Cambridge Weight Loss Scientist: Your Brain Fights Weight Loss! Why Diets Are So Hard To Stick To, The Truth About Calories & How To Keep Weight Off | Prof Giles Yeo

0:00Your brain hates it when you lose weight. People say that 95 % of diets don't work. And that's not true, technically. 95 % of diets we can't stick to. That's the truth. Question is, how much fat is too much fat? That's the$65 million question. Now that differs between person to person. Everybody has a different amount of fat that they can store safely. If you were to put it into a percentage, how much of our weight management is contributed from genetics versus nurture? So there is a number, actually. So Professor Giles Yeo is one of the world's leading scientists in the genetics and neuroscience of obesity, hunger and body weight.

0:36A professor of molecular neuroendocrinology at the University of Cambridge, he has spent over three decades uncovering genes, brain circuits and hormones that influence appetite. We know actually of over a thousand genes that influence food noise, that influence our appetite. One mutation, one gene and suddenly, oh, I like fatty food. Oh, I don't like sugar as much. We as humans have been evolved to adapt to a feast-famine environment. The problem is today we live in a feast-feast environment, right? So it's toxic. But then what you're telling me is that once I achieve my ideal body weight, I'm going to stay in a prolonged state of pain because I'm going to be feeling like I'm starving.

1:16Actually, he still loves food. He still eats food. He just needs less food. Is he still on the drugs? He's still on the drugs. For now. You spent your career in understanding obesity and also helping people tackle obesity. How did you feel as a father when your own son was obese?

1:39Giles, I want to say this correctly because it's a complex word, but you're a professor of molecular neuroendocrinology at the University of Cambridge. Now, if I was a 10-year-old boy, how would you explain to me your area of expertise? Okay, so a couple of things. I mean, first of all, the title is a mouthful. What the hell is that? And the reality is when you become a professor at Cambridge, you get to pick your name, which is fantastic. Except, here's the big but, is that you have to pick your title that no one else in the university has. So by the time I got my professor, you know, all the big ones have gone.

2:16Professor of genetics, gone. Professor of biochemistry, gone. Even the professor of neuroendocrinology gone. So I ended up with molecular neuroendocrinology. All right, what is that? Molecular, we know we look at things at the molecular level, small level. Neuro, we know, which is looking at the brain. Endocrinology is the study of hormones. All right, and hormones are our body's long distance command and control system. So in other words, one organ secretes a chemical signal. It travels through the blood to signal to another organ to control that organ. That's a hormone. Okay, incidence of hormone.

2:48Testosterone is a hormone. So if you put that all together, molecular, neuro, hormones, I am a professor of hormones south of the neck that communicates with the brain. That's what I study. Why is this important to you? Well, our brain does, I say most, all of the command and control of the body. I mean, clearly every part of the body is important. Your heart is important. Everything is important. But the command and control, the overseeing of what actually happens, happens with the brain. and your brain is connected to the rest of your body, communicates with the rest of your body through wired circuits.

3:24So these are nerves, okay? And this is what we know. So there's a direct electrical impulses, but actually most of the information that comes from different organs, from many different things, okay? Not just food, which we're going to talk about today, okay? Then communicate with the brain via hormones. So these hormones represent almost what happens in your body south of the neck, happens here, and they communicate with the brain. So it's important because depending on what you study, you don't have to study food intake. You can study sexual behavior, stress, salt, how you regulate salt, anything.

3:59I just happen to study food intake. So how these hormones talk to the brain and the interface is crucial to understanding, first of all, the biology, understanding what happens when it goes wrong, and how you then are able to treat it or tackle it when it goes wrong. That's why it's important. You have dedicated your career, pretty much your life, in understanding why the effort levels is different to so many people when it comes to regulating their hunger, staying on weight or losing weight. What has been the biggest discovery so far in your career? Okay, I'll answer that in two different ways.

4:38I think my personal biggest discovery happened probably within less than a year of me starting this whole business, entering obesity. But interestingly, it's also the one that I had least to do with. Let me explain what I mean. So I finished my PhD. I'd always been interested in genetics. So I've always been interested in why we are the same, i.e. what makes us human, and why we are different. Okay, those are the two things, which means genetics. Okay, so what makes us human, but what makes me look different from you? Always been interested than that. And I ended up in therefore studying a field about body weight because, you know, we're the same, but we're different.

5:16And this was by chance, literally by chance. I was a geneticist. I was looking for a job and I ended up in a job in an obesity lab. And so what then happened was the first day of my job, my boss at the time, Steve O 'Ratley, gave me a gene. He says, oh, look, he was the first to identify genes that when had mutations in it, ended up with really severe obesity. So these are very, very rare conditions. He needed a geneticist. I was a geneticist. And he says, study this gene. And this gene, the name of the gene is the MC4 receptor, but the crucial bit of it is it's part of the fat-sensing pathway of the body.

5:56So your brain needs to know two pieces of information in order to influence your feeding behavior. It needs to know your long-term energy signals, how much fat you have, how long you would last without food. and it needs to understand your short-term energy signals, meaning what am I drinking, eating, okay? And all of these are hormonal, okay? And they signal to the brain. And the MC4 receptor is one of the crucial receptors within the brain that senses how much fat you have. And so within six months of me starting that job, we found the first mutations in humans in that receptor that cause severe obesity.

6:28And we now know that it is the most common cause. It's not that common, but in terms of severe obesity, it's probably the most common cause. So I would say that's probably my biggest discovery, but the one I had least to do with, at least initially, because my boss just said, look at this gene. Fascinating. I think this also validates what a lot of people have been feeling in this day and age, which is that perhaps obesity is not only related to external factors, but perhaps we were born with a condition that we just can't explain that makes it so much harder for a given person to lose weight or on the contrary, to be overweight.

7:04Not correct. So, I mean, it's not, I mean, the external circumstances matter, okay, obviously. But if you look at what the root cause of obesity is, I would say it's people with a susceptible biology, so people who find it more difficult to say no to food, meeting a risky or permissive, whatever adjective you want to use, environment, okay? And I think it's the clash of those two things that then has resulted in the issues of obesity that we have today. I want to democratize the term obesity because I feel like in this day and age, we're using it perhaps in the wrong way. What is the clinical definition of obesity?

7:46That has shifted over. So I've been in this business for 30 years. It has shifted from when I started till now. So most of your listeners will understand obesity just by BMI, body mass index. Your weight divided by your height squared, okay? And we know the numbers. Most of us know the numbers where 20 to 25 BMI is normal. 25 to 30 is overweight. Above 30, you have obesity. And so that was the first definition of obesity, a BMI above 30. But I think it's now becoming clear that that is just not nuanced enough. So BMI, in terms of as a number, was originally the people who were studied, the very narrow section of the human species.

8:30They were white middle-aged men at the time. And that was sort of the BMI markers for obesity and what have you. But we're obviously far more than white middle-aged men. The moment you begin to kind of look around, then you realize that BMI is simply that. It's a ratio between your weight and your height. It doesn't tell you anything about your health. Okay, so now let's back away. And so now, if we're not looking just at a number on a scale, the number of kilos or the number of pounds, what the hell are we talking about? So I think now the field is beginning to accept that obesity is carrying too much fat, that it begins to influence your health.

9:08And I think that is the definition of obesity. The question is, how much fat is too much fat? That's the$65 million question. Now that differs between person to person, okay? Where I can carry 10 kilos of fat, you might carry five kilos of fat, whatever, all right? But yet we may have different susceptibility to specific diseases. So everybody has a different amount of fat that they can store safely. So you have skinny people with diabetes, you have relatively large people, okay? Perfectly healthy. So I think obesity is far, far more than a number on the scale. Carrying too much fat that it begins to influence your health.

9:49So by definition, it's a disease because it's already influencing your health. That's what obesity is. And then how can we determine? So what are the symptoms to understand if obesity is influencing our health? Look, okay, so here's the difficulty. If you had access to a doctor with a sort of a lab and everything like that, you could do it okay because you need to measure certain things there's some things that will appear do you have high blood pressure um and then there's stuff that you actually have to then begin to measure inside right what are your cholesterol levels right what is your uh blood sugar levels after you eat um all kinds of measures like this indicate metabolic health the problem is everything which i've just said there requires someone to come along and poke you and and measure you and you need a doctor.

10:38So I think there are ways of determining metabolic health. This is what we're talking about. When you visit a doctor, what we and many others are trying to do is, is there a way of measuring your metabolic health without having to do that? Can we sort of make some kind of predictions? Now that, we are not there yet. So there are measures of health that we can definitely look at. But we want to be able to identify these measures in far larger numbers of people without necessarily a doctor and far, far earlier. Because the earlier we begin to sort of find out if someone is beginning to sort of deviate from health in its broadest sense, the sooner you intervene, dietary, exercise, pharmaceutically, it doesn't really matter.

11:29but typically as you know prevention is better than cure all right so if you can prevent the most serious thing to happen to begin with that is what we're shooting for that's the aim we're not there yet if someone is listening to this at home looks at their belly and they're like i don't think i'm very very big but you know there's a considerable amount of fat but i wouldn't call myself obese how can they know if that's uh dangerous for them i think they're too unsisted i'm not a medical doctor, okay? So, I'm a scientist. So, I think a couple of things. If you really think you have a problem and feel a problem, I would see you're a doctor.

12:04But if you are Joe Schmo, Jane Doe, you're sat at home, I think the easiest way to tell whether or not you are, at least in your mind, healthy is can you do the things you want to do? Now, let's leave aside how you look like. I mean, I wish I looked like Brad Pitt, but that's just life, okay? So, can you do what you want to do? And I mean basic things. I'm not talking about whether or not you're looking like someone with a six-pack, can you walk up the stairs without being out of breath? That might be a hurdle for some people. Can you double up the stairs? If you're older, can you carry your grandchildren?

12:37Do you have issues carrying your shopping from the car? These are all basic. Can you get up the chair without going oof? Things like this. Can you get out of the car? People's health are very much relative to themselves. You're going to have a young, fit person and going to say, that's a stupid way of measuring health. But many people in middle age do have problems doubling up the stairs, do have problems carrying their kids. So I think what you want to do is you want to look at yourself. Are you having problems doing some very basic things you wish you could do better? And if you feel that, well, then I think that means it's time to have a conversation internally at least, and maybe with your doctor.

13:21Is this too much? You know, am I now becoming unhealthy. I think that's probably the easiest way to do it. Are you doing what you want to do? Are you having difficulties doing just what you want to do? That's very powerful. I want to shift slightly the conversation to how the brain interacts with our hunger levels. So what is the relationship between our brain and our hunger levels? So let me go back away for a bit and rather than just talk about hunger, because hunger is just one aspect of our eating. Most people think about hunger. If I could reintroduce the topic, rather as hunger, but appetite.

13:57We talk about appetite. Do you have a good appetite today? You know, oh, I have real appetite for a steak today. Okay, appetite. And I think that's probably a better description of what sort of what I study. Now, appetite is an interesting term because it's not just one thing appetite i would say consists of at least three different um uh phenomenon okay hunger is one of them and that's pure the grumbly tummy you know the feeling we get before we sit down and actually eat fullness now people think that fullness and hunger are connected they are but they're actually two completely different things two completely different parts of the brain, two completely different circuits, but related.

14:39How full do you feel? Okay. And these are two completely different parts of the brain. You touch the back of the head. Why is that? So the back of the head here is called the hindbrain. So where your neck meets the head. Okay. There is a part of the brain there. It's called the hindbrain, the back of the brain. That regulates fullness. So in fact, it regulates how full you get from, I am comfortably full. Oh my God, I'm so full. Oh my God, I'm so full. I feel a bit sick. Oh my God, I'm going to puke. that range, the very visceral feeling, back here. People call it the lizard brain. This is the oldest part of the brain.

15:13It does not a lot of thinking at all. It reacts very, very quickly. Visceral brain, oldest part of the brain. Most vertebrates down to lizards, they call it lizard brain because we have oldest part of the brain. Now, hunger is regulated by a part of the brain called the hypothalamus. And for people who don't know where that is, bridge of the nose, base of the brain, and it sits right above a gland called the pituitary. but it's the deepest part of the brain. In human beings, it's the size of your thumbnail and it's a shape of an almond. And it acts as a key fuel sensor within it senses these hormones, okay?

15:46Coming from the south of the neck. And that regulates your hunger. And they both talk to each other, right? Because how hungry you feel means you are less full. If you're very full, you are less hungry. Too much. Now, the third part of appetite is reward or how nice you feel when you eat. And this is a slightly, it's up here, okay? So it's a reward element. It's not as well distinct as hindbrain and hypothalamus, but it's there. And so all three are like a triangle. They're three completely different parts of the brain. Stuck in the middle is the term appetite because three different parts of the brain, but they all speak to each other, all right?

16:30So for example, if you are, We know that if we're really, really hungry, the simplest foods taste fantastic. A bit of bread, a bit of rice, a bit of cheese, right? So because you're very, very hungry. So your reward, how nice the food needs to taste drops. Whereas if you're really, really full at the end of a meal, for example, you're not going to have some more rice. You need desserts. You need foods that come along and bop you on the head with flavor, all right? Because the fuller you become, the higher the bar for how nice the food has to be before you eat it. So that is appetite. And this is internal information.

17:08Because clearly you then have, as we described, external information. Yellow M's on the side of the highway. Whatever. But that's what I think appetite is. It's a triangle. And depending on your genetics, some people need more food to feel nice. Other people feel more or less full than others. Other people feel more or less hungry than others. but they all speak to each other. And in total, some people have a greater appetite for food. Other people have a lesser appetite for food. That is the role of the brain in regulating your appetite. And also, does that mean that some people have more of a sweet tooth than others because their reward brain is more heightened?

17:47No, that's something actually slightly different. So that has to do with specific genes that actually feed into it. I'll give you an example. Your sweet tooth question is a good one. This is not the only gene that has to do with sweet tooth. But so that you asked me what my personal, you know, greatest discovery was. And we talked about the MC4 receptor, MC4R, which is this fat sensor. Now about 0.3%, so not a great deal, but actually quite a 0.3 % of the human population will have mutations within the MC4R gene. So you extrapolate that to the UK population, 67 million people. That's more than 200 ,000 people.

18:30If you go to the United States, more than a million people are going to have mutations within them. So rare, but not that rare. China, you'd have somewhere between 7 or 8 million people. Okay, so it's sort of rare, but not that rare. Okay, so when you have a mutation within this gene, you eat more, you end up with really, you're quite large. At 18 years old, you're probably something on the range of nearly 20 kilos heavier than someone else. Okay, so it's quite a big difference. But that's just your size. what's interesting is it also changes what you like to eat. So this is work not done by me.

19:02This was work done by my colleague, Sadaf Ruki, Professor Sadaf Ruki. She still works with me in the Institute up in Cambridge. She took individuals, this was called the chicken korma, which is a type of curry, chicken curry and eaten mess study. All right, so let me explain this. So why chicken curry? Chicken curry, because you can adjust the amount of fat in the curry by whisking in vegetable oil, okay? So you can set up sort of like a Goldilocks selection of a very little fat, a medium amount of fat, lots of fat. So here's the study. You had people with mutations in this gene, MC4R. You had people who were the same size as people with the MC4R gene, but no mutations.

19:44So these are now people without the mutation. And then you had controls. So people who didn't have obesity. One by one, they walked into a room and there were three trays of curry. So they had to taste small, medium, large in terms of the amount of fat. And they had to taste the curry, rate the one they liked the most, and then eat that one. And look, it's a personal taste, right? Some people like fatty foods. Other people don't like personal taste. What was interesting was everybody with an MC4R mutation went for the high fat option. We were going, oh, okay. Well, maybe if it makes you eat more, it just makes you eat more calories.

20:22Then we get to the Eat and Mess study. So for you, listen, I don't know if you know what eaten mess is. Do you know what a pavlova is? I think we've all had a raspberry or a strawberry pavlova. It's a dessert. Yeah, it's a dessert. Okay, meringue, whipped cream, fruit. And eaten mess is what happens when you drop the pavlova on the floor and put it back into a bowl. It's a mushta. Okay, but what you can do with an eaten mess is adjust the sugar. This is back to your question about the sugar. So now you can change the amount of sugar in the meringue in the whipped cream. So now you completely reset up the study, but rather than fat, you have sugar.

20:54And what is interesting is everybody with the mutation in the MC4 receptor, you would have thought, oh, they would have gone for the high sugar option because they're trying to eat more. Nope, they all went for the low sugar option. And once again, some people have sweet tooth, some people don't. One mutation, one gene, and suddenly, oh, I like fatty food. Oh, I don't like sugar as much. So this is a slightly extreme example, but this is, like I said, 200 ,000 people in the UK, a million people in the United States. It's not that few. So you ask the question, do people have a sweet tooth or not?

21:28Do people prefer savory food? The answer is yes. And there may be some learned and cultural element to it. I don't think so though, actually, because I think culture does inform the type of food we like to eat, but I think it seldom informs whether or not we like a very specific macronutrient. My wife and I, my wife's English, she's white. she both and i both my wife and i love carbohydrates um my wife's carbohydrate preference happens to come in a form of bread and pastry okay my but i could take a i could take a leave bread i could never eat a sandwich again in my life and i'd be fine i don't not like bread i just my i don't want to back myself into a stereotype but my favorite kind of carbohydrates is rice or noodles okay so my love of rice and noodles versus my wife's love of bread is culture.

22:20Our love of carbohydrates is biology. And so I think that there are going to be elements in which they're going to be learned and elements of which that are taught. I think having a sweet tooth, having a love of refined carbohydrates, that is going to be biology. Whether or not you prefer a baklava or a meringue or sweet tea, I think that's culture. You mentioned the MC4 receptor as perhaps a gene mutation that makes us either like more fats or less sugars. Can you give me some other examples from genetic changes? Okay. So there are other genetic changes. I don't remember the names of the specific genes.

22:58This is not my area of expertise, for example. But there is one specific gene. It's in the taste receptor that actually influences whether or not you are a supertaster or not. Do you taste bitter flavor or don't you taste bitter flavor? I did a presentation at the Royal Institution here in London, in which we did a demonstration. So about half of the human species have this genetic change, which makes you a super taster, which means that you taste this bitter flavor, and half of the human population don't. So it's quite a large number. So now we're talking huge numbers of people. So it's down to this chemical.

23:33And this is the chemical that's found in brassica. So cabbages, Brussels sprouts, broccoli. But you can buy the chemicals, not poisonous. So the experiment was this. and I did this in kids because this was a royal institution. We were doing a lecture largely. So I got 10 kids up onto stage and we gave them all a little piece of paper with a dot of this chemical, which comes from cabbage. And they all had to put it on their tongue. I did the same thing. I know I'm a super taster because I did this experiment myself. And so they put just a little paper on their tongue so you taste a little bit of the chemical.

24:07And these were kids, which is always the funny thing. So half of the kids literally went, Like, right? I could taste it, but I'm not a kid, so I didn't spit it out. The other half of the kids were going, what the hell are wrong with these people? So what happened there was half the kids that were being tested had this, it's not a mutation. Mutation means a disease. This genetic change, all right, which made them taste this bitterness. And so when people say, ooh, I don't like cabbage or I don't like Brussels sprouts, it's too bitter. They probably, if you can taste it, it doesn't mean you don't like it.

24:43But to dislike it, you have to taste it. So it's likely that if you don't like something like Brussels sprouts or broccoli, it's not because you don't have any taste in food. It's probably because you can taste that bitterness and you just don't like that bitterness. So that's another classic example of why some people love cabbage or Brussels sprouts or whatever during Christmas time. You know, and other people cannot bear it. They cannot bear it. I think most people go about life without knowing if they have any of these genetic anomalies. My first question would be, should we know about them?

25:18And if so, how can we get tested? Should we know about them? Look, I think the Brussels sprout thing is probably not. I think it's a bit of fun. Like I now know, for example, that I can taste, but I don't mind Brussels sprouts. I just taste the bitterness, but I don't mind the bitterness. I think it's fun to know that I think something like Brussels sprout tasting comes under what I would call infotainment. It's information that entertains rather than it being critical. MC4 receptor, I think, is a separate thing. Because the MC4 receptor not only makes you eat more fat and less sugar, it also gives you risk of obesity.

25:57So that's very, very different. and we now know of drugs, and this is separate from the drugs that we all talk about today, such as Ozempic and Wigovi and Mujaric, different set of drugs, okay? These are drugs that specifically target the fat-sensing pathway. And we know drugs that can work for people with that broken fat sensor, for example. So I think if you have a broken fat sensor, that's a very different thing. So I think it really depends on what these changes are. There are many things which influence why we like or don't like certain foods, okay? But there are very, the other example, I'll give you a couple more examples.

26:34People thinking, no, I don't have this. Asparagus. We know, many of us know, the smell you get in your Wii after you have asparagus. What's interesting is there are two separate genes that are involved. You have the gene to, do you make the smell when you eat the asparagus? And you have the gene of, do you smell the smell? And I may very well be speaking and people are, smell? Sorry, this is the first I've heard. asparagus, what smell? And then other people will take it. I don't make the smell. And so, there are genes involved there. Coriander, okay? And the Americans would call it cilantro, all right?

27:08So, I love coriander. I love cilantro. I'll eat it. Whereas other people, I mean, there are really some famous chefs, for example, chefs that hate it. They think it tastes like soap. And once again, this is not, oh, you have no taste. You have no taste. Maybe you don't have taste, but not for coriander. Because there is, for example, a genetic mutation that makes, not mutation. Once again, they're not mutations, but a genetic variation that makes some people taste soapiness and coriander and others not. None of these affect your body weight. And so, these will also form infotainment because it's just fun, right?

27:43But I think the bigger message is that when we have been judging someone for their taste in food, I wouldn't begin to think it's someone's taste or upbringing. Someone doesn't have any class. Don't be saying shit like that. I really do believe that your like or dislike for many foods, not all foods, but for many foods, have a strong biological underlying. I want to bring the conversation back to appetite. I'd like to understand the inner mechanics of how different hormones, perhaps from our gut, trigger our appetite regulation through the three different parts of our brain that you've mentioned.

28:21That's an excellent question. So signals from your, they're all hormonal. Okay, signals from your fat. So these are going to be a long-term energy signals. They largely govern starvation to hunger, which means that they turn on what happens when you starve. You need to find food. You need to do things. Those signals come from your fat. Fullness signals, illness signals tend to come from your gut. Okay, so if you then now begin to look at my triangle of appetite sit in between. so your gut hormones tend to signal more. They signal to pretty much all of the rest of the brain, but their primary signaling is to the hindbrain to indicate fullness.

29:01That's why drugs like Ozempic, Wegovi, Munjaro, which are weaponized, they're modified gut hormones, make you feel fuller. Then you have other hormones which then signal to the hypothalamus, and this is the hunger and starvation. This includes the MC4 receptor, which acts as a sensor. So those goes in via the hunger element. Then you have the reward pathways. Now those are going to be more dopamine. There's going to be other things that sit within the brain for there. And those are signaled from both the gut hormones and the fat hormones as well. So it depends what hormones we're talking about.

29:36Let's talk about leptin, for example. Yeah. So leptin is a fat sensing, is one of the key fat hormones. It's not the only fat hormone. There are actually a number of different fat hormones, but this is the key one. So for those of you who don't know what leptin is, leptin is secreted exclusively from fat, exclusively from white fat. And it circulates in your blood in proportion to the amount of fat you have. So the more fat you have, the more leptin you have. There is a variation. So in other words, how much leptin you have for a kilo of fat is going to differ from how much leptin I have for a kilo of fat.

30:09But within our internal cells, it acts as a good sensor. So your brain senses leptin levels, and it knows, do I have a kilo of fat because I'm an Olympic athlete? Do I have 10 kilos of fat? Do I have 50 kilos of fat because I have severe obesity? But the role of this leptin, I mean, leptin does many, many different things, but the key role of leptin is to inform your brain how much fat you have, but where you have dangerously low levels of fat. Okay, so because if you don't have leptin, it means you don't have fat. When don't you have fat? You don't have fat when you're starving. So what leptin's role is, as it disappears, okay, because you have less and less fat because you're starving, your brain triggers a series of events to make you survive.

30:54And it does a number of different things. So the first thing it makes you do is eat, obviously, okay? And as I said, if you're really hungry, the simplest foods taste delicious. We, Steve, Steve O 'Ratley has found mutations, super, super rare mutations. So since 1997, when the first mutations were reported, There's maybe 100 families in the world. This is super rare, all right? So these kids have severe obesity. So they're probably, what, three, four years old. They are 40 kilos, right? Look, I'm 70 kilos, right? So this is three, four-year-olds who are more than two-thirds my body weight, something severely, because they have a brain who thinks they're starving.

31:34So while they have carried a lot of weight, they don't have leptin. So their brain can't sense how much fat they have. In fact, they think they have no fat at all because they have no leptin. And so as a result, these kids have to have their freezer doors locked because they'll actually eat frozen food, right? So to keep themselves alive. Now they won't eat poison because that's, you'd be dead, okay? They won't eat non-food. So in other words, you're not going to eat this table. That's another disease. It's called PICA. A different talk, different discussion. But these kids have a voracious appetite.

32:08And you might think, oh my God, frozen food. That's weird. And it is weird. It's a pathology if you have a mutation. But actually, if you think about it, if you were actually starving, like plane crash, you know, in the Andes, your partner's looking delicious starving, would you eat frozen food to keep yourself alive? Yes, you would. So in other words, this weird behavior of eating foods that you're going, what are you eating? Which under normal circumstances, we would not find palatable. We would not find delicious. But under real starvation, you'd eat it. Frozen food, for example, is a classic example.

32:41So that's what leptin does. Leptin drops away. And when it drops below a certain level, a dangerous level, it begins to make you really eat whatever is available to keep yourself alive. Even to the extremes of eating another human being? Yes. I think the answer is going to be yes. All right. Who knows? Who knows? But there are odd situations in which you find yourself in starvation. who knows what people will do at that edge of starvation but I think for certain people, yes And that's these regulated levels of leptin Yes Fascinating I just want to be clear I'm just saying that not everyone with no leptin is going to start eating people I'm just saying that the drive to eat becomes overwhelming when you don't have leptin is my point I want us to define another term that I think would help myself and the audience understand better the mechanics of how our brain regulates overall appetite.

33:41What is the melanocortin pathway? So the melanocortin pathway sits around the MC4 receptor, the melanocortin 4 receptor, which we've already been talking about. That's in the hypothalamus. That's in the hypothalamus. The MC4 receptor is in many places of the brain, but yes, within the hypothalamus. So the melanocortin pathway is everything we've been discussing. It's leptin coming from fat, signaling to the hypothalamus, and then eventually hitting the melanocortin-4 receptor. That is the melanocortin pathway. It is the fat-sensing pathway in your brain. So, would then the melanocortin pathway and the MC4 receptors explain, depending on how they function, if they are overly stimulated or understimulated, why some people have more or less foot noise?

34:33Yes. It's not the only pathway, but yes. So, if you begin to look, I talked about mutations within the MC4 receptor, and that is 0.3%. That does mean that 99.7 % of us don't have this mutation. Mutation meaning a genetic change that breaks the receptor. But many, many, many of us have very subtle changes in these genes that don't influence the function of the receptor in any measurable way at all. But probably something along the lines of 10-20 % of us have changes in the MC4 receptor, for example, which are more subtle. Which means maybe when you go into the curry test, eat and mess test, we won't necessarily go for the high fat.

35:18But if you study 100 ,000 people, you'll suddenly see that more people with these subtle changes might go for the high fat option or the low sugar option and might feel a little bit more hungry than someone else. So we know actually of over 1 ,000 genes that influence food noise, that influence our appetite. The MC4 receptor, leptin, you know, these are just a few of those genes. But yes, very subtle variations influence what we're now thinking about as food noise, which to me is a new term, actually. I haven't heard the term food noise till these GLP-1 drugs came on the scene. But I'm now beginning to understand that it is just another name for appetite.

36:01So in other words, some people have just this real appetitive drive. They think about food all the time, or they're hungry all the time, or they feel less full. I think that's food noise, depending on who you are. And I think that's why these are the genes that influence food noise. If genetics and biology make such a substantial difference through our weight management, where does personal responsibility fit in? Look, I think there is always going to be some level of personal responsibility. It's our health. It's our children's health. And I think you need to try and do something about it. I think where the genes come in is how difficult it makes it for you.

36:37Now, leaving aside the mutations, which are rare, as I said, and they really put such a heavy burden on your biology, I think personal choice pretty much goes out the window. But for the 99.7 % of us, I think there are going to be individuals who, because of their genetic roll of the dice, just find it easy to say, oh one slice of pizza no i'm all good um for other people two slices for other people the whole pizza and it doesn't mean that you can't have less pizza it's just that the whole pizza people uh just find it more difficult so i think my analogy is is is probably this okay you can have good hands of imagine if your genetics is like a hand of cards you can have good hands you can have bad hands um but you can still and the only people you can blame are your parents because says where they've come from.

37:28But you can win with a bad hand in poker, for example. It's just more difficult. I'll give you another better example. Like I will never, ever be able to run as fast as Usain Bolt, okay? And it's because of my genes. That's what I tell myself anyway. But it doesn't mean that if I train, I won't be able to run faster than I do now. So I think ultimately that's what our genes do. Our genes probably set some limits. Some people are never going to be skinny ever okay in this food environment clearly if you change the environment then maybe they can be but today in the world of deliverance and and the world we live in there are some people who will never be skinny because it's going to be nearly impossible but that doesn't mean that if you try a little harder you won't be a little bit lighter if you were to put it into a percentage how much of our weight management is contributed from genetics versus nurture what we live and the way we live?

38:24So there is a number, actually. So, I mean, like with most human traits and behaviors in terms of as a geneticist, most of our understanding of this, of the genes, have come from the study of twins, like identical twins and non-identical twins. And just briefly, just let me summarize what twin studies are. So you clearly have identical twins, and they are, for all intents and purposes, genetic clones of each other. So they share 100 % of genes. and then you have non-identical twins and they would share as much genetic material as you would with your siblings or your parents, 50%. So if you study a large enough cohort of twins, tens of thousands of twin pairs, identical and non-identical, then you can begin to ask questions.

39:08Now we're talking about body weight, all right? Or feeding behavior. So we can say, okay, well, if you share all of your genes, how do you behave? How do you change in weight? Versus if you share half your genes. And if you do that, you can calculate what we call heritability, which means that genes versus the environment. So if you do that, then the heritability of body weight, feeding behavior, is about 40 to 70%, a pretty big range. It's a big range because the environment plays such a big role. But if we take the average, then it's roughly 50-50. So I would say it's probably around, I'm simplifying here, it's probably around 50 % your biological drive and 50 % the environment.

39:51Wow. Perhaps I was incredibly naive here, but I would have thought we had much more agency over our body weight. Body weight is an interesting thing because it's so public. And not only in terms of clearly what we look like, because you can't hide your body weight broadly, right? Everyone can see you. It's also interesting because the single biggest behavior that causes that body weight, small, medium, or large, is also public. when you go to a restaurant, I know exactly what you're eating. When we go to the supermarket, okay, I know exactly what you've put into the basket. And so we have this, it's one of the weird traits.

40:32Unlike hair color or eye color, you can see, but nothing we can do can actually influence it, right? How healthy your heart is. It's all invisible. I have no idea how fit you are. I mean, you look fit, but I had no idea how fit you are. The thing about body weight is, first of all, I can see it. And second of all, I can see your behavior that could lead to it. I think that's probably why we think there's more agency. So we all model, our brains are two steps away from a chimp. I mean, so we've still got very, really quite ancient brains in which we model the world in which we see blueberry, poison, red berry, lion, whatever.

41:10That's how we've survived. Okay, we kind of model the world. So we understand our own hunger and therefore how much we need to eat and what we need to do to avoid becoming food, these major things. So we tend to try and judge, because we're humans, what people are eating and therefore look like based on our own feeling. So I may very well only need two slices of pizza to be full. Oh, look at that lady. She needs the whole pizza, you greedy person. Because I'm judging her behavior based on my feeling. I think that's why people think that feeding, that we have more agency over our feeding behavior than we imagine.

41:47Interesting.

41:51I have a question about ultra-processed foods and how they influence our appetite. And the question is the following. Do ultra-processed foods, are they composed by a set of ingredients that make us produce less leptin, which then affect our hypothalamus and our MC4 receptors, and hence we don't think that we are as full, so we keep eating more of those? Or do they hyper-stimulate our reward system in that upper part of our brain, and we like it so much and we can't get enough of it, so we continue eating, which both results are the same, excess of eating? Good question. I think it's a mix of both.

42:33So I think if I might clarify, so ultra-processed foods, for people who don't know what they are, it's different from processed foods. So I think almost everything of what we eat is processed to some degree, aside from if you walked into your garden and pulled an apple off a tree. That's not processed. But everything else, if you cook something, it's a process. If you cure something, if you salt something, if you brew something, they're all processed. Is that bad? No, no, no. It's not bad. They've kept us alive, right? First of all, they helped us preserve food, you know, because obviously in a time before refrigeration, you had a harvest, you didn't have a harvest, you needed to preserve food so that you had food over the winter.

43:11Those were all processes. It kept us alive. Cooking kept us alive because it killed the poisons, you know, and it made us easier to get the calories from the food. Okay, so processing. Ultra processing is a contemporary process, probably only, I would say, 40, 50 years old, if that, and really, really accelerated probably over the past 20 years or so, in which these are industrial processes that we are unable to replicate in a domestic kitchen. So this includes food extrusion, almost breaking apart food into their component parts and re-engineered food. So anything you do in your kitchen is going to be a process, but it's not ultra-processed because you're cooking something.

43:54Anything you do in a regular restaurant, if you go to a restaurant and there's a chef doing the things like that, they're not ultra-processed. Now the problem, so there is a technical definition of ultra-processed, this industrial processing. Just one caveat, then I'll answer your question. My problem with the term ultra-processed is it's a technical term. I don't think it's a very good term to indicate whether a food is healthy or unhealthy. So I think technically we can define what's ultra-processed. And within the whole ultra-processed umbrella, there are going to be foods that are terrible for us and we need to eat a lot less of, most ultra-processed foods.

44:28But there are also going to be foods which are technically ultra-processed, but fine for us. They may not taste as good, but they're fine for us. Okay, that's my caveat with ultra-processed. Which ones? All right, let me give you an example. I mean, my favorite example is supermarket bread, okay? Compared to homemade bread. Now, taste aside, let's leave aside taste. Obviously, I prefer homemade bread, sourdough, crunchy, delicious, rather than a supermarket square, okay? Of course. But a couple of things. Bread pretty much is made of flour, water, yeast, salt, and maybe a little bit of sugar. In the supermarket bread, maybe there's some emulsifiers, there are other things.

45:08But the base thing about bread is still exactly the same. Now, clearly, the way you make it changes the flavor, it changes the texture, and tastes different. But actually, bread is bread. And it's ultra-processed bread, yes, and it's homemade bread. The problem with homemade bread or fancy-schmancy bread that you can get at these places, You can spend three to five pounds in US dollars, anywhere from five to eight dollars a loaf, which is fine. I can afford it. I'm privileged. A lot of people can't afford that. You go to the supermarket and you spend, whatever, 35, 50 cents, less than a dollar a loaf.

45:46There's nothing wrong with supermarket bread. It's just ultra processed. Classic example. Another example is yogurt. Now yogurt is fermented. That's the process. Nothing wrong with it. But if you buy, I don't want to say brand names, those square yogurts with the little corner. So suddenly the yogurt itself is only going to be processed. But suddenly if you tip in that little corner square of crunchy stuff or jam or sweet stuff, suddenly the whole yogurt becomes ultra processed. So that I don't understand, right? Because just by adding something, a little bit of something that is ultra processed into your normal yogurt, suddenly the whole yogurt becomes ultra processed.

46:21I find that difficult to try and understand why then suddenly the whole thing becomes evil for you or poisonous for you. Whereas there are foods that are completely constructed, all right, that we know, turkey twizzlers, certain nuggets, come on, I mean, they barely contain any chicken, okay? So I think there are extremes. All right, so given that aside, why, but most ultra-processed foods are not great for you. Okay, I just want to be clear. Back to your question. Let's do the flavor first. Because ultra-processed foods are constructed, okay, the ultra-processing removes most of the flavor from the food.

47:01Now, where does flavor come from? It comes from the holy trinity, sugar, salt, fat, all right? So, if there's no sugar, salt, fat, you have to add sugar, salt, fat. So, ultra-processed foods tend to be very, very high in salt, sugar, and fat because they had no flavor once you've broken everything down. And so you engineer the flavor, which means that it is hitting those rewards. Boom, like Christmas tree lights. Everything is delicious. So are they hyper palatable? Do they make your brain light up like a Christmas tree? I don't know if you ever watched Ratatouille. Okay. Ratatouille, when Emil, I think, was going, taste the grape.

47:38Taste the cheese. Bread and the cheese. And that's what happens with ultra processed foods. So that's true. The second thing, however, is you're asking about, therefore, the hormones. The other problem with ultra-processed foods is that they're very calorically available, which means that you're able to extract calories very, very simply from the food. Let me explain what caloric availability is first. So if you have sweet corn, corn on the cob, and you have 100 calories of corn on the cob and eat it, And if you looked in the loo the next day, you can see it. So clearly you haven't absorbed 100 calories of sweet corn.

48:18If, however, you convert corn into a masa, you desiccate it, you then create corn tortilla, you make cornbread. Suddenly, exactly the same source of food, you can get a lot more calories out. So that is caloric availability. How you process the food. I'm not anti-cornbread or anti-corn on the cob. I'm just describing a process. The processing of food is like an external stomach. It comes out, it goes... It makes it easier for you to extract the calories from the food. Now, cooking increases the caloric availability of food. That's why it's important. Ultra-processing really makes the calories available because you've pre-digested the food.

49:00That's what ultra-processing is. You've taken chicken, whatever. You've almost pre-digested it down to a powder. and then you sort of stick it back together again. Which means that when you eat it, there's very, very little digestion that, okay, there is digestion, but a lot less than if you ate chicken. If you had a chicken leg and just ate a chicken, you know, you have to go through the meat, there's chewing, maybe you like the skin, maybe there's some, you know, tendons, whatever it is, it's a piece of meat. If you eat a nugget that's been pretty much slammed down to some powder and then reconstitute it, then it almost dissolves in your mouth, right?

49:41So you don't, it's still chicken-based, I guess, but you don't actually have to work for it. So if you have 400 calories of chicken compared to 400 calories of a chicken nugget, you're going to get far more calories. You can't add more calories. Far closer to that 400-calorie mark than if you actually ate a chicken leg. That's the second problem with ultra-processed foods. You get a lot more calories out of them and you get a lot more salt, sugar, and fat. It's a double process. That's why ultra-processed foods in general are not great for you. So in very simple terms, we are burning calories through the sheer effort of chewing and digesting something that is more of a whole food rather than something processed.

50:27Correct. Interesting. So 400 calories of chicken nuggets are going to become something closer to 400 actual calories versus... 300 calories or 350 calories in a chicken leg, for example, or chicken breast, whatever it is like to eat. Before we talk about diet, because I do want to explore the world of diet with you. What do you think stressed us to our appetite as far as the brain is concerned? Let's talk about me and my wife again. I know I keep talking about me and my wife, but it's useful for me to sort of illustrate it certainly in my head. Okay, so when I get stressed, I eat. Now, we need to differentiate between tiger stress, which everybody responds the same to.

51:14Run like hell, we're not thinking about food, right? So tiger stress is different. It has cortisol and it has adrenaline, okay? You're running like hell. Okay, let's leave that aside. Two potent hormones. Two potent hormones. We are doing, we're running. Okay, so now we're talking about work stress, exam stress, life stress. So I respond to stress by eating. Okay, I have a comfort food. What happens when I get stressed is my face is into a bowl of noodles. Terrible. Whereas, interestingly, my wife, when she gets stressed, she loses her appetite. She goes, oh my God, I've lost my appetite. But you can literally take half of the human species and divide them into two.

51:53There are going to be people who eat when they're stressed, and there are going to be people who completely lose their appetite when they get stressed. Is that their genetic predisposition? The answer is probably going to be yes. We don't actually know why. I mean, I can give you the, we don't know yet the genetic or molecular explanation. I can give you the evolutionary explanation why it happens. So look, being stressed is unpleasant, correct? And so what you want is to remove the unpleasantness. And so people then look to do things that are pleasant to remove the unpleasantness. And for many of us, it's food.

52:27Food is one of the great joy for me at any rate. Food is one of the great joys of life. And so I would turn to food. If I'm stressed and feeling unpleasant, I'm going to go and eat because it makes me feel pleasant. For other people who maybe they don't love food as much, we'll do something else. Maybe they go bungee jumping. Maybe they like to work out. Maybe they do drugs of abuse. Maybe they drink alcohol. There are going to be people who therefore, when they're stressed, tap into other things, which I think make them feel nice. That I think is the evolutionary reason. It's the common denominator across all of them that we're all trying to tap into our reward system of our brain.

53:02Yes. But the roots to that reward system. So the reward system of the brain is exactly the same place whether we're talking about sex, drugs, rock and roll, or food. It's the same place. How we get there is different, right? Because obviously I'm eating something, I'm injecting something, I'm drinking something, I'm jumping off a plane, whatever. But yes, we're all trying to hit that reward pathway to remove the unpleasantness of being stressed. Is it dopamine what we're seeking there? Dopamine is one of the things. Serotonin is another. It's not only dopamine. But yeah, dopamine are one of the key pleasure hormones, or at least they train the part of the brain and link the reward parts of the brain to a certain behavior.

53:41So in other words, this behavior makes me feel nice. Dopamine gets secreted. Your brain then begins to learn, this feels nice, this feels nice. So that we don't even have to do it now. Now I have to just look at a plate of food or alcohol or think about jumping and my dopamine gets released. So the dopamine is the training element of it that sort of teaches your brain what feels nice and what doesn't feel nice. But it is not the only home run. A slightly different question, but why is keeping weight off so much harder than losing weight in the first place? Excellent question. You're right. Most people can probably sort of tough it out for two weeks, four weeks, lose a bunch of weight, and then suddenly life becomes difficult.

54:22The big reason is because your brain hates it when you lose weight. It doesn't matter whether or not you started large or you started not so large, or if you've lost five pounds or if you've lost 50 pounds. If you lose weight from an evolutionary perspective, your brain considers it a big red flag. It considers it reducing your chances of survival. And so it does everything in its power to actually drag yourself back up again. So it does it in two different ways. So if you've lost weight, after the initial euphoria, if you do this in a dietary perspective, rather than pharmaceutically, after the initial, oh my God, look, you know, your initial motivation, you've stood on the scales, you've lost some weight.

55:03After that, and then suddenly the hard miles comes, your brain does two things. It makes you feel hungry. Anyone who's been on a diet knows that after the initial period of time, you begin to feel hungry. Okay. That's your brain telling you eat, eat, eat. And so you now have to begin to fight that. But the second thing is more, I'm going to use the word insidious, but that makes it sound bad. I mean, non-executive. You don't actually feel it, but your brain begins to lower your body's metabolism. So you become more efficient. So that for a given calorie of food, you're able to do more. Now, not by much, a few percent, but you don't even sense it in order to drag yourself up.

55:40So let me imagine if I had a twin so i'm 70 kilos but my twin used to be 80 kilos but is now 70 kilos all right but we now look exactly the same my twin is going to have to eat less than me to maintain his 70 kilos compared to me who's never been 80 kilos forever we think forever it's a pretty difficult experiment to do because it's forever but at least studies that we have we not me personally studies that the community have done in animals and mice indicates for a pretty long time. Okay? So, and the reason behind that is because your brain is trying to bring you up to where you were before rather than where you have never been before.

56:27Even if where you were before wasn't healthy for you. Yeah. Your brain doesn't sense it as health. The problem with it being unhealthy, it is because of the environment that we're in. So we as humans, actually, we as a living creature, have been evolved to adapt to a feast-famine environment. So sometimes you had the turnip and the antelope, sometimes you didn't. Sometimes we had food, sometimes we didn't. That's how we were developed, evolved in order to survive. So when there's food, we eat it, store it and eat it. And when there's no food, we have to burn the outdoors. The problem is today we live in a feast, feast environment, right?

57:07So it's toxic. So like I said, two steps away from a chimp brain, we haven't yet been able to adapt to this feast, feast environment that we're living in because we are used to a feast, famine environment. So unhealthy only in today's...

57:27So our genes are still Homo sapiens, but our environment has developed into something that is not fit for purpose for our genes. I think the other way around. I don't think our genes, fit for purpose is a very strong word, but yeah, our genes, the thing about genes and adaptation is they take thousands of years to adapt. okay so we have adapted for example to the agricultural diet so agriculture is 10 12 000 years old okay so uh milk um alcohol you know things like things you know high amounts of sugar high amounts of carb we have adapted to be able to actually eat these but this is because it's happened over 10 000 years okay the issue is this environment food environment we live in is what 40 years old yeah or we haven't yet adapted to to this i don't know if we're going to be able to I think it's happened too quickly for us to adapt without doing something about it.

58:23Somebody listening to our episode right now might be thinking, Professor Giles, so you are obviously encouraging people to control their weight, to not be obese. But then what you're telling me is that once I achieve my ideal body weight, I'm going to stay in a prolonged state of pain because I would have to eat less and feel and know that I'm eating less. I'm going to be feeling like I'm starving. what would you say to that person? I'm not trying to be depressing.

58:54Okay, if you put it like that, then yes, that's true. But I think all I'm doing is stating the biology. I think ultimately what I'm trying to say is that, but that when we're dealing... Just a quick break. What I said is scientifically correct, right? What you've said is scientifically accurate. I mean, you've described it in more emotive terms. Yeah, because that's probably somebody wanting to lose weight. That's the way they're feeling it. That is what they're thinking. And it's really depressing. And that is why. So people say, here's the interesting thing. People say that 95 % of diets don't work.

59:28And that's not true, technically. 95 % of diets we can't stick to. That's the truth. So, I mean, there's some crackpot diets, okay? But most diets, leaving aside the pretty explanation on the website or on the side of the pack, they sort of work. The diets that work, if we're talking about losing weight, diets that work are diets that somehow put together a strategy of making you eat less so you lose weight. Ultimately, that's a diet that works. But as we've said, we can't stick to the damn diet, which is why the weight comes back on. So what that tells us is a couple of things. There is a lot of biology underlying the process.

1:00:10And the only way that we're going to fully fix the problem, if we don't use drugs, okay, the only way to fully fix the problem is to obviously make some behavioral changes, portion sizes, what have you. But as I said, that's tough. The reality is from a societal perspective, we need to also fix society. We need to fix the food environment. That's more difficult. That's a more complex discussion because that is governments, that's legislation, that's public health. so i think we need to think about it in two in two ways we need to sort of look what we can do as an individual but that is always going to be limited um but i do things like this i speak to you i go i give lectures i i do the research i do so that we can then turn our attention to the people that make the laws to the people that regulate how many uh takeaway shops or chicken shops can be next to a primary school that regulates when you walk into um bp or or shell whatever it is to go get your your your gas that i'm there to get gas why am i being assaulted by chocolate why does that you know those are the kind of rules that i can't influence as an individual but government stands so i think we need to think about from two different sets of problems

1:01:27you've written a book which is called why calories don't count Why calories don't count? So whenever I say why calories don't count, clearly people think I'm anti-physics. Now look, I understand, obviously, that 200 calories of potato chips is twice 100 calories of potato chips. So clearly they count in terms of as an amount of food. But even then, it's only an amount of food if you're considering exactly the same amount of food. because 200 grams of carrots is twice the amount of weight of 100 grams of potato chips. But that's a stupid comparison because I'm talking about carrots versus potato chips.

1:02:11That's the problem with the calorie. So a calorie gives you the amount of a type of food you're eating, but it's entirely nutrient blind. So it doesn't tell you, certainly it doesn't tell you how much fat, sugar, salt, carbs, fiber. it tells you nothing about the nutritional content of the food, just how much. So they count in its very one-dimensional sense. Which is? Like amount of food. So literally like grams. It's as useful as saying grams. Okay. I'm having a hundred grams of chicken breast. Excellence. I'm having a hundred grams of carrots and I'm having a hundred grams of mashed potatoes and a hundred grams of donut.

1:02:53Does that make sense for me if I say this to you? It doesn't. But yet we think about the calorie like it makes sense. So that's my problem. So it gives you, the calorie is not the perfect analogy, but pretty much the calorie is like saying grams of something rather than saying it's chicken or rather than saying it's a carrot, it's a donut. I'm not making a judgment call. I love donuts. I'm not making a judgment call. But the moment you begin to compare the calories that you get from a donut to the calories you get from a carrot, I've got some issues. What's a calorie? A calorie is the amount of, it's a unit of energy.

1:03:26A calorie is the amount of heat you need to heat up one liter of water, one degree Celsius at sea level. That's a calorie. I think right now we're using the term calorie or calories to understand how much should we eat. And if we are consuming more calories or we're on a deficit of calories because we burn more than what we consume. was the initial intention for coming up with the idea of calories to track that or was it just to understand how much energy are we consuming a day and then how much of that energy can we expend oh my god i mean when when the term calorie first so calorie comes from calor which is heat which is why some of the gas providers in the world is called calor all right because it's heat so calorie is a unit of heat originally described to actually just measure heat.

1:04:20Like they did it using, I think, was it the French that first came up with the word calorie? And they were trying to, when you lit dynamite, an explosion, gunpowder, they were trying to figure out how much heat was given off. That's what calories were designed literally to measure heat. Then people began to realized that actually the amount of heat being given off was representing the amount of energy being given off. So then people began to use the calories in agriculture. They wanted to know if you were farming cattle or sheep or chickens or whatever, they wanted to know how much food, when you fed a cattle how much food, how much product, meat, milk, eggs would you actually produce.

1:05:04Farmers obviously need to know that. That's pretty important. That's when next was when calories actually went to. It was only really quite late that it began to come into human food or humans at all. And this was probably the late 1800s, 1880 to 1900 or so. There was a guy called Atwater, okay, a professor Atwater, who was a professor of biochemistry in the state of Connecticut, okay? But he did a sabbatical and he went for a couple of years to Germany. So at the time in the late 1800s, The peak of calorie research around food was sitting around Germany, that area, for any number of different reasons.

1:05:45So Wilbur Atwater, that was his name, Professor Wilbur Atwater, went to Germany to learn about calories and food and learn about a technology called BOM calorimetry. And BOM calorimetry is just very simple. You take food and you desiccate it, you dry it. Because for human beings, we can't extract calories from water. If you're a nuclear power reactor, you can extract calories from water. We're not a nuclear power reactor. So you dry the food, and then literally you burn the food. And around this sort of like a sealed container in which you're burning the food, there is a jacket of water of known volume, whatever, X liters, and there's a thermometer in it.

1:06:23So literally you burn the food and you measure how much the temperature went up. That's the number of calories in the food. That was called bomb calorimetry. So he learned this technique and he brought it back to the United States. And between 1880 and 1900, he then started doing this to food. So his goal at the time, so this would have been broadly speaking, I mean, obviously this is in the United States, but broadly speaking, the Victorian era, right? So heavy industrialization in which people were moving away from the farms almost into the cities in order to work. And this was true in many countries.

1:06:58and when the people were living in the cities in the factories and doing the things how were we going to feed a rapidly growing urbanized population with food cheaply so that was his aim so his aim was to sort of went in and he spent 20 years burning all kinds of food carrots okay didn't have donuts at the time carrots fish whatever whatever it was it was burning and he made these detailed notes about how and he was the one that then and then he fed them to people people then went to the toilet and he burnt people's okay now you know how much went in and how much came out and at water was the one that worked out these numbers that all of us learned in high school okay four calories for a gram of carbohydrate four calories for a gram of protein and nine calories for a gram of fat those are called the at water factors he calculated them between 1880 and 1900 these are still how we calculate calories today all right it's an old science and that is where he he he was the first person to apply calories to the food but in order to try and feed a rapidly growing urbanized population during the industrialized era we have established that if we consume whole foods versus ultra processed foods it takes us more of an effort to metabolize the whole foods hence why we are perhaps absorbing 80 of the calories rather than 100 % of the calories.

1:08:25If we take the same example, chicken leg, whole food versus chicken nuggets, one is nutrient dense with a lot of protein, the other one has far less proteins. Would one keep us more satiated than the other? And if so, why is that? Is it because of our gut microbiome or is it because of our brain receptors? There's no simple answer to that, but the answer, Okay, so the simple answer to that is yes, one is more satiating than the other because protein, so a calorie of protein, so now we go to calories. Okay, I know they don't count, but in terms of just an at-water calorie of protein makes you feel fuller than a calorie of fat, which makes you feel fuller than a calorie of carbohydrate in that order.

1:09:09Okay, so protein is more satiating. Why? Two reasons. so protein is chemically the most complex of the macronutrients fat and carbs are very simple because they're only made of carbon hydrogen and oxygen okay but in different configurations that's all fat and carbs carbon hydrogen oxygen protein is more complex because it contains a lot of nitrogen as well as well as other things which means that it is just more difficult to deal with so it takes longer to digest and foods that take longer to digest travel further down the gut more gut hormones are released which signal to the back of the brain which let you feel fuller so protein makes you feel fuller a given calorie of protein first second even once it's absorbed into your body protein takes a lot more energy to metabolize once again because of the nitrogen okay because fat and carbs you just kind of shift the the atoms around it cost some energy protein costs a freaking load of energy.

1:10:06So for every, people don't know this, for every 100 calories of pure protein, we seldom eat pure protein, but I just imagine, okay, 100 calories of pure protein, we are only ever able to use 70 calories, 7-0. 30 calories for every 100 calories of protein we eat is given off as heat because we have to deal with protein. And so compared to fat, if we have 100 calories of fat, we get 100 calories of fat, okay, for that. So if you go back to that description about clearly a chicken leg or chicken breast or something like that with a lot of protein in it versus a nugget in which now you've had to add fat, sugar, salt, and what have you.

1:10:44Just by the fact that there's more protein, it's going to make you feel fuller. Fascinating. I want to shift the conversation into weight loss drugs. Yep. What are GLP-1 and GIP drugs and how do they work? Let's go back to what I talked about with regards to the hormones. Now we're not talking about the fat hormones, leptin is a fat hormone, but we're now talking about the gut hormones. So these are short-term signals. Now, actually, there are 20 gut hormones in our body, not just two. Two of them are GYP and GLP-1, but there are 20 gut hormones in our body. 18 of the gut hormones, so most of them, make you feel fuller.

1:11:22And when you eat and the food kind of travels through your gut and out the other side, a whole repertoire, a mix, a very fine mix of these 20 hormones are released to inform your brain a number of different things. It tells you how much food you're eating just by weight. It tells you where in the gut it is, and it tells you what you've eaten, how much fat, sugar, salt, carbs, everything. It lets your brain know. Your brain seldom tells you, but your brain knows. Okay, for this. And most of them make you feel fuller. JIP and GLP-1 are two of these. Now, the problem with JIP and GLP-1 is that their half-life is very short.

1:11:59So we've known about JIP and GLP-1 for decades. In terms of the biology, I've been in the field for 30 years. I've known about GYP and GLP-1 for 30 years. We've known that they've made you feel fuller. They were never hugely useful in the early years as drugs because their half-life is very short, two minutes. So the moment they can secrete it from the gut, they get chopped up. Your gut hormones are designed to be volatile because they're designed to reflect what's in your stomach or gut at a given period of time. So it needs to be volatile. So it's signaling our brain, this is what you've eaten very quickly.

1:12:30Yeah, pretty much. So they weren't useful as drugs, is my point. Because if you inject native GLP-1 and GYP, it just gets chopped up. There's absolutely no value. Where the magic comes is if you can keep it in the blood for longer. And ultimately, that's what these drug companies have done. They have designed versions of GLP-1 and GYP. So there's simply modified versions of native hormones in our body. But now the half-life goes from two minutes to 10 days. Right? That doesn't sound healthy. That's an interesting take on it. So the science of it has shown that actually it is fine because what all you're doing broadly for most people, not for everybody, what happens is you are changing the hormonal balance in your body.

1:13:18And so therefore it changes that mix and ultimately that then changes your feeding behavior. So these drugs in effect make you feel fuller quicker. And you're right. In some circumstances, you might think, that doesn't sound good. If you take a volatile drug and then suddenly make a difference, that's not what we're doing. So what you're doing is you're changing the baseline in some people. The volatility is still there because you're still eating. Your GLP-1s are still going up and down. Your GYP is still going up and down. All your other gut hormones are still there. But because you've sort of lived, imagine it as a thermostat, where you are set at 32 degrees Celsius.

1:13:56What all you've done is these drugs have sort of ticked it down two, three, four degrees, depending on what drug, depending on who you are. So what's going to happen when you take these drugs? So this is what these drugs are. They're modified versions of natural hormones. But one of the questions that people ask me is, well, won't you, if you take it, won't you OD on them? Won't you just disappear? You'll go, boop, disappear. No, you won't. So what all that happens is because you are changing the thermostat, you then drop to a lower level and then you begin to plateau again. You won't disappear entirely.

1:14:28All you're doing on a given drug at a given dose, you arrive at a new plateau level and stay there. But if you come off the drug, your weight goes back up again because then you've changed the baseline. You've turned the thermostat back up to 32 degrees again. Foles, I quickly interrupted you there, but you were saying that, so they're increasing these modified from our native hormones, GIP and GLP-1 within our bloodstream. But then what happens? So that signals the brain that we are full. That you're fuller than you are. So they don't make, because ultimately we still, even someone that's on a GLP-1 drug, you still get hungry because you still need to eat.

1:15:06I mean, I've been on the record of saying this and my son is 25, by the way. So he allows me to talk about these things. But my son has been on these GLP-1 drugs since January of 2025. So my son went to university and over three or four years gained 50 pounds. And so we had this discussion. Anyway, after the discussion, we ended up, I ended up paying for him to go into these drugs. And he's now my size. So he's lost the 50 pounds. He's very, very healthy. What he tells me, he describes the way is like going into a petrol station with the tank half full. So he still likes to go to the petrol station.

1:15:45He still wants the diesel, but he just needs half the amount of diesel and he can walk out. And so that's the way he describes it, where actually he still loves food. He still eats food. He still needs food. he just needs less food. Is he still on the drugs? He's still on the drugs, for now. How long should people stay on the drugs? It's an excellent question. I think the likelihood is for many people, I'm not going to say all because I don't think that's true, that these drugs are likely to be long-term drugs, if not forever drugs. Now that sounds scary. The moment I say it, I know people say, oh my God, that's scary.

1:16:19But a lot of your listeners will either be on or know people that are on high blood pressure drugs. okay high blood pressure drugs are forever drugs you take one pill in the morning your blood pressure is normal no one says oh mr smith mr lee um your blood pressure is now normal stop the drugs because your blood pressure will become abnormal again right and so i think we need to think about these uh weight loss medications like that if you come off the drugs the weight will go back to where they were before your eating behavior will go back you need to frame the question these are not cosmetic tools.

1:16:54It's not hair gel. It's not, I'm not an expert. It's not hair gel. It's not lipstick. Okay. They are a drug to treat a disease. So if you've got obesity, you are at high risk of cancer, high risk of high blood pressure, heart disease, you have to take the cost-benefit analysis. Meaning that, okay, these drugs have some side effects, gastrointestinal largely, but side effects. But the cost-benefit analysis of not treating my obesity is far worse than treating it. So you understand that. And so therefore, all drugs have side effects. If you're using it purely as a cosmetic tool to fit into your bikini, to fit into your jeans, the cost-benefit analysis begins to shift.

1:17:37Putting lipstick and hair gel shouldn't have a cost-benefit analysis because it's just cosmetic. So I'm not here to judge who chooses to take these drugs or not. That's not my point. My point is that we just need to frame it as drugs. These are not cosmetic tools. People use them as cosmetic tools. We can debate the wisdom and doing, but they were designed as drugs to treat a disease. Can you talk to me about those side effects and risks? They're going to be the common side effects that we've all heard of. And these showed up in the trial, so we've always known about them. And they reflect the biology of these gut hormones.

1:18:16And these tend to be nausea. That's probably the most common one where people feel... I'm not saying nausea like people are puking in a corner, but it's almost like if you eat too much, suddenly, right? That kind of feeling. Or these are gut hormones, so they alter the flow, the speed of food that goes through the tube. So the other side effects are the other end. Either too fast or too slow. Diarrhea or constipation. So those are the common ones. Now, and those are related to the biology of the drugs, but probably the most famous one that people are talking about as a side effect is the loss of muscle mass.

1:18:55This is what everyone is panicking about. Oh my God, you know, I have taken the drug. I've lost a bunch of weight, but now I've got a zempic face. You know, whatever. You know, suddenly I'm looking haggardy. It is true, okay, that there's a loss of lean mass, but it's not specific to the drugs. Many people don't know this. when you lose weight, particularly if you lose weight quickly, you lose 60-40. 60 % fat, which is what you've signed up to do, so yay, but 40 % muscle. And people are going, I didn't sign up to lose muscle. Why does this happen? Largely because, say you've lost a substantial amount of weight.

1:19:33Say you used to be 300, you're now 200 pounds, okay? It's 100 pounds you don't have to cart around anymore. Muscle is very expensive to keep around. And so you will keep enough muscle to move your body weight around. So if you've lost a substantial amount of weight, particularly quickly, your muscles will then just shrink. This doesn't mean it's not a problem, okay? Because at the moment, the vast majority of people on these drugs are taking it privately. 80-90 % of people are taking it privately. So you have to be able to afford the drugs. 80 % of the people taking the drugs are women. It's a complex reason.

1:20:14Women tend to care about more what they look like than men. Men tend to not like going to look at doctors. These are just generalized views, but 80 % of GLP-1 users are women, and they have to be able to afford it. So 80 % of users tend to be women of a certain age, between 45 and 60-year-old. This is where you are wealthy. So you are either perimenopausal or menopausal, which means a couple of different things. But suddenly now, you've accelerated that muscle loss because you're now taking these drugs. So they're not specific to the drugs, but they are part of the problem. And we need now to sort of have a public information while I'm doing this, where you can't use these drugs in isolation.

1:20:58So in other words, if you're taking these drugs to lose weight, you have to make sure you maintain a high-quality diet, largely making sure you eat enough protein, fiber, and micronutrients. And you need to be moving. You need to exercise to mitigate against the muscle mass loss. And that's what you need to do. So that's probably the biggest one that everyone panics about. It's a real problem. So what we need to do is we need to mitigate against it. We need to tell people that you can't just inject a drug and say, I'm going to be healthier because all you're going to be is lighter. Yes, you will be healthier in a sense because you're now reducing the amount of fat.

1:21:33But you don't want to just be lighter. You want to be healthier. And so you want to then put things in place to make sure that when you're on the drug, you become lighter and healthier. Should they supplement that muscle loss with an excess of protein? You need to supplement it with enough protein. So I know I didn't give you a straight answer there. No, that was a straight answer. You need enough protein. The thing about protein is unlike fat and carbs in our body, we can store fat and we can store carbs. We can't store protein on our body. So all the protein we are using is active. It's either there to build something or it's there to repair something.

1:22:10So you need to eat enough protein so that your muscle loss is then mitigated. If you eat too much protein, it becomes fat. So you need to eat enough protein in order to do that. And micronutrient loss is another major thing. Some people may need to consider supplementation if they're on these medications because your appetite is suppressed. So you're eating less, but you still need X amount of protein and fiber and certainly your vitamins and iron and calcium. It's a tricky time to be living in. Who should not be taking these drugs? I'll answer it in another way, if I might. My biggest fear about these drugs is not the side effects.

1:22:53my biggest fear about these drugs is that there is no lower weight limit in which they begin to work so let's go back to the 300 pound individual you need to go down to 200 pounds that the drugs may very well be for you the problem is they will also suppress the appetite of a 17 year old girl oh boy who is 70 pounds that's the problem those are the people who should not get the drug you shouldn't be a 16 17 you shouldn't be any age to be fair but the really vulnerable teenage individual who are trying to look sexy trying to look good maybe obsessing about food maybe obsessing about the way you are looking um those are the individuals that should not be allowed within a country mile of these drugs because they don't only work on people who are overweight.

1:23:48They will suppress your appetite no matter how skinny you are. That's the problem. Those are the people who should not get anywhere close to these drugs.

1:24:00Let's talk about practical solutions to obesity. All right. Can you walk me through your 1635 framework? My 1635? So this is what to count instead of calories. All right. And I think there are some simple rules to follow. It was interesting. I wrote the book. This is the Why Calories Don't Count book. And I gave it to the publisher. And my publisher came back to me and says, this is very negative. I'm going, what do you mean it's very negative? He says, it's all this complex things. It's nuanced. There is no plan. I said, what plan? Yo. I said, there is no yo plan anyway. So I came back and I thought, okay, well, I'm not trying to sell a diet.

1:24:41I'm not trying to push anything. But I think there'll probably be some generalized rules that if we follow, then it doesn't matter what diet you're on, we can follow. And that's my 16.35. So 16 is the percent of protein we probably need. Now, this number is not set in stone because it depends what you're doing. You need to eat enough protein. And for most of us healthy individuals, 16 % of your total energy intake should probably be protein. You don't want to eat too much because either it gets converted into fat or it stresses out your kidneys. So enough. If you're old, if you're a kid, if you're an Olympic athlete, this is going to all differ.

1:25:23Okay, if you're in cancer treatment, if you are in ICU, I'm talking about a healthy individual. So enough protein. And I don't only mean steak. So when people say protein, people think, oh my God, I'm going to eat steak. Any kind of protein we do, from beans, from tofu, anything, animal or plant. 30 grams of fiber. At the moment, on average, we're probably only eating 15 grams of fiber. And fiber only comes from plants, fruits, vegetables. So what I'm saying is, eat more fruits and vegetables. Like seriously, we need to double the amount of fiber we're actually eating. And 5 % of free sugars. Try and limit what you eat of free sugars to 5 % or less energy-wise.

1:26:07What is a free sugar? So a free sugar is a sugar that's been detached from the fiber it came in to begin with. So it's anything. So free sugar is obviously the white powdered stuff, but it's also honey it's also maple syrup it's also algarve nectar that is all it's also orange juice where you've actually removed the fiber okay so that is the sugar where we don't digest we drink it it gets absorbed whereas all the sugar that is tied up in a fiber if you eat an orange if you eat an apple if you eat whatever it is you like to eat the carbohydrates in them they limit the amount of the fiber limits the amount of carbohydrates you can get out anyway and also slows it down.

1:26:50So the free sugar element of it, keep the 5 % or less. And if you do that 16, 30, 5, then you can be vegan, you can be keto, you can be Chinese, you can be Indian, you can be whatever the hell you want or are and follow those things. And I think automatically your diet will become more healthy. Walk me through an ideal day where we apply this framework from breakfast, lunch, and dinner. I don't like to think about it in the form of a day because I think you could hit a day, which is the weekend, which is your children's birthday party. You could hit a day in which is your mates go away, do. You could be getting married that day.

1:27:29So if you think about it to the day, I think you end up being obsessing about your food. I like to think about it over a week. Why? Because over a week, then you have work days, you have weekends, you have nights at the pub. And so over a week, I think we need to try and therefore eat enough protein and fat and carbs and sugar. And it takes into account the fact that if you've had a party the night before, if your children's birthday is there, and if you have a children's birthday party, you want a cake, don't be stupid, right? But you don't want cake every day, I think is probably my point. So I like to think about this over the period of a week and consider it over a period of a week rather than over a day.

1:28:08I want to ask you more of a personal question since you've very gracefully opened the window into your son's former obesity you've spent your career in understanding obesity and also helping people tackle obesity how did you feel as a father when your own son was obese interesting question worried i never did ah, I probably lie. Did I ever blame him? A little bit in me. I'm going to be true because I'm human. Because I'm human, right? But obviously I had to fight. I had to fight the instinct. And so my wife was more vocal about this than me. I want to point out. No, we sat down, we discussed. And look, we tried to put a lot of, I am fortunate enough where I am privileged enough to be able to sort of put things in place, help him pay for a gym membership, buy specific tons of air fryers and stuff.

1:29:04So look, I know that I can afford to help him. So I've tried to help him to put some things in place to behaviorally get him to improve his diet. Two things. He loved his food, like me. He loves his food. And so this is fine. I do love my food. I love to exercise and I love my food. And that keeps me in check and in balance, so to speak okay he loves his food but hates to exercise and i think that was part of the problem um so we got worried more than anything and i also know the numbers right because he's young he's young right he's not like me if i'm you know whatever but young people have the opportunity to become because an unhealthy young person becomes an unhealthy old person and so it was more worried than anything and so that's where we got to the point where we decided that actually the drugs may very well for him because he wants to stop these drugs eventually.

1:30:00So I told him, look, stay on them for two years, which is the period of time in which the trials have been done, and then stop and see whether or not, because then since then, he's been trying to put behavioral changes into place. He now knows how to cook better, what kind of foods to buy in his freezer, so that even when he's suddenly hungry, he doesn't just reach for a chocolate bar. There's chicken breasts in the freezer, there's some vegetables and an air fryer. You can even rapidly begin to cook something when you get hungry. So probably let's go to the end of 2027, which will be the two years, and then stop and see whether or not with his new behavior, he now cycles to work.

1:30:40He tries to go to the gym in the morning and swims before he goes to work, for example. Can he maintain that when he's not on the drugs? I'll report back. Do you think you could have or should have done anything different in your parenting, in your education to have avoided his obesity? No, I don't think it's a lack of information problem. Because the reality is when he was in the house and I do the cooking in the house, he didn't have an obesity problem. Because what happens at home, it's not like a restaurant, right? We don't have a lot of snacks in the house. It's just not for any evangelical reason.

1:31:19is just what we buy in a supermarket. So when he's at home, I cook the food, he sits down, I give him the food, he eats the food. The problem was, he then went to university and then suddenly, you know, we were fortunate that we live in a little village outside Cambridge. Lovely, leafy, but it's so far away from anything, Deliveroo doesn't deliver there. So there was, you can't get Deliveroo deliveries there. So in other words, if you need food and you're a teenager, you either eat what's in the fridge or the next time you go out with your mates. So it's constrained. Less temptation. Whereas you're in a university town.

1:31:54Doesn't matter which university town. Suddenly the ability to respond. So there's nothing that I could have said to him. I think that would have made a difference. I think his drive, this is people with susceptible biology meeting a permissive environment. In our house, in a little village outside Cambridge, it is not a permissive environment because there's no food around the place, right? You go to a university town, any downtown area, suddenly that biology smacks into the environment. If you could speak directly to someone who struggled with their weight and believes that this makes them weak, what would you say to this person?

1:32:30It's not. Look, you got to know that if you're struggling with your weight, you are fighting your biology. Here's the problem, okay? So don't try and lean into what someone is calling. And if you go to social media, you go da-da-da-da-da, It says, new me, new you, new year. Here is the solution. The problem with a lot of these solutions that are being sold to you by influencers, it's very often, it's my way or the highway, which means that if you do it my way, this will work for you. If you do it my way, this is the effortless way to lose weight. Bollocks, lies, complete lies, okay? Weight loss is difficult for all the reasons we have discussed.

1:33:11If you find it difficult, it's not because you're bad. it's not because you know you are weak it's because you're fighting biology so you need to put together strategies for yourself to try and keep the weight off so maintain the environment you can maintain that typically is your household so reflect what is it you like to eat and when if you stress eat for example and you know you do we know who we are what do you stress eat like i said for me is noodles is it chocolate is it this is it that and maybe limit those types of foods within in your household. Control where you need to control. Then, if you think about the big bad world out there, it is what it is.

1:33:51Sometimes you've got to go to a friend's party. You go to a friend's party. You're not going there to be a party pooper. You don't want to not enjoy life. But sometimes you can strategize. So in other words, if you know, and this is largely, for example, if you're thinking about work, all right? Because that's, going to a friend's party is not an everyday event. Going to work is an everyday event. How do you then strategize around where you have your lunch at work? Are you bringing in a sandwich? or takeaways? Are you eating? So I would do that. First of all, it's going to be hard. And if you just think about it over a period of time, just because you have one bad meal doesn't mean you're a bad person.

1:34:30Doesn't mean it derails anything. Think about it over a slow and long process. That's what you've got to do. Professor Giles, this is my last Thriving Minds question for you. If you had to compress all your knowledge into one essential piece of advice that we all must implement in our daily lives, what would it be? Do you know, I actually know an answer to that. And I think I've thought about it hard, variety. I think too in everything, I think too many of us do the same thing over and over again. And this includes what we drink, what kind of exercise we do. If you can implement a little bit of variety in everything.

1:35:08So for example, this week, can you suddenly find a new vegetable you've never eaten in your life or a new source of protein or a new kind of exercise or new anything. I think variety. Because I think the moment we do some variety, I think automatically we become healthier, we become better. So I would say variety. Beautiful. Variety. Thank you so much. I've enjoyed this in multiple ways. But primarily, I personally believe that we turn to identify the root cause of obesity towards our self-discipline and our choices. So I really appreciate you helping me understand that biology and also the inner mechanics of how our brain works in conjunction with our hormones play a very, very important role into our relationship with food.

1:36:01So thank you so much. Thank you for having me.

1:36:11Thank you.