What has been shown is that in things like bariatric surgery, for example, different types of bariatric surgery, one of the main consequences of bariatric surgery is that you do get a resensitization of those pathways. pathways. So in patients with obesity, for example, one of the consequences of, well, is it a consequence or a cause? We don't yet know, but certainly one of the factors of obesity is you get a reduction in the secretion of these gut hormones. So all these hormones that are meant to sense or signal satiety, they go through the floor basically in patients with obesity.

15:09Dr. Simon Cork: And if you look at what happens to those post-bariatric surgery, they go through the roof and that is likely to resensitize all of these pathways. So, so bariatric surgery is really interesting because a lot of people think the mechanism behind bariatric surgery is you're making your stomach smaller. One of the most common types of bariatric surgery is what's called sleeve gastrectomy, where you, you take a portion of the stomach out. The main reason why it works is not because you reduce the stomach size or that, that, that helps, but a, because you've got rid of all of the cells in the stomach, which secrete ghrelin, which is the hunger hormone, but also you're now, Now, the levels of gut hormones, the GLP-1, the PYY in the GI tract go through the roof.

15:49Dr. Simon Cork: And that's all of those signals that they go either through the vagus nerve or directly in the brain.

15:53Dr Karan Raj: Are they going through the roof because the stomach is smaller? So their perception of stretch is greater. The amplitude of stretch is greater because you're going from a smaller stomach to...

16:03Dr. Simon Cork: I don't think it's the amplitude of stretch. I don't think we fully know, but I think a couple of reasons. So one of the reasons why we think that the levels of gut hormones decrease in patients with obesity is because they get too sensitized. So in the intestines, we have these specialized cells called enteroendocrine cells, which are the specialized cells that secrete these gut hormones. The way that they sense nutrients in the GI tract is they've got loads of receptors on them. So taste receptors, same kind of receptors we find in our tongue, they've got smell receptors on them, but they've also got nutrient receptors.

16:35Dr. Simon Cork: If you overstimulate those cells with lots and lots of food, then they desensitize they internalize those receptors and they're no longer responsive to food intake if you reduce the amount of food that you can eat then one of the consequences of that is that they resensitize those um receptors we also think there's probably some impact on inflammation so as body weight starts to drop inflammation starts to drop as well but we certainly see that these effects on gut hormones happen before we see any weight loss and the

17:08Dr Karan Raj: increase is principally what's driving weight loss so a lot of people obviously now are using glp1s to amplify the usual signals if they have some dysregulated appetite and maybe a component as you just mentioned the weight loss and an anti-inflammatory response of the weight loss doing something as well in your opinion based on some of the studies that you've been doing on the vagus nerve and how that can influence appetite is there any way that we could externally stimulate the vagus nerve to suppress appetite?

17:39Dr. Simon Cork: I think there's a lot of, the vagus nerve's got a lot of hype recently, largely from kind of the pseudoscience community and the wellness community about resetting the vagus nerve or how to stimulate. There's no evidence that you can do any of that really, you know, through any self-mediated effects. One of the, an interesting area of medicine is looking at actually stimulating the vagus nerve with a, with a external, almost like a pacemaker. And that's shown some impact on, on weight loss. But in terms of, you know, meditative techniques or anything to, to try and improve vagus nerve, certainly not from the stomach, the, the, the GI tract perspective.

18:24Dr. Simon Cork: There's no evidence yet that you can, you can drive changes in the sensitivity naturally, shall we say.

18:31Dr Karan Raj: I want to talk about something that's quite personal to me and about some medical conditions that I suffered from. I used to have high cholesterol and fatty liver disease, and that primarily stemmed from a severe lack of fiber in my diet. And on my quest for finding the perfect fiber supplement over the last few years that could help me add more fiber into my diet, I couldn't find one that ticked all the boxes that I wanted and the high bar that I set for myself. So I built Loam Science. What I'm most proud of is not the product. I know that's great, but it's the fact that we've run two clinical trials on it, two randomized controlled trials, which is far more than the vast majority of supplements on the market will ever do.

19:06Dr Karan Raj: And we've got even more coming because I'm a doctor first and foremost and a scientist. And I wanted to build something that I could actually stand behind with data and not just rely on good branding. So if you want to understand what's inside Loam Science and why, the science is all on the website and the link is in the show notes. the problem we face nowadays is that you know with the rise of people taking glp1 medications i think you know for example in america the stats are one in six to one in seven americans are on a glp1 therapy a lot of people who are taking them are not resigned to the fact that they have to be on them lifelong because if we think about glp1 medications they're more like anti-hypertensives than antibiotics.

19:48Dr Karan Raj: When you're taking the medication, you see the benefits. When you remove that stimulus, the chemical hormonal stimulus, you lose the benefits. Just like if you stop going to the gym, you'll stop seeing the gains. And then in all of the studies that we've seen in the SEMOUT trial, the STEP trial, we see a regain of weight and a return to baseline of any metabolic improvements that they gained as well. You know, when people are switched back to placebo after being on tezapatide or on semaglutide, what can we do from a gut brain perspective to maintain the benefits so i think it's in order

20:24Dr. Simon Cork: to understand why that happens it's important to understand what glp1 is doing naturally so glp1 is one of those gut hormones that's released studies have shown that it sensitizes the vagus nerve to to stretch so it increases those signals but interestingly we we know that glp1 works in the brain, right? So I published a paper about 10 years ago now, mapping the brain, showing that there's GLP-1 receptors throughout the brain, but there's also a population of neurons of brain cells in the brainstem, which themselves secrete GLP-1. And actually there's lots of evidence now showing that the GLP-1 system in your intestines and the GLP-1 system in your brain are two completely distinct and separate systems.

21:04Dr. Simon Cork: Have different functional roles. Not different functional roles, but it was thought for a long time and it's certainly hypothesized. They're not governed by each other. Exactly. That the GLP-1 receptors in the brain were responding to GLP-1 released from the gut. But actually now what we think is happening is that the GLP-1 that's released from the gut is signaling to the vagus nerve and the GLP-1 brain cells in the brain are responsive to those vagus nerve signals that then themselves release GLP-1 throughout the brain.

21:31Dr Karan Raj: But is it still bidirectional in the sense that the GLP-1 system in the brain and the receptors in the brain can have an influence on the gut environment?

21:39Dr. Simon Cork: Yes. So once the signals have reached the brain, those 20 % of signals of the vagus nerve, nerves that are going down the vagus nerve, do things like suppress activity in the stomach. But what GLP-1 is doing in the brain is also quite interesting because when we look at where those receptors are and where we look at where those neurons send their axons, send their projections throughout the brain, they're impacting on areas of the brain that are involved in what we would call homeostatic feeding. So areas like the hypothalamus, which is a region kind of at the base of the brain, which governs whether you feel hungry or not.

22:13Dr. Simon Cork: And when GLP-1 is released on those, it silences the hunger neurons and upregulates the satiety ones. But it also stimulates areas of the brain involved in pleasure, right? And what we call hedonic feeding, the dessert menu that comes out at the end of your three-course meal. But what it's doing really in the hypothalamus is it's suppressing hunger, right? Suppressing the feeling of hunger. Now, if we think back to that set point theory of when we lose weight, what's happening? The hunger signal, your hypothalamus starts firing off to tell you that you are losing weight. You need to be hunger and drives hunger.

22:51Dr. Simon Cork: GLP-1 is silencing that. If we think of the thermostat analogy of if your body weight goes down, you know, the central heating comes on almost. glp1s are switching off the central heating right so it makes it easier to lose weight through diet and exercise alone so all of those physiological consequences of weight loss of hunger of tiredness glp1s the the drugs that are now being used to treat obesity essentially act by switching the central heating off turning off all of those signals that make it much much easier to lose

23:23Dr Karan Raj: weight yeah i guess i believe that glp1s are teaching us more about obesity than we've ever known before, just based on their mechanism of action, how much we're understanding about that and how complex obesity is that, you know, it's to kind of dissuade those people who historically have said that weight gain and loss is purely about willpower. It's showing us that there are dysregulated mental pathways and circuitries in the brain. But I'm also fascinated because even in those people who are non-responders to GLP-1s who, you know, defined as losing less than 5 % of their body weight are still seeing some benefits, whether it's like a food noise and a turning down of the volume of that incessant intrusive thoughts.

24:05Dr Karan Raj: But also to your point, the psychological component of obesity, where there is the food noise and there is the drive to eat something that sort of hedonic pleasure circuitry, which is amplified that's turned down. And there's a spectrum, right? Where people on maybe very high doses as a percentage of people who experience anhedonia and a loss of pleasure in typical activities. And I think there's even some studies showing that there's a degree of disjuicier and distaste for something, you know, that your favorite foods might taste bad. Maybe that's part of how GLP-1s work from a brain element.

24:40Dr Karan Raj: There've been some suggestions, emerging research that maybe outline how GLP-1 therapies could be investigated in addiction, building on that anhedonia, because that is part of an addiction spectrum. So how strongly do you feel, how bullish are you on how GLP-1s can be used outside of weight loss and anti-inflammation, but used for addictions, for nicotine addiction, tobacco, for alcohol, drugs? What do you think?

25:09Dr. Simon Cork: I think there's emerging evidence that they may be a role to play. And I'm being purposefully hesitant because I think the evidence is emerging. There is anecdotal evidence on patients that are on these drugs that their alcohol consumption has decreased. Their smoking consumption has decreased. It's, I'd say, anecdotal at the minute. There is some emerging good studies. There's certainly, there's a lot of preclinical studies in animals showing GLP-1s can affect things like amphetamine consumption and alcohol consumption. But I think once you start to get into pure, true addiction, and addiction, the neurobiology of addiction is certainly not my expertise, but once you start getting into that, an addiction is different to a habitual consumption, right?

25:58Dr. Simon Cork: You might have, you know, we know that alcohol consumption amongst certain people, you know, middle-aged, middle-class people is increasing. it's not necessarily an addiction but more of a cultural habitual increase and for those patients we might find that for those people so we might find that that glp ones have a good impact on their reduction because it turns off the the pleasurable aspect of what they're consuming but in true addiction so in patients with you know real alcohol addiction or drug addiction i think that's probably where we start to find that these are less impactful because you're talking about huge neurobiological rewiring of the brain in those instances, lots of different areas of the brain that are impacted that might be outside of the scope of these drugs.

26:43Dr Karan Raj: There is some suggestion that GLP-1 drugs are not just gut drugs and not just anti-BST drugs, but actually anti-inflammatory drugs. Again, going back to the case in point of people who are non-responders, even though they don't lose weight or lose significant weight, they still see reductions in fatty liver disease, joint pain, blood pressure reductions, sleep apnea reversal, suggesting there is some anti-inflammatory component of that. Now, with the GLP-1 receptors in the brain and how GLP-1s work, and maybe some suggestion that there could be some etiology in certain mental health conditions where there is an inflammatory component to some mental health conditions where it's exacerbated by inflammation.

27:26Dr Karan Raj: Could there be a role in which GLP-1 is used as part of a new paradigm for treating cognitive issues?

27:33Dr. Simon Cork: Potentially, and if the evidence is there, I think when we start to look at different types of mental health issues and the neurobiology of mental health issues, it's incredibly complex and probably takes us outside of the scope fully of what GLP-1s are doing. One of the reasons why GLP-1s have become such a successful weight loss story is because they're quite clean in how they work. If we look back over the last 20, 25 years of anti-obesity medications, it's been littered with drugs that have had significant side effects, some of them mental health issues. So there were some drugs that came out about 20 years ago that increased suicidal ideation, for example.

28:14Dr. Simon Cork: And so one of the reasons why GLP-1s are so successful is because they largely just target the appetite center. You know, they're really targeting weight loss and ignoring everything else. So there may be some conditions in which we see, psychiatric conditions in which we see a benefit, but I think that evidence is still emerging. What is being shown is in other areas like cardiovascular disease, for example. We published a paper this year showing that patients who are taking these drugs have a 14 % reduction in all-cause mortality from cardiovascular disease and hospitalization with cardiovascular disease.

28:54Dr. Simon Cork: And some studies are showing that that may be independent of weight loss. What we don't have yet is thousands of patients on these drugs who do not have obesity or type 2 diabetes. And that's part of the problem is that trying to disentangle what is a, when we look at things like cardiovascular disease or Alzheimer's or psychiatric conditions, what is a direct impact on those systems and what is indirect consequent to reducing body weight or improving blood glucose or reducing inflammation? what is a side effect of reducing all of that and generally improving overall health.

29:37Dr Karan Raj: Yeah. I mean, you can have a recent study looking at GOP-1s and cardiovascular disease risk. And there have been other similar studies as well, suggesting that a third of the benefit on reducing cardiovascular disease risk can be independent of weight loss. It seems to be the headline. Would you agree with that?

29:55Dr. Simon Cork: I think, again, I think we need to be cautious with that because, as I say, what we don't have are thousands of people on these drugs who don't have obesity. And so we don't know if those people who are otherwise healthy weights would respond in the same way. It's a huge confounding factor. Yeah. So we don't yet know. What we do know is that there are GLP-1 receptors in the heart. There are GLP-1 receptors in the vascular chain. There are GLP-1 receptors in parts of the brain that control your cardiovascular system. So certainly it's plausible that there are weight loss independent effects. We don't actually know what those receptors are doing normally in those areas.

30:31Dr. Simon Cork: We don't fully understand their role. But it's plausible that there are weight loss independent impacts on things like cardiovascular health. And as I said, there's other conditions as well for which we're starting to see some impacts. So Alzheimer's disease, for example, neurodegeneration. Again, we just published a paper recently showing that if in animal models of Alzheimer's disease, if you give these drugs, it prevents the buildup of proteins that are associated with Alzheimer's disease, which is in itself really interesting. But what we don't have is real translational data to show. So there's an interesting study, I think, that came out of Denmark quite recently that showed patients who had been on these drugs for type 2 diabetes have a lower incidence of Alzheimer's disease when they've been on them for sort of 10, 15 years.

31:21Dr. Simon Cork: But we don't have much data in that. But again, what's driving that? Is it weight loss? Is it improved glycemic control, improved blood sugar control, reduced inflammation, direct effects on the brain? We don't know yet.

31:33Dr Karan Raj: So right now how we're using GLP-1s in obesity is on the premise that people have this food noise and they have this increased drive for hunger and they don't have, you know, it's more hunger rather than not enough satiety. Sure. And there was a recent study out of the Mayo Clinic, which looked at various phenotypes of obesity and they came up with one cohort within the patient population they studied, which is this hungry phenotype, hungry gut phenotype. And the hungry gut phenotype was not one that was driven purely by intrusive food noise and insatiable hunger, but more so the lack of fullness.

32:19Dr Karan Raj: And this related to their GI motility, the gastric emptying rates. And they found that this hungry gut phenotype responded even better to tizepatide than the other normal types of obesity, which suggests that we're still some way from personalization when it comes to GLP-1 therapy. And, you know, adding in the another complexity of gut brain signaling as well, it seems like that's another sort of Pandora's box we've yet to fully open to truly personalize GLP-1 therapy for people.

32:51Dr. Simon Cork: Yeah. And we know that if we look at the clinical studies around GLP-1, the clinical trials you know they show a nice clean average of 15 to 20 percent weight loss when we start to look at the real world impacts of these that varies quite a lot and it varies quite a lot for a lot of different reasons like you say the underlying pathophysiology of obesity is so varied you know the genetics of obesity we're only really start just starting to unpack now and it will vary for for different people so so what's causing the obesity is not always driven by changes in our sensitivity to satiety hormones, for example.

33:29Dr. Simon Cork: So in those patients for whom it isn't, their responsiveness to more GLP-1 might actually be quite blunted. So we're starting to understand a lot more about what's driving obesity. But what I think is important is that even in patients who might not respond at 15, 20, 25 % weight loss, what we determine is clinically significant weight loss is 5%, right? So most diets and exercise alone will result in about three to 4 % weight loss, and that will fluctuate. You have to be on that for life. If you are losing 5 % weight loss, whether that's on your own or through GLP-1s, you're probably not going to see an awful lot in the mirror, right?

34:11Dr. Simon Cork: If you are 150 kilos and you lose 5 % body weight, you now weigh 143, 142 kilos, right? You're not going to see much change in the mirror. And that's often what, when people are dieting on their own and they're dealing with all this consequences of feeling hungry all the time and feeling grumpy and tired, that's the kicker of motivation, right? But what we know is if you lose 5 % weight loss, your blood pressure will decrease probably by as much as it would do on antihypertensive medications. Your inflammatory markers will decrease. Your risk of cancer will decrease dramatically. basically. So although not everyone on these drugs will reach this nice 15, 20, 25 % plateau of weight loss that the clinical trials are showing, if they're losing 5 % weight loss, which is kind of a clinical baseline that doctors use to say whether they're going to keep you on or not, it's going to have a massive impact on your health.

35:05Dr. Simon Cork: You might not see it in the mirror to some extent, but it's going to have a huge impact on your health. Even things like your future risk of osteoarthritis in your knees and hips and things like that. All of these things which might take years to pan out and you might have to play the long game on this. It's going to have a huge impact on all of those outcomes. So I think if people are on these drugs and they're not seeing huge amounts of weight loss, if they're a low responder, I don't think, or if they're losing weight without these drugs, if people are losing weight through diet and exercise alone and seeing around 5%, 6 % weight loss, keep at it.

35:43Dr. Simon Cork: I know it's hard, it's easy for me to say sat here, but the outcomes, the clinical outcomes, the health outcomes of losing just that little bit of weight are significant.

35:52Dr Karan Raj: Yeah, I think we're probably, you know, society forces us to engage with vanity metrics. What's the number on the scale? What do we look like on the mirror? And that often probably hides or masks the true benefits of even small weight.

36:08Dr. Simon Cork: I mean, like you said earlier, these drugs or probably created the biggest social conversation around obesity we've had in a generation. A lot of people view obesity societally as an aesthetic issue, an issue of body image, when actually obesity has been classed as a disease since about 2013. So in the scientific, in the medical community, we know that obesity is a disease and it's a disease state because it impacts so many health outcomes, but also because there's a defined biological, what we call pathogenesis, you know, there's biological drivers that cause it, which mean that you can't just always die your way out of it.

36:46Dr. Simon Cork: So we know, you know, we know it's a huge, a huge problem, but, but I think what it, what these drugs have shifted, hopefully the conversation around is seeing obesity, not just as a, as a body image, aesthetic issue, but as a driver of better health.

37:02Dr Karan Raj: Yeah. And I also, I think, you know, it's very valuable the research you're doing to further establish the baseline role that the brain plays in obesity, the gut physiology, independent of willpower or anything that we can do that there are these physiological factors sometimes beyond our control that maybe not resign us to a certain fate, but certainly predispose us to challenges from baseline. But at least now we can acknowledge these things and you know we're in the early innings of you know single dual triple you know receptor agonists coming with ritatratide next year potentially and then you know four or five you know agonist receptor agonists and then a cocktail of different things how they may target different aspects of you know metabolic dysfunction obesity so you know simon thank you so much for joining me.

37:53Dr Karan Raj: Pleasure. Thank you ever so much.