New Science of Weight Loss | A Masterclass

0:08Dr. Was that a difficult decision for you personally, being a bariatric surgeon, to decide to start a GLP-1 medication? It was a matter of seeing other people use it. I had prescribed it for a number of my patients and some patients who had failed bariatric surgery and I was happy with their results. I never thought about it for me. Until such time as Eli Lilly said, we're going to make it available to the public. And until such time as I had a friend of mine who grew up in the same city I did. She used to drink a lot of alcohol. She basically stopped drinking. She stopped smoking and started losing weight.

0:44I said, wow, that's a great thing for you. And then another nurse that I worked with, I kept watching her go down and down and down. And I said, you know, I think I should give this a try. So I called a friend of mine who's an obesity physician. and I said, I need to get a prescription for this. And he said, what's the name of the patient? I said, it's me. And without missing a beat, he said, how tall are you and what's your weight? And a week later, I had ZepBound. Now, I'm a surgeon. I'm a weight loss surgeon and I hate needles. I don't mind needles in anybody else. I can put a needle in you today in the parking lot and save your life and bring back a lung.

1:20but by golly when I have to inject myself I am like a six-year-old kid who wants a lollipop afterwards you know but I do it was it difficult being a are you still doing surgery now no I'm finished yeah but at the time when when you started ZepBound yeah yeah I think you mentioned the word shame was it was it difficult being a bariatric surgeon and being overweight yourself It was. I felt like I was hypocritical. I felt like I was living a lie because most of what you do in bariatric surgery is not do the surgery. It's teaching people how to eat afterwards. And one of the reasons I became certified in culinary medicine is I had looked around the surgery world and said, we don't have any protocol to tell people how to eat.

2:09We have a lot of people saying, oh, you should do low carb. Like almost everybody in this space, many of us started out on some low-carb journey somewhere and thought that was the bananas and then realized very quickly, no, it's not. And I had been down that road also. And so I decided, you know, I really, I like to cook. And I noticed I did a little study in my patients who are post-op and my patients who cooked did better than my patients who didn't. I said, that's interesting. Maybe I'll, and then the certification program came for culinary medicine. And so I went for it. That opened up a whole field of nutrition that I had never read before.

2:50And so in culinary medicine, you are required to do, I mean, there's tons and tons and tons of basic peer-reviewed nutritional research. And it was sort of like there I started learning, oh, the Mediterranean diet isn't just a diet of a geographic region. It really has some significance in terms of how it's done. there's really a scientific basis for it. So I was helping all these people lose weight and I was slowly gaining weight. And I would look at my pictures of myself in support groups that I would have. And here's this guy with a belly walking around helping all of these patients who've had weight loss surgery lose weight.

3:27Not one of them said anything to me about my weight. Never once in the thousands of patients that I operated on. But in me, it was sort of like this bit of shame what is someone not appreciating or not understanding if they're listening and maybe they've lost weight successfully on changing their diet and they're of the view that people don't need these drugs they're just not doing the dietary changes properly what is that always moving the goalposts though right if you don't do it this way that's why you didn't lose the weight. But I'm sure that's something that you come across the wall. All the time.

4:09Every day there's someone that's challenging me saying, you didn't need to be on a GLP-1, you just didn't have any discipline. And my first thing is discipline. I'm a damn surgeon for God's sake. I can stay up all night operating and I went through all the things to become a surgeon. I have plenty of discipline. I have plenty of willpower. Willpower as BS as far as this disease is concerned. What I did not have was a change in my brain that turned off food noise, something I didn't know I had until 12 hours after my first injection with ZepBound. 12 hours after I injected, all of a sudden I noticed something had changed in my brain.

4:45I couldn't describe it. The best way I describe it now is, have you ever slept in a city that has lots of city noise? Oh, in New York. Right. And when you leave that city and you go to someplace quiet. Isn't that a little weird when you go to sleep? Totally. You get used to the noise. Right. That's how food noise is. You don't even know it's there. And then when it's gone, it's gone. And it's like, there's something gone and I don't know what it is. And that head hunger food noise is sort of this relentless thing going after you. And you don't know it's there, but it's clearly there. Other things change too.

5:21I used to have a couple of glasses of wine at night with dinner. Now I rarely have wine. I got rid of five wine clubs. Most of my wine has gone to giving it away to other people. My tastes have changed. So now if I don't like the wine, I will just put it down and not drink it. And whereas before I would power through it, maybe open up another bottle. And that's different to satiety or feeling full. Correct. Those are two different feelings entirely because you can be full and still eat. let me give you have you ever been to a great michelin star restaurant yeah okay you were full and then they came out with dessert wasn't a problem eating the dessert was it no i mean it it it's a once it's most most evenings for me i'll finish dinner and i have feel full but then i'm i'm you're able to eat something sweet right and there's nothing wrong with that by the way dessert is not the reason that i had gained you know the weight but um that food noise is something you can't describe to someone who is sitting in Alaska and never been in the city lights.

6:27Is the food noise, would you say it is like relatively between people? It's not an equal playing field. Correct. So in my family, so I grew up at a time when food in America changed. Okay. I grew up in the sixties in Alaska when you had basic food and about 15 % of your diet was maybe ultra processed. I was a poor kid in Alaska. My dad was a professor at the University of Alaska. And so we didn't know we were poor. We had salmon three times a week because you could get salmon anywhere free. And when I went to college in the 70s, all of a sudden, these ultra processed foods had become cheaper because they'd become more abundant.

7:12And then they became cheaper still and they became an important part of our diet. It was easy to grab something. And for me, that set off a small trigger in my brain somewhere. And people will say, well, you should just eat whole food unprocessed. You know what? That's my diet. That's been my diet for years now. It did not change my weight. It did not change food noise in me at all. People say, oh, if you would just be all low-carb. Well, I did low-carb for a long time. Most of my patients I did bariatric surgery on did low-carb. Oprah Winfrey did lots of low-carb. And guess what? In fact, one can make a case that as low-carb increased in the nation, so did obesity.

8:00Those sad little correlations that really doesn't mean anything. yeah and a lot of those diets people do tend to lose weight in the short term yeah but it comes back yeah and they attribute it to pasta i remember the very first time i was on low carb and i go to italy for the very first time with my brother he's going to italy and i had been on this atkins version thought i knew everything about nutrition because it's a very good circular closed system. Well, as I was going there, I was thinking, well, do I go off Atkins or do I stay on it? And then the mad cow disease hit Italy. And it's like, I'm going to go off Atkins.

8:41And I get to Italy. My first thing is, being not a young man and terribly unsophisticated, why are all these Italians eating pasta and vegetables and maybe a little bit of meat? They're all better looking than I am. They all dress better than I am, but they're all thin. What is wrong with these people? Didn't they read the book? They missed the memo. I know. And so I start eating there like the natives in Italy were eating in the region. I was in Sardinian Rome. And it's like, I came back and it's like, I'm expecting that the scale is going to be up five, 10 pounds. And it was down five. It's like, wow, well, I was wrong about that.

9:20What I didn't realize was that You know, it really is calories, but it really is different. And then go to Asia. I remember going to Asia, and this was when I was a young man. This was before I had a problem. But I remember being in Asia, and I would see the monks eat. And monks are shoveling in rice like they had never eaten before. And they are as thin as a rail. And I remember thinking back, how could Atkins have been wrong about this? There's something different about them. Yeah, they're not eating a lot of meat. By the way, when we introduced more meat into China, when it was been back to China or Beijing, you can tell the wealthy people who are eating more meat in their diet, they're gaining more weight.

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11:15so coming back to the kind of mismatch between our biology and the food environment what is it that makes these drugs particularly effective well i think what's fascinating for me and and what makes them so effective is the quietening of the food noise and food noise is not actually a scientifically determined term yet i think it will be soon but it's different for everybody so different people have different forms of food noise. But what this seems to be particularly effective for is reducing the desire to consume foods that are marketed to us, basically. So food environment as it stands in places like the US, the UK, Australia, it's an obesogenic food environment, which basically means it's a food environment which biologically is promoting obesity.

12:03And that's quite a strong statement, but it's true. So like, it's not just me that thinks this or says this. And what these drugs do is they essentially make the advertising and the marketing and the hyperpalatability of these foods less attractive. So you biologically, physically don't actually want it anymore. And we see this across hyperpalatable fatty foods and very sweet foods, but we also see it across alcohol and tobacco. So I guess one thing that is exciting is that the public health impact of this drug is actually a bit broader than just helping people to improve their food consumption and metabolic health in that way.

12:47Quite a large number of people see that they just don't really want to drink as much. In the book, I give an example of one of my patients and of all the stories, of course, have changed, but I've had a few patients who actually drank more than they should have for their health, and they were aware of that. But it was really the GLP-1 medications that made them stop drinking so much because they just didn't want to drink. So there's this combined effect of resisting what we're being marketed and advertised all the time. Because at the moment, our food environment is pushing us to purchase. So it's a very pro-consumption food environment.

13:25There's coffee stores at every corner. There's adverts on television, on Instagram, on TikTok, any social media platform, radio, out-of-home advertising. And the cheapest, most accessible, most convenient foods tend to be hyperpalatable, nutrient-lacking foods that don't do anything to support our health. And these drugs make you kind of not want to eat them. so that's huge because you suddenly have so I remember one of the very first people I spoke to who had started taking these drugs for specifically for weight loss and obesity she said to me for the first time in her adult life she had time to think about something other than food and to me I was like wow I mean she's like I now have time to think about other things food is not my primary driver and my primary thought all day.

14:16So it opens this window. I love to talk about windows of opportunity, Simon. There's lots of different windows of opportunity across the life course. These drugs offer a window of opportunity for people to actually decide, choose, being mindful about what they're going to eat next with the noise of like the advertising and marketing turned right down. So you become much more empowered to make the food choices you want to make. I mean, it's a pretty big deal. I think that's where it's giving the power back to the people that are taking these drugs. And listen, you don't have to take a GLP-1, by the way, to help reduce food noise, of course.

14:55But for people who have really struggled with this a lot of their lives, it's a massive switch. What I'm hearing is that it's not necessarily an even playing field when it comes to someone's desire to eat certain foods. Because I think there is an assumption out there, and I've seen people kind of make this claim or have this position, well, I lost an enormous amount of weight changing my diet without a GLP-1. Therefore, I'm evidence that discipline and willpower is enough. but what I'm hearing from you is that that's a difficult thing to say given that there are differences between individuals in terms of the food noise and what that experience is like.

15:39Absolutely. So I mentioned that we all have the same number of cells, the L cells that have the potential to create these peptides, but the end of that line is our brain and our hypothalamus is the region of the brain that is most responsible for food reward, food-seeking behaviour. And the hypothalamus, those regions of the brain, is where you see the differences in genetics, is where you see intergenerational changes. So for example, if a woman is living with obesity and becomes pregnant, if she has leptin resistance during the pregnancy, it changes the actual wiring of the hypothalamus in that baby, who will then go on to have a much higher food-seeking food reward system than a baby who wasn't born to a mother living with obesity.

16:32Now, this is not always the case. I'm just giving you an example. It's not fair to compare people and say, well, everyone has the same setup. We don't. So genetics plays a huge part and a huge role in how our brain is set up and wired to respond to that food noise and to respond to those cues. So whilst we, as I said, we all have this really great potential in our gut, we don't all have the same wiring in our brains to respond to the same signals. And so it would be wrong to assume that because one person is able to lose, I've had great success stories of people losing weight without medication, right?

17:13But it's not for everyone. That's why, you know, If it was just a case of willpower, then we wouldn't be in this situation. It's not like we've had a mass collapse in willpower over the past two generations. That's not what's happened. If you were to send our ancestors from 500 years ago into now, the present time, they would have been just as vulnerable to this environment. Yeah, well, arguably, some of the epigenetic changes means that our children are more vulnerable than our ancestors 500 years ago. So including some of the things I just mentioned, like we have a lot of babies are born to mothers who have metabolic dysfunction now, and that does put them at a disadvantage.

17:57And it's not a genetic change yet. Of course, you don't change genes in one generation. It's mostly epigenetics. So even 500 years ago, they may have stood a slightly better chance, but it's worsened generation by generation since sort of the 50s, which is sad, right and so it means we also need to help people to undo some of this effect that the food environment has had on our health totally we might need to get you back for an episode on nutrition in the first thousand days of of life my my passion project we'll make sure we do that yeah i'd love to do that how do you think about kind of continuing your line of thinking there how do you think about the cause of obesity and metabolic issues and you've alluded to the fact there that the food environment is it as simple as a kind of gene environment mismatch where we have these genes that kind of drive us to eat beyond our physical hunger and that helped us survive but then today it's it's sort of counterproductive because we don't have these periods of famine and why do some people, if you agree with that, why do some people struggle with that environment more than others?

19:13I do agree with that. I think it's overly simplistic, but the general idea is right. And you're not gonna find an expert in obesity that disagrees with that. It's just that food nowadays is way more than just this interaction with environment. It's emotions, it's sharing good times, sharing bad times, being bored, everything revolves around food. It's just insane. It's just insane. Everything we do, food has to be involved no matter what. And when you have that kind of culture and you have this predisposition from our genetics, it's really hard to tackle, really hard to tackle. That's why I'm not saying that GLPs are the cure for this, but at least they tackle one big part of that equation and that's the reality of it why do some people struggle more than others like if someone's listening and they're they're thinking i've tried to lose weight it's been really really hard for me but then i go on social media and there's people saying they lost 100 pounds on a ketogenic or a vegan diet and it worked really well for them i tried and it didn't i mean so many factors i think i had this discussion with a dear friend of mine, Dr.

20:30Sofia Cienfuegos. She's an intermediate fasting researcher out in Chicago. And I think in one of her studies, they measure basal metabolic rate, baseline, and after the intervention, which the intervention was TRE, time-restricted eating. And she was surprised, even her as a PhD in nutrition, she was surprised how prevalent is for some, especially women, to have a very low basal metabolic rate, like low, like in the 800s, 900 calories per day. So you would be, imagine how much restriction you have to undergo to really lose weight. And I don't know how common that is. I don't know. I wouldn't be able to tell you that it's happening one out of every thousand people.

21:16I don't know. But we know that that's a reality for some. And also we see that with some people who are on GLP-1s. We have these amazing responders and we have people that barely respond, especially people with type 2 diabetes. And we have no idea what that is. So whenever you compare a GLP study in terms of weight loss, you'll see that pure obesity without diabetes averages 16 to 22 percent between semaglutide and intersepatite. But when you choose people with obesity and type 2 diabetes, that percentage drops from 10 to 16 percent. Why that is, nobody knows.

22:05i want to to dive into how these medications work and how they're helping people in this environment that we find ourselves in which you describe as a mismatch between our biology and genetics and the environment that we live in today but just to canvas or frame this conversation when we say glp1 medications what are we actually talking about so we're talking about a class of drugs that mimic existing endocrine cell hormonal pathways that we have in our bodies glp1 is one of the peptides that regulates satiety and appetite there are other peptides right so we now have drugs that already have mimicking GLP-1 and GIP.

22:53So we already have drugs that do more than just the one. But if you think about these peptides as being part of a whole system that from the gut signal to the pancreas and to the brain to change our metabolism and to change actually our food seeking and food reward behavior. Now, it's really important to note that the way that our bodies naturally produce these peptides means that they're quite short-lived. So GLP-1, when you make it in your gut, and we all have the cells to make GLP-1 in our bodies, about 2 % of the cells in our gut produce GLP-1. GLP-1 in our bodies is always produced with PYY, which is another peptide that hasn't yet been put into a drug, but people are trying.

23:40And so when we naturally release it, GLP-1 is pretty short-lived, a couple of minutes, but PYY is longer-lived. So typically, when we release GLP-1 and PYY together, there's like a short-term effect of satiety and of regulating your blood sugar levels through the pancreas, and then a longer-term effect with PYY. The medication is a much longer-acting version of the GLP-1, so it lasts like days. It does not die off in a few minutes. So even though it's true that we make our own endogenous, our own peptides, they do not behave in the same way as the ones in the drugs. So one of the biggest sort of myths that you see online is, you know, I don't know, take my supplement and you will naturally have the same levels of GFP1.

24:30It's not the case. Like, let's be super clear. But it's interesting now with the newer drugs, so the GFP1 GIP dual agonists have an even stronger effect because you're tapping into two different pathways. And I think we're going to see more of these emerge. I think if PYY does get put into a stable compound, that will be a game changer as well, because it has this really specific effect on appetite in the brain, more so than the pancreas. But yeah, so that's how they kind of work. You're just mimicking the same pathway, a little bit like you had type 2 diabetes, type 1 diabetes, and you just take insulin or any other hormone replacement, right?

25:08So levothyroxine, if you have Hashimoto's, for example, so your thyroid doesn't produce the hormone. So it's a replacement, but unlike insulin or levothyroxine, you're modulating a signal, especially acts on the brain. That's interesting, firstly, about the supplements, the magnitude of the effect being very different, because a supplement may be at a point, I guess, to some science showing that a particular ingredient increases GLP-1 made in the gut. But what you're saying is the magnitude of that and the duration of that increase is vastly different. When you take one of these drugs and you increase GLP-1 levels in the body exogenously, is it similar to taking a hormone like testosterone where your body's own natural production shuts down?

26:00Yeah, no, not so much, right? So it's the way that GLP-1s are released really thanks to your gut. So they're massively influenced by the food you eat, your gut microbiome composition, and then how that gut microbiome composition feeds L-cells in the gut, which are the specialized enteroendocrine cells that make these peptides. But there isn't, with testosterone, if you take testosterone to your point, your testes will be like, cool, I'm not needed here because there's a direct feedback loop from testosterone levels. It's not the same with GLP-1. So GLP-1 medications don't necessarily shut off your endogenous production.

26:38The risk of that happening is that you just don't eat enough food and the food that you're eating isn't at all sort of directed or nourishing your gut. And then the risk of your endogenous levels falling further than pre-treatment is obviously there but it's not quite as direct a feedback loop as something like testosterone how does a venomous reptile in in uh the american southwest have something to do with this class of medications or this story of glp ones when i was looking up like the history of the drugs i was like interesting to find out how these things come about and there's this like reptile called the Gila monster that lives in Southern America, if that makes sense.

27:22And it's really not a very attractive animal, if you look it up, it's not a very charismatic lizard. And it moves really slowly and it eats very rarely. So it's like this amazing thing where they eat very rarely, they'll have a massive meal. And scientists were interested in why, despite this huge meal event, these reptiles didn't seem to have very big changes in their metabolism. So their postprandial glucose was stable. So they were interested in what was happening in these reptiles, and they found that they had naturally super high GLP-1 production. So essentially, these reptiles were fine for a long time because they weren't that hungry.

28:07And when they ate, the gastric slowdown, GLP-1 does also cause gastrointestinal tract to slow down. So you take longer to absorb nutrients. You're much fuller for much longer. All of this helps the Giller monster to continue for days and weeks without eating. And critically, the effects on the pancreas means that insulin is secreted in response to glucose increase, but without causing hypoglycemia. so without like too much insulin being released and then risking that dip in your glucose levels. So they found the gila monster, they isolated the peptide. And at the same time, another group of scientists found the same thing in another fish.

28:47So there was actually two groups of scientists, one looking at a gila monster, one looking at like a fish. And they both found this peptide effect. And it took quite a long time to isolate, test and be able to use it in medicine. but i just yeah it's funny a lot of things come from nature simon as you know and it's just fascinating to think this little little lizard has brought us to this massive discovery wow and just to be clear so today the if you take wagovi or ozempic or something like that that's they're not farming lizards or fish they're now making that that same compound that they discovered in those animals presumably synthetically yeah yeah exactly yeah yeah don't worry there's no animals have been harmed in the making of your zempic coming back to to hunger and to food noise we've spoken about food noise what's the the distinction between food noise and hunger yeah great question so there's like three types of hunger which is kind of surprising when you think about it but if we think about them separately, it really helps to picture their mechanism.

30:00So hedonic hunger is that hunger for pleasure. So that is very influenced by external food noise and food cues. So it's the smelling the doughnuts when you walk past the doughnut shop, or it's, you know, deciding that actually you're going to have the dessert, even though you're pretty full from dinner. That's hedonic hunger. That's, you want something usually because of the taste, the texture, or the emotional association with it. And that is brain driven. That is just your brain doing its thing. And actually with hedonic hunger, it can often override biological appetite signal. So, you know, your body might be like, Hey, I'm pretty full.

30:36And then you're like, I don't care. I want the trifle or like the chocolate brownie. So that's hedonic hunger. Then there's homeostatic hunger, which is like your classic biological hunger. You're running low on reserves. Your blood glucose is starting to dip, your ghrelin is going up, perhaps, you know, your body fat is at a sort of healthy level. So your leptin isn't super high. You don't have signals to say we've got loads of energy. So when that starts to shift, your homostatic hunger and your gut peptides are quiet because they haven't got anything to eat. That's when it's like, actually, I'm hungry.

31:12I I need to eat something because I'm running out of what I need to carry on. So that's what you see in like a newborn baby. Like that is homeostatic hunger all day. The minute their energy and their reserve starts to drop, they will scream. And then there's the newest member of the hunger family is microbiota driven hunger. So in the past maybe 15 years or so, there's emerging evidence that your microbes actually signal hunger for their own survival. So if you consider that these little microbes want to survive, obviously, and they're using us as their spaceship, they will send signals to make sure that you're eating the food that they need to thrive.

31:54So if you're a microbe that loves blueberry fiber, you will send up blueberry messaging and sort of drive. Now the microbiota-driven hunger is a new concept and it's through vagal nerve signaling and in their blood. So like in some specific peptides in the blood messages there, but we're not sure how much, so like how strong that is. Anecdotally, you do hear when people change their diets, they will say, oh God, I would never think to have chickpeas, but now I've started eating them. I love the taste of them and I want to, I will have them, like I will order them more frequently or I will buy them in my shop.

32:31But I find that super, super fascinating. Professor John Crean's work has shown some of these mechanisms in rats and mice and how you can modulate the microbiome and it changes eating behaviors. So it's quite cool. Yeah. So is that based on only on exposure? Like what I'm hearing from you is that certain parts of food, like chickpeas get down to the microbiome, they're, you know, quote unquote feeding on them and then, you know, essentially sending out signals because they want more of that. Does it work the other way? If you, if you are eating a very ultra processed food diet and the microbes are not getting enough substrate?

33:08So when it's a really, I love how you've asked that question because often people think, well, if I don't eat chickpeas, it doesn't matter because I don't really care if I don't get the benefits of chickpeas. But what happens is if you don't eat chickpeas and the chickpea lovers die out or they reduce their abundance, whatever you are eating. So maybe it's, you know, maybe you're having a burger every day that still provides substrate for your microbes, right? so the ones who can will switch to eating the burger the ones who already love burger grow in abundance and your chickpea signal starts to die down and you get more microbe like more burger signal now it's not just through exposure so to your point it's we also know that dysbiosis of the gut so when there's like a gut microbiome which is not very friendly or healthy ecosystem So it's disrupted.

33:57There is reduced bacterial species and strains that make short-chain fatty acids. So when it's disrupted, it's not very helpful. It's not a happy garden. Then that also changes your food preferences. And like a third pathway is if we think about sleep and stress. So we know that if you have disrupted sleep, it actually changes what gut microbiome species flourish. So you then have a change in that ecosystem. And so essentially, think of it as like the ecosystem changes for several different reasons. And depending on the change, it sends different signals for what it needs. Unfortunately, if you've had loads of seed deprivation or lots of stress, then we tend to choose higher energy density, quicker energy release foods.

34:46So really refined carbohydrates and added sugars. So it's a bit of a cycle because then that causes disruption to the microbiome. And then that in turn drives more of the same. So it's several different pathways, we think, but it has a clear way in which it's working independently of hedonic and homeostatic hunger. So this explains, at least in part, why it would be easy to assume that when someone's overweight, their hunger just should be really low because there's a lot of excess energy stored on the body and that can be used directly as a substrate to produce energy, the fat, or it can be converted into glucose through gluconeogenesis.

35:29So why does this person have such a drive to eat food? But what you're saying is that because there are these three distinct types of hunger, the hedonic hunger and microbiome-driven and hunger can still be motivating that person to seek calories despite having excessive body fat. That and also at some points, some of the messengers that are there to help us not feel hungry can stop being effective. So this is really an important point. Most of the messengers and the signaling we have available to us are there to promote satiety. And I think this is a good point to distinguish between satiety and fullness.

36:13So when you're full, you've just eaten, your stretch receptors in the stomach is stretched and you feel that kind of fullness. It's quite a temporary feeling. Satiety is a longer term sort of satisfaction from your meal, which comes from the four phase signaling pathway that happens if you eat a well-balanced meal. That's the gut peptide sequence. Now, if you think about leptin, which is the messenger that says it goes from your fat cells and it goes like, hey, we have fat stores. don't worry about eating because we can use some of the stool. What happens in people who are chronically overweight or living with obesity, that leptin signal, which says like, we have enough fat stool, we have enough fat stool, the brain becomes resistant to it.

36:56So a little bit like we see insulin resistance with type 2 diabetes, it just stops responding. So ironically, what can often happen is people can be living with obesity and really excess fat storage, but the leptin messenger is not getting through, right? And therefore they feel really hungry. Like they're actually starving. And it's super sad because people judge so quickly. They're like, how could you possibly be hungry when you have so much energy stored? But if the messengers aren't working properly, or if the brain is not receiving the messages in the way that it should, then you do end up in the situation where there's an internal mismatch between the hunger you're feeling and the energy you actually have available to you.

37:47And that's really tricky, but that's like when medications like this just can transform someone's life because you're just powering up that message so high that you finally start to feel not hungry, which is, and that can transform how someone can approach their diet, their exercise, and their day, their life. But it is important to recognize that there is this resistance that can take place. What are things that we understand can help those messengers work better? So if we think about this from a prevention point of view, so perhaps you put on a little bit of weight recently, or you have been overweight for a while, but you want to try and lose that weight without medication first, you can help support your endogenous production of these signals.

38:34So let's talk about the endogenous production first. A lot of what the book is about is looking at the evidence for what kinds of dietary patterns and what kinds of foods support the ecosystem of the gut that helps these specialized cells, whether it's the L cells or the I cells, there's actually lots of different types, to produce these peptides that are designed for the satiety piece, so for the long-term satisfaction of the meal. By eating in a way that helps us to tap into this four phase, so the first phase is your sensory phase of eating. That's when you see the food, you smell the food, you interact with it, you taste it.

39:14Very important part of the initial signaling from your brain to say there is food coming, let's prepare. This is super important in our modern food environment, where often we will open a pack and just eat it. There's no interaction with the food. Or worse still, open a bottle and drink your meal. No smelling, no colors, no seeing, no texture. This is, it just bypasses that initial sensory phase. Often while scrolling or watching TV. Or walking, taking the, yeah, like, or just doing something completely different. Which, you know, is also important because our nervous system is designed to either be in action mode or to be in like absorption mode or digest mode.

39:57And if you're like running and on a phone call to your boss and shoveling like a packed sandwich in your mouth, your nervous system is not primed. You're not in your parasympathetic. Okay. So there's a really interesting point on that on nutrient absorption, but let's just park it there for a minute. So you have this initial sensory phase and then you have the gastric phase. So your stomach, this is the fullness piece where if your meal has high volume, so you're eating kale and nuts and seeds and like chopped veggies, there's enough volume in your stomach to actually activate the stretch receptors in your stomach that send a signal to your brain to be like, woohoo, we have food, we're full.

40:38Now again, Simon, like if you're drinking your meal or if you're eating like a little snack bar, that's not going to do that because it's not, it doesn't have the volume. So high volume eating is such an underappreciated mechanism to help with weight loss. Because as soon as you switch to high volume food, you are filling yourself up, your stomach up, and it then takes longer for that gastric emptying. So you're mimicking some of these benefits of GLP-1s by just slowing everything down a bit. Then you have small intestine has specialized receptors for nutrient sensing, and that the sort of distal part of the small intestine is where you get the first L cells and stuff so that GLP-1 starts to be released.

41:26So for that piece, when we think about the small intestine and its activation, having a meal that actually contains a good amount of protein, a good amount of complex carbohydrates that haven't already been absorbed in the first half of the small intestine and also having healthy fats, right, that are going to reach these nutrient sensors and send off that wave. So by now, maybe it's been maybe an hour and a half to two hours since you had your meal and you still have satiety signaling activated if you've eaten this kind of food. And then the last bit, the colonic part, fourth phase, is in the large intestine.

42:04And here is where we really get to reap the rewards of a high fiber diet. So if you've had a diet that is high in fiber and is also high in healthy plant oils, fats, so avocados, nuts, and seeds, omega-3 fatty acids, all those kinds of things, the L cells just love it. And you will then have this release of GLP-1 PYY maybe two to three hours after your meal. So now you see you have this way of eating that supports the four phases of satiety by having the correct foods present in your diet that stimulate a sequence of preparation, fullness, and satiety signals. that means that going from breakfast to lunch is no longer a struggle so your homeostatic hunger is supporting you from not needing to eat again quickly yeah this is i forgot the original question but here we are this speaks though directly to why kind of grinds my gears when i hear people just oversimplify nutrition and say calorie is a calorie it doesn't matter but but the the quality of those 500 calories is really impacting that person's experience Makes all the difference.

43:16So, I mean, calories in, calories out, you can't argue with physics, sure. But then you have to understand metabolism and physiology to understand how that plays out. Because we're not a Bunsen burner. We don't just burn stuff at the same rate, in the same place. It just doesn't work like that. So it's not even that I'm anti that, it's just that's just a tiny piece of the puzzle. There's so much more going on. It's objectively accurate, but it just overlooks the fact that certain foods and meals can leave you feeling more full and satiated, which makes sticking to an appropriate number of calories much easier.

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46:53when a patient comes to see you and they do want to lose weight and or reverse their metabolic markers so so you're in alignment on that what's the decision making process with regards to whether you start with diet and lifestyle alone or diet and lifestyle plus medications or just medications? Patient preference. I hear them. It's like, what is it exactly that you're looking for? If they're looking for something that is not reality-based, like let's say you have a 50-year-old woman or men that they want to look like a 20-year-old. I hear them out. I try to set expectations. And then I offer the alternatives.

47:37I got to tell you that I'm sure if a physician is listening to this podcast, they know they can relate. We have patients, they just don't want any medications. They want to continue through the route of calorie deficit, exercise, and mind control. And that's fine. I personally do not try to convince them on the first visit. I basically tell them that obesity is a neuroendocrine disease that resides in the central nervous system. I do my best to explain that this is not their fault. I try not to overdo it because you really want to earn their trust. And I think that that's such a massive spiel for the first time.

48:16And then we'll see, we'll start working together. And with time, a lot of these patients, they end up saying, you know what? I see it. I'm struggling. I'm hungry all the time. All I can think about is food. So let me give it a try. Now, morally or professionally, I think we should be giving lifestyle ago but these medications have proven to be massively successful that I think it's completely okay if from the get-go you start with these medications and lifestyle modifications at the same time and let's say you get to that part of the conversation where there's agreement to commence with a GLP-1 or similar medication with so many different GLP-1s that are available now How do you decide which GLP one to prescribe for the patient that's sitting in front of you?

49:09It's money, insurance coverage, and expectations. Obviously, this is not so straightforward, but let's say I have a patient with class two obesity, a BMI over 35 for folks who are listening, and they have obstructive sleep apnea. They are on CPAP. So that kind of patients where you need more weight loss, more fat loss, more visceral fat loss, and you want these OSA protection, you go with tersepatide, which is Z-bound or Munjaro because Munjaro has been proven to be excellent for OSA. If you have a patient who has class one obesity, let's say a BMI of 32 and heart attack, you know, three years ago, then semaglutide would be the way to go.

49:57Why? Because you don't need that much weight loss and you have strong data and FDA approval for semaglutide to prevent the, for secondary prevention of cardiovascular disease. That's basically how you manage these kind of patients. But right now, it's very common to see patients that have neither, no OSA, no heart disease, no diabetes, that they just have obesity. So we have tons of options. We have the same, we have Z-Bound, we have Wigovi, but we also have Orphogliprine and we have Wigovi pill, which are very effective peels. And just a very broad overview, Wegovipeal, the number expected for weight loss is around 14%.

50:41And with Orphoglipron is around 11.5%. So if we feel like the patient needs a little bit more weight loss, we go with Wegovipeal. If it just needs like 10 % weight loss, we can go with Orphoglipron. And these two options, Simon, are way cheaper. I mean, Wigovi peel, if your insurance doesn't cover, it's$150 per month for the first two months. And I think it goes to$250. I might be mistaken. Maybe$250,$270. And the same goes for Orphoglipron. Are those oral forms safe and well-tolerated in terms of liver function? Yes. They're super well-tolerated. The difference is that Wigovi peel is, again, it's semaglutide.

51:25It's like the same substance that you inject with Wigovi. the exact same substance. It just has this technology called SNAC, where you need to take this pill with four ounces of water. You need to be standing up for 30 minutes and you have to wait 30 minutes to eat something. So it's fully absorbed. Whereas Orphoglipron is a non-peptide GLP. So it's actually the first non-peptide GLP, which means it's not a peptide, right? And you can take it whenever you want. You don't have any food restrictions, water restrictions. You can swallow it with coffee, with whatever. So those are the main differences.

52:05In terms of tolerance, both have very similar degrees of adverse events, like nausea, vomiting, constipation, pretty much the same. And what's the difference between Wagovi or semaglutide, a GLP-1 agonist, and ZEP-bound, these kind of dual agonists in terms of function or what does that second receptor agonist kind of offer to the patient? I think, I mean, we all know this. Z-bound is way more powerful for weight loss than Wigovi. Definitely. I would say that you can increase up to 5, 7 % more weight loss with Z-bound than with Wigovi. And we also know that with this GIP agonist portion of Z-bound, we have theoretically more liver fat metabolism.

52:56And some researchers have said that probably this dual agonist also keeps your basal metabolic rate more constant throughout the weight loss, which means that you and I know that when we lose weight with diet, with calorie deficit, our BMR goes down a little bit to compensate, right? But apparently with medications like Z-Bound, this BMR doesn't go down. So this is extremely useful for folks with obesity. So I would say that set bound is definitely more powerful than weak OV in terms of weight loss reduction. But again, sometimes you don't need as much. Sometimes all you need is 10 % and that's it.

53:39And if that's the case, we have so many alternatives nowadays that is crazy. That's actually becoming overwhelming up to the point that where should I choose? Seems like there's a new trial coming out every other day. Every other day. Yeah, every other day. Yeah, it's going to be so dizzying to follow this news and choose the right medication, but it's always been like that. I mean, if you think about it in terms of diabetes, we have bioglitazone, we have metformin, we have genuvia, we have, you know, glipiside, we have like SGL2 inhibitors. We have so many medications. It's normal that for each human condition, we have plenty of molecules.

54:25How do you think about dosing the GLP-1s at an individual patient level? Is that something that there's a set of guidelines on yet? There are, but every patient is different. I say this because I see my own patients. I don't belong to any organization. I have my own private practice. So I spend a lot of time with my patients. And as you know, I emphasize lifestyle to a super high degree. I help my patients coordinate their entire life in a way that they become super healthy. And these medications, they just nudge them to that weight where they see all these benefits. And when you do that, when you focus a lot on behavior, on cognitive behavior therapy, resistance training, impulse control, healthy diet, high fiber, lean proteins, hydration, smoking, and alcohol cessation, you know, Simon, you would be surprised that patients do not require a lot of dosing of these medications.

55:30and there's this company in Denmark that basically they are a telemedicine platform but they did scientific studies with their population and they emphasize lifestyle to obsession. Like everything is lifestyle, cognitive behavioral therapy, coaching, following the patients, like the way it should be done. But they do use semaglutide and they showed that the average of semaglutide use per patient was around one milligram per week with an average of weight loss around 14-15%, which if you think about it, is less than 50 % the highest dose of semaglutide for weight loss. And their proposition is that we're not doing coaching strongly enough.

56:19And I do agree with that. I do agree with that. When you focus on that part, when you follow your patients, when you accompany them, you don't need that much dosing. Of course, there's always this patient that has this super high appetite, this terrible appetite dysregulation, which is also very common that you require high doses. But you would be surprised that with the right coaching, the right guidance, even small doses go a long way.

56:50I want to circle back to prehab. I know you have a lot to say there and I know my audience is thirsty, excuse the pun, for that information. Before we get there, how effective would you say these drugs are and whether it's the drug that is modulating one receptor or binding to one receptor or two or three relative to typical dietary interventions for weight loss like doing a low-fat diet or a low-carb diet? they're much more effective in terms of weight loss and the rate at which that's going to happen. So the likelihood that you're going to lose weight taking these medications within, say, a six-month period is really high.

57:36So there are non-responders, which I think is really important to touch on. Depending on which data you look at, the non-responders in the clinical trials that are really closely monitored with exercise, intervention, nutrition support, psychological support is about 5 % to 10%, pretty low. But when you look at real world data and some of the other trials, it can go up to 20%, which is really high. So like, you know, up to one in five people will take these medications at the highest dose and will lose no weight, which, by the way, having worked with some of these people, it's so disappointing.

58:10So you're expecting a miracle drug that's going to finally help you not live with obesity any longer, finally help with your metabolic health. And then sometimes some, I mean, two of my patients I've worked with were on these drugs at max dose for six months and lost no weight, which is pretty wild when you think about the narrative that there is around these drugs, right? So important to remember that not everyone responds the same way. Lots of theories as to why, possibly some receptor mismatch, like potentially people have less expression of the receptor. We don't know yet, but they are effective when they work.

58:47However, we also know that discontinuation is really high. So up to three quarters of people discontinue the drug within about 18 months. And we also know that then following discontinuation, half of those that stopped are likely to restart again when their weight creeps back up. So what we are seeing is that there is this sort of trend that could become even more prevalent of, I don't want to call it yo-yo GLP, but one, but you see what I'm saying? So there is a slight trend of that happening, but you know, it's more effective. You'll lose more weight in a shorter period of time, but it's not a magic bullet.

59:26You need to do the dietary and lifestyle interventions if you want to sustain the weight loss and improve your metabolic health in the long term. Right. Because presumably if you're using it in that kind of cyclical yo-yo way, but you're not dialing in the nutrition and resistance training, that's coming at some consequence for your body composition. Yes, exactly. So one of the red flags is that there is a higher risk. And listen, I think this could change with some of the novel drugs that are being developed to go alongside these medicines that could help preserve muscle mass. But there is a risk that if you're taking these drugs without the proper support, you'll lose like up to 40 % of the mass that you'll lose could be musculoskeletal mass.

1:00:16And then when you regain the weight, the majority of the weight regained is likely to be fat tissue. And so the risk of sarcopenic obesity, where you have lower muscle mass than when you started, compared to your body mass, so that percentage, that ratio between the lean mass and the fat mass, you don't want the fat mass percentage or ratio to be even higher when you regain the weight. So sarcopenic obesity is something I talk about in the book. It's a risk, but it's only a risk if these drugs are not taken with the correct infrastructure. And it's the same risk as yo-yo diet, extreme yo-yo dieting.

1:00:59So people who lose extreme amounts of weight with the cabbage soup diet will similarly lose muscle mass as well. So it's not an exclusive issue to GLP-1 medications, right? Any rapid weight loss from quite severe dietary restriction where you consume far less food will result in some lean mass loss. Let's just be clear. But it's just that it's happening a lot quicker with these drugs. So there is a risk with this yo-yo up and down. We have seen though that some of the longer term follow-up studies show that actually a quarter of people taking GLP-1s don't regain all the weight they lost. So there might still be this benefit for a fair amount of the population where they'll still retain some of that lost weight further down the line, which is good.

1:01:46So even if you do stop taking the drug and you start to regain some weight, you may not regain all of it, which would put you, if we're talking about obesity in this case, would put you in better metabolic health than when you started.

1:02:06Speaking of side effects, what are the most common side effects you see clinically when prescribing these medications? And how often are you seeing patients want to come off of them? To answer the first question, nausea and constipation are the big ones. I would say that the third one is diarrhea. Obviously, it sounds awful. It happens to a lot of people on these medications, but also, fortunately, it's not so severe that people have to stop. Just in a very, very minor percentage, people have to stop. So yeah, that's that. That's reassuring. Your second question, it all comes down to psychology, Simon.

1:02:44A lot of people with obesity, they feel guilt. So they've been struggling with obesity their entire life. They've been told that they have this moral and character flaw that made them obese. And all of a sudden, they're taking these medications and all of a sudden they're improving. And you would think that they're happy, and they are, and most of them remain happy. But some patients are like, oh no does this mean that i was wrong and i needed a medication to fix this like i want to prove myself that i can do it without medication because they have so much guilt that their entire decision making capacity is around that and it's very common that they want to come off these medications obviously as a doctor you don't impose your point of view you hear you respond you present alternatives.

1:03:39But at the end of the day, a lot of patients stop these medications. What's the alternative way of thinking about that as a patient? My best example, the one that I talk to my patients about, is that this guilt for being healthy on a medication is almost exclusive of obesity. I tell my patients, you don't see a patient with asthma feeling guilty about able to breathe well when they do their albuterol. You don't see that. It's unheard of. You don't see a patient with hypertension feeling guilty of having less renal disease because they're taking medications. No, it's almost exclusive of obesity.

1:04:19And that tells them that this is because of the social stigma. So I got to say that this argument works well. I would say that it works 50 % of the time with patients and they are like, oh yeah, that makes sense. Why shouldn't I be happy with a medication when millions of other people with different conditions are also happy with different medications? But for 50 % of patients, they still feel the guilt and they still feel the urge to try. Talk to us about the importance of nutrition while on a GLP-1 and eating less calories. What are the things that you educate your patients about? You want them to be thinking about?

1:05:01And perhaps what are some of the pitfalls if someone's not focusing on the types of foods that they're eating? I've had this discussion with a lot of folks, doctors. I've been preaching the Mediterranean diet for so long or a diet high in fruits, vegetables, whole grains, legumes, healthy proteins. I've been doing this for so long. And I got to tell you that when you have a patient on a GLP-1, it's so easy to convey that message because it's probably the only way to eat that really makes them feel great. They don't have constipation. They don't have nausea. They feel light. Their lipids improve.

1:05:43Everything improves. So it's so easy to implement a high fiber, high monosaturated fat diet on a GLP that it almost feels like cheating. And I've done the math. I've done nutrition clinical histories on patients pre and post GLP ones. And you see patients that were, you know, Simon eating 18 grams of fibers before that. And all of a sudden they're eating 40, which, yeah. Why? Because it makes them feel better and they don't have constipation. They don't have diarrhea. They feel full. They feel great. So my biggest message at the beginning of treatment is fiber, like focus on fiber, focus on veggies, whole grains, legumes, fruits.

1:06:31Don't shy away from these foods. And I do emphasize lean proteins like tofu, fish, chicken, egg whites, yogurt. I tend to emphasize that as well. And for healthy fats, walnuts, almonds, olive oil. Go crazy on those. And I don't know if you've heard about it, but obviously these centers in your brain that deal with appetite, they also deal with thirst regulation. And if patients are not paying attention, they can get dehydrated pretty easily. I mean, you've seen it, right? I've seen it. Patients call me and say like, hey, Dr. Mao, I'm feeling dizzy. Is this because of the medication? And I was like, no, have you been drinking water?

1:07:20Well, now that you mention it, I don't feel the urge. So this happens very often. So you have to be on top of hydration. I actually ask my patients to buy on Amazon those containers that say 10 a.m., 11 a.m., 3 p.m. in order for them to drink at least two liters of water per day. Does the addition of more fiber to the diet, have you been, have you seen clinically that's helping with those common GI side effects that patients could otherwise experience? I do. We don't have a strong data, but this is like a very common topic among obesity medicine physicians. The more fiber they eat, I mean, obviously up to the point, but the more fiber, the more veggies, fruit, veggie soups that they eat, the less side effects they experience for sure.

1:08:09Are you getting patients that are fearful of carbohydrates? When you mention that type of eating pattern, is there still this idea that people are kind of exposed to on social media that healthy diet to lose weight is low carb, carbohydrates are fattening? Is that something you're still being presented with? I don't try to reverse that mentality right away because I fear that I might lose the confidence of my patient. So I go easy. I first assess what are they willing to compromise. If they're not willing to compromise their keto way of eating, I try to modify the fats at least. I try to promote more morning saturated fats, a little bit of fiber.

1:08:55If they're not willing to eat as much fiber as I want as a physician, because I know that constipation can be pretty bad in someone on a GLP-1, if they're not paying attention, I start a fiber supplement. And I continue the keto because that's what they want. And with time, I try to emphasize, I try to talk to them about the data behind plant forward diets, Mediterranean, DASH diets, and some come around, some don't. Here's something that doesn't get talked about nearly enough. Male fertility contributes to about half of all infertility cases, yet most men barely think about it, and many sadly assume fertility is a woman's problem.

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1:12:25that gets me thinking about the clinical trials have they i know that their outcome of interest is weight loss have they coupled the drug with advice from dietitians that are helping people make sensible food choices and looked at the nutritional adequacy of the diet along with the weight loss? Yes. So all the RCTs, this is why all the guidelines by the major societies in obesity medicine, nutrition, all the clinical trials have full dietetic support, structured exercise program and psychological support. So, you know, we touched on the fact that clinical trial outcomes and real world data can be quite different.

1:13:06And one of the big reasons why they differ so much is because in the clinical trials, you are giving the drug to patients where it is medically indicated. So the population actually needs the drug. It's not taken just to add it to your supplement and drug stack. And they have a full lifestyle dietetic support. It's part of the treatment plan. So, I mean, if you've read the books, I've said this a lot of times in that book, it's not an afterthought. is an integrated part of the treatment plan for success of these drugs. And so in all the clinical trials that have fantastic weight loss, 20 % of body weight, improved cardiometabolic health outcomes, decreased inflammatory markers, they have a full framework that ensures that they are nutritionally replete, that they are not losing loads of lean mass, because it's really important to say that the three times a week resistance exercise is really critical.

1:14:07It's more critical than the protein. Like the protein is important, but if you're doing the protein without the resistance training, you can't preserve your muscle mass. So these aren't nice to have things. And so if you're somebody who is taking the drug for like body composition optimization, so you don't actually medically need them and you're quite blasé about the nutrition and the exercise stuff it it's not going to support your health in the long term at all like that's as I said it's essentially medically induced malnourishment which is not the goal I think so how does someone navigate the the protein piece I think the resistance training piece there is pretty simple you need to do resistance training three times a week it doesn't have to be fancy you don't have to go to high rocks or anything you can be banned you know yeah or own body weight.

1:14:53Yeah. Right. On the protein side, though, if someone is just not hungry at all, is that feedback that the dose is too high and you need to find a dose that allows you to consume, I think in the book you write 1.2 to 1.6 grams of protein per kilogram. Is that how you would navigate that? Yes. I think if the medication is causing a complete refusal of eating full stop. So I think a lot of people do describe that they're just not very hungry, but they'll still eat and it's okay. If it's so bad that you actually don't want to eat at all, then it's definitely worth reviewing the dose, reviewing maybe the medication, like maybe switching to a different one.

1:15:33So if you're in a Juul, you might switch to a single agonist, but that's something that your doctor can advise you on. And the way to try and get enough protein, so the reason why this is one of the only life stages or one of the only times when we actually recommend increasing protein intake to above like one is because one gram per kilogram is because we have to sort of index on the protein as an essential part to maintain the muscle and bone health. So typically a normal adult, even if they're pretty active, you know, they'll be absolutely fine. Don't need to count how much protein they're getting, to be honest.

1:16:09Like that protein deficiency is not an issue in the general population. But when we come to GLP-1 treatment, there has to be an awareness of how much protein you should be trying to get, because otherwise that maintenance of the lean tissue is going to be quite tricky. And here again, in the same sort of way that fiber supplementation can be helpful for the prehab side, protein supplementation can be helpful, especially when you're titrating doses up. So when you're finding that lowest effective dose on the day that you increase your dose, you're most likely to be impacted with really low appetite.

1:16:47And this is where like a simple pea protein or soy protein isolate added to a smoothie could make a lot of difference in terms of achieving your protein needs. But as I go through in the book, there's ways you can do this with food. It's not an issue and you don't have to start eating steak every day. That will go against the whole point of the medication. So there's ways you can absolutely do this using different types of foods, combining foods together to give you plenty of protein without increasing volume too much.

1:17:21After I had done my culinary medicine training and I was going back over my patients, I took all of my patients who were willing to do this study, and I said, let's find out what they're eating by good food frequency questionnaires, which we validated. And we had 186 patients that agreed to the study. Ultimately, some dropped out. And we found that people who had a Mediterranean diet score, and the score I used was the nine-point scale from zero to nine, who had a score of five to nine at five years, lost and kept off their weight. People who had a score of four was a scattergram. It could be either in the highest 50 or lowest 50%.

1:18:01People who had a score of zero to three were typically either had gained their weight back or had not achieved the average weight loss we would expect at five years. So on a simple scale, we saw eating better had better results for weight loss surgery patients. As a GLP-1 user, one of the things I advocate to GLP-1 users who come across me in social media is, yes, this type of diet, which is more plant forward, less meat centric, which has more whole grains, which has more fiber of multiple types, is far better for you health-wise by all the metrics we see. And in our studies in weight loss surgery patients, tends to not have the same effect.

1:18:45It has a better effect on you losing weight and keeping it off. So as someone who has lost 50 pounds and is using ZEP bound to reduce food noise, you're still a believer in diet quality. I am. I mean, there's more than weight loss for diet quality, right? I mean, one of the things that always concerned me in those few lost years that I was in the low carb community was what am i doing to my arteries you know what on earth am i doing to my darn arteries here terry we're gonna get there don't worry that's a topic we'll hit it's a common topic these days so that was one of the concerns i had i remember sitting here one morning you know the 900th morning in a row that i'm having steak and eggs or something thinking what's wrong with having some granola and and and greek yogurt but how could that be wrong and fruit what's wrong with What do you mean I can't eat carrots because they have too much sugar in them?

1:19:39So it gets a little, you know, crazy. But yeah, so as a GLP-1 user, I still advocate eating, and you can say it in different ways. Eat more plant-forward foods. Eat more fiber. Have more fiber sources. Have more of a variety of plants. Let me show you some great cooking techniques that we can do to make it better. I have a confession. I hate vegetables. There are not many vegetables I like. so when i make a spaghetti sauce i take root vegetables i roast them in the oven i put them into my tomato sauce for my whole wheat pasta i don't taste any one of those beautiful and it's delicious when you were talking there about the higher or greater the adherence to the mediterranean diet kind of more weight people lost and yes the better they did long term yeah do you think that adherence piece why some people can adhere to the Mediterranean diet better than others comes back to food noise is that one of the variables I'm not sure if it comes back to food noise because remember we with weight loss surgery we eliminate food noise too we called it something different than we called it head hunger and they would tell you I've lost my head hunger now we call it food noise and now we are trying to quantify it with different questionnaires.

1:20:53But they clearly had lost that and they were searching for new foods to eat. And so it's not that I, at that time when I was doing these studies and following them, that I was sort of advocating it more for cardiovascular health and I didn't know what it would do for weight loss, but I was just curious where they were. Oh, by the way, the low carb people really didn't do well, by the way, long-term, sorry to say. But a lot of people sort of naturally gravitated toward it because, and I can tell you as a GLP-1 user, I understand this, you like flavors more. You know what's not flavorful? A lot of low-carb foods don't have a lot of flavor.

1:21:30I mean, fat I know is a flavor, but it gets boring on your palate quickly. If you've ever had a great Stetson salad, which has, you know, pumpkin seeds and avocado and dried cranberries and you know you have a ton of flavors there that just explode in your mouth and as a GLP-1 user I like flavor more than I ever used to. I think that might come as a surprise to some people who presume that when you start a GLP-1 medication you may be giving up some of your joy for food but it sounds like you have more joy for food now than you did when you've tried some of these other diets like low carb diets

1:22:20how do you speak about resistance training to your your patients and back to the beginning of this conversation you mentioned mad minimum effective dose if we're thinking about exercise more broadly resistance training and cardio what what is the minimum effective dose as you know I'm very much into exercise. I love it. I love exercise physiology. Obviously, I'm not an expert. I'm just someone who likes to read, has been treating patients with these for a long period of time. I don't know if you're familiar with Notebook LM. Are you familiar with Notebook LM? Yeah, it's great. I use it. It's phenomenal.

1:22:58I got to tell you that as a physician is the biggest breakthrough of the last 20 years. I don't know. It's crazy. So I have all my clinical guidelines for exercise in one notebook. And working on it for five months, I finally reached to a point where I had a very, very good set of directions for people to do my instructions. I have pamphlets, I have instruction manuals, I give them lists of exercise, and I tend to emphasize at the very least two sessions per week, which you and I know that that's the MED for resistance training, and total body exercises. And we start with, depending on their baseline, one set per exercise, two sets, and eventually progress to three sets per exercise.

1:23:51And we talk about the repetition maximum. I put it in a way that they understand, like if they have two more repetitions in the tank, that's where they should stop all that stuff is written in my manual in my notebook because i have all the clinical guidelines there and that's how i start a conversation and then obviously you have to reassess every visit and then you realize for instance that your patient has two jobs there's no way they're going to go to the gym and there's just no way that they're gonna buy equipment for their home because they just don't have time period and that's where body weight training has a place.

1:24:32You and I know that, is it ideal for hypertrophy? Probably not. Probably not number one. That's definitely weights, but that's something. That's how I address the issue. I basically have the clinical guidelines tailored to the patient, and if they can do resistance training the proper way, I find alternatives. And then in terms of cardio, I'm sure people have questions. What is cardio? If I do cardio, Am I going to lose muscle? Is it going to affect that resistance training I've done? I mean, probably you have a better way of communicating this than me. I'm going to tell you why I communicate it to my patients.

1:25:11You and I know that saying that doing cardio and resistance training in the same session, it's not bad up to a point. But in terms of making it more practical for patients, I like to say, just do your resistance training and your cardio session separately. I say Monday, Wednesday, and Friday, let's say the resistance training, cardio Tuesday, Thursday, and Saturday. And in terms of cardio, I talk about effort. And we start with 20 minutes per session. We go to 30 minutes. And if they reach 30 to 45 minutes per session of cardio, I'm super pleased, like super pleased. I don't even push anymore.

1:25:48And at some point, you and I, we got to talk about that as well. It's all about psychology. Like with my private practice population, there are people like you, like young, that they read, that they go into research and they read everything about optimization of exercise. And when they reach 45, they say, Dr. Mao, I want more and more. And they end up doing an hour, 90 minutes, 95. They start measuring their lactate levels and doing all this stuff. But at what point enough is enough? At what point enough is better than trying to optimize every single corner of your life? And I gotta tell you, Simon, it's tricky, especially for overachievers.

1:26:29It's super tricky. They get into this rabbit hole. They wanna know more. They wanna feel more. They want more muscle mass. It's really tough. So that is another thing that it would be very wise if you discuss that in your podcast with a clinical psychologist or something like that.

1:26:52You mentioned before that the clinical studies looking at these medications usually combine it with some nutrition advice from a dietician. There's exercise and psychological support. On the psychological support side of things, there's this quote in your book. You say, shame does not support growth or change. Instead, it encourages withdrawal and avoidance. And in fact, you dedicated pretty much a whole chapter to shame and weight stigma. So if someone is taking a GLP-1 agonist and they're losing weight, finally, it's working, something that works, and then they're sort of made to feel like they've cheated.

1:27:35How do you or would you talk to that person that feels that way? So I think it's so important to recognize that this entire system we've spoken about doesn't always work perfectly. And in the same way that this medication can help support metabolic health through mechanisms such as weight loss, you would never go up to somebody who is taking medication for their thyroid and be like, cheated. You know, you should have more iodine when you had the chance. It's like, no one would do that. So this idea that a medicine that solves the single biggest public health crisis of our time, which is the diabetes pandemic, metabolic health disorders, like metabolic health syndrome is the biggest problem we have as a society for early death and disability.

1:28:32So for anyone who tries to shame someone for taking an effective medicine to prevent that or to help reverse it or help improve outcomes. I mean, it just doesn't make sense when you think about it, right? So medicine is never cheating. Say, you know, if you have pneumonia and you take an antibiotic, it's not cheating. And that's okay. That's an infectious disease. But with any chronic condition that requires medication, you know, we know obesity is a chronic relapsing condition. It is not a lifestyle choice. So there's never a place for shame for me when someone seeks the appropriate medical care for a condition that's potentially impacting, shortening their life.

1:29:16There's no place for it. And I think hopefully we're moving away from that, though I hear you. I think it's still embedded in our society. And I have dedicated a whole chapter to it because there's so much evidence to show how detrimental shame and stigma can be for health outcomes across all sorts of health conditions, like mental health, all sorts of conditions. And I think just being aware of that and helping healthcare professionals to be aware of that as well, so that they can sort of be mindful of how somebody with these conditions might be feeling and how they might experience this journey, right?

1:29:51It's just, for me, it's an awareness piece but if you frame it with any other chronic condition you would never you would never shame someone would you you got to keep fat out of the muscle fat out of the arteries liver fat out of the brain and and the right and the the very first right and um most indicative marker is the belly fat, intra-abdominal fat, right? So if you see intra-abdominal fat, you know that most probably you have fat in muscle, you have fat in the liver, you have ectopic fat. Other than just observing someone, is that something that you would become aware of through doing a blood test and looking at biomarkers or is it a scan?

1:30:47Yes, that's a beautiful question. So this is a work in progress. So we started several years ago with a crude indicator, BMI, Body Mass Index. And this was started by insurance companies, Simon, because they had an interest and they still have an interest. So BMI is a simple crude index correcting weight for height. But we realized that this is not as we realize what is happening, that this is not reflecting ectopic fat. So then we started looking into waist circumference. Which is a little bit more specific to like body fat distribution. Exactly, a little bit more specific, right? But again, different races have different numbers and they tend to have, say, Southeast Asians, they tend to have lower BMI's, but for a lower BMI, they don't have a lot of subcutaneous tissue.

1:31:50They accumulate fat in the stomach, but still is not the best, right? We need to refine it. So now, inexpensive markers, right? We correct waist circumference for height. We have to correct it, right? Because the waist circumference depends also on height, But if one wanted to be even more specific, we now know which are the hormones that are secreted from overall fat. And this is leptin. You gave it the hormone leptin from the Greek word leptos, meaning thin. We are talking about obesity, but I can explain to you what happens in anorexia nervosa or thin people. Because these are mirror images.

1:32:33And there is another hormone that we have done a lot of work on. It's called adiponectin. And adiponectin reflects the intra-abdominal fat. And this is a hormone and an inflammatory marker, anti-inflammatory marker. And the more the intra-abdominal fat, the lower the levels of this hormone. The higher the risk for diabetes and fatty liver disease and cardiovascular disease. So you can measure it. So the more intra-abdominal fat... The lower the levels of this beneficial protective hormone. Adiponectin. Yes. And you can request that on a standard blood test? Most laboratories should have it. The big laboratories have both of them.

1:33:17It's not yet standard biomedical practice, but we are getting there. It's research that is becoming practice. But if you go to LabCorp, or I don't want to advertise any, the big national laboratories, they can measure it. Now, you mentioned about scans, right? MRIs or CAT scans. Yes, we can measure it. With CAT scans or MRIs, we can measure not only how much fat you have, but also whether the fat is in muscle or in the liver. And they're pretty accurate. The problem is that they are expensive. So you cannot do it many times. You cannot follow people with that. You can break the bank. What do you think about a DEXA scan or liver ultrasound?

1:34:09Yes. So the liver ultrasound, and there are several companies that are making ultrasounds for the liver, is very specific but not sensitive enough. So if you have more than... let me start by saying that a normal person should have no more than 5 % fat in the liver. So the ultrasound is very specific if the amount of fat in the liver is more than 30%. Between 5 % and 30 % is a gray zone that is not pretty good in picking it up. So if you have a lot of fat, the ultrasound will find it. but if you have between 5 % and 30 % it's not as good as an MRI or measuring it so that makes it not a great option for a lot of people who might be on the fence no we are not using ultrasounds these days for fatty liver disease and DEXA?

1:35:08DEXA scan is pretty good in terms of overall fat we don't have it is not available everywhere. It's not as expensive as an MRI, but more expensive than running a hormone.

1:35:26It cannot tell us a lot about which organ has fat or not, but it can tell us the overall fat mass. Yes. So if someone's kind of listening and they're just thinking, I'd like to generally know where my metabolic health is at. Weight circumference to height ratio. Yes, for sure. And any particular blood biomarkers that you would also want them to look at? If a laboratory has adiponectin, I would run adiponectin. Another very simple measurement is triglycerides over HDL ratio. So if you start having ectopic fat and insulin resistance, your triglycerides keep going up and the good cholesterol HDL starts going down so this is a red flag okay so triglyceride HDL ratio waist circumference to height ratio this is how I would be starting and then if you see that these are abnormal if you if you see your primary care doctor and you see these are abnormal, I would run a panel, right?

1:36:39The full cholesterol profile, glucose, right? One by one, right? The diseases that we know of, right? There is non-invasive tests like FIB4 for fatty liver disease, uric acid for arthritis, right? And you name it, right? So your doctor will prescribe these.

1:37:03A few years ago, we did a large study and we followed people for several years, 10 years. 5 ,000 people, 10 ,000 people with diabetes, randomized in two groups. One was 5 ,000 people, multi-center, controlled trial, go home, lose weight, follow the advice of your primary care doctor and the other one follow toolbox approach everything that we could see a dietician every two weeks exercise physiologist take medications like not the medications we have today but the medications we had a few years ago and predictably people would lose with the intensive intervention about nine ten percent year one and then they would start regaining it why is the body fighting back despite having excessive body fat it has excessive body fat and is used to it let's put it this way right it's like a new set point it's a new set point it has to defend the original set point it's which is crazy right but i can't remember it's the set point exactly before you were exactly exactly so it probably needs more time more time than a year or two right to go back right or more progressive weight loss because that's probably how we are built right we are built to adjust so you you gain weight let's say you gain weight and you become a hundred kilograms or 220 pounds and you are at that weight for some time now your body essentially says this is our new normal and from that point 100 kilograms you go on a diet you lose let's say 10 kilograms you're at 90 your body is confused and says we need to get you back to 100.

1:38:58And I think that similar to each and every system the faster you lose the weight the more pronounced is the desire of your body to go back to baseline. You have to adapt to a new environment. And our body needs time. To resensitize the systems.

1:39:23What happens once you get that person to the point where they've lost the weight, sustained it, if you haven't changed their dietary pattern and the environment, and they go back to eating hyperpalatable, energy-dense foods, do they just end up back in the same position 10 or 15 years later? They may, right? So if you don't improve the environment, let's put it this way, and then I'll come to the specifics, right? Anyone will be more prone to fall. If you talk to people, though, who are on these medications, and we have done these studies, and we have also taken pictures of their brains with MRIs, they'll tell you that the same food that they were eating earlier is much less appealing now.

1:40:16So their brain sees the same food in a different way. So they have a healthier approach to food. So this changes the way we approach food. Now, there are three main areas in the brain, and I hope I'm not going too deep. So, one is the hypothalamus. This is homeostasis. And this has a lot to do. This is functions of our body that we don't feel, don't control. Like, our heart works day and night, we don't control it. This is homeostasis. Our temperature is the same. We go out in a cold environment and we upregulate heat production and this is hypothalamus, sleep. The hypothalamus has a major role in food intake.

1:41:14We get used to things, right? And things work like that. For humans, there is another set of nuclei in the brain, higher than the hypothalamus, is the reward centers. and a lot of people eat because they feel more rewarded. They need the reward. We need the reward, right? So think about it, right? We celebrate. We eat, right? We feel depressed. We also eat, right? And there is another center in the prefrontal cortex. This is executive function. So you will see where I'm going, right? Executive function is the control. So our brain has a lot of control. So you mentioned earlier about the environment of food, right?

1:42:01I will give another example. We go to a biomedical conference or a wedding, right? And there is a reception. There is plenty of food out there. Some of us, when they get to the food, will be more vigilant. Executive function, right? Don't eat. Others, without even feeling, they start... excuse my expression, grazing.

1:42:29And this is how we operate. Executive function, control, reward, and homeostasis. And what these medications do, and we have seen this with MRIs, is that they make you feel rewarded faster. The less calories. Less calories. And you have better executive function. These areas of the brain light up. which is amazing. I've seen some interesting, at least anecdotes, and you've probably read about this, where people have been prescribed with a GLP-1 agonist for weight loss, but they also perhaps have had an issue with alcohol or gambling, and have noticed that it's actually helped reduce other behaviors that they would classify as destructive.

1:43:19Beneficial and unintended it, right? Consequences of using these medications, right? Yeah, it's true. We have not studied it very well, but it makes sense, right? I mean, I told you about the reward centers, the control, right? Yes. So this is, it's not scientifically proven at this point, but there is enough reports for people to start doing trials. Right, and there's some mechanistic kind of plausibility, I guess there. It makes sense. I told you several years ago I had a neuroscientist, very good neuroscientist in my group, and we decided to do, she did it, I helped design the studies putting women, obese women and men, in the magnet, MRI, do neurocognitive and neuroimaging tests.

1:44:14Neurocognitive testing is like questionnaires, right? You know, prone to gambling, you know, stop, non-stop, right? You drive, right? You see the yellow sign. Do you speed or do you stop? It's simple things, but right? Smoking, as you said, alcohol. Before and after giving these medications. And you see, you see, actually see the areas of the brain, the reward centers. lighting up, or the executive centers lighting up and correlating with the neurocognitive testing. So, there is the physiology background. Whether we prove it or not remains to be seen, but chances are, knowing the physiology, that we will see that these medications have an effect.

1:45:00That's what I would predict. We'll see. You may invite me in a couple of years and we can talk more.

1:45:10The other thing that just came up for me there where you were talking about insulin going up makes me think about semaglutide and GLP-1 agonists. So perhaps you could kind of explain what these drugs are, why they're sort of, I guess, picking up, becoming more popular with regards to treatment of obesity and just how they're kind of working. Yeah, sure. So first of all, let me start by saying that I have no conflicts of interest with the pharmaceutical industry. So this is purely my opinion based on the evidence. And my opinion is that these drugs are awesome. so uh they just are much more effective than anything that came before them uh more effective and more safe glp1 is a gut hormone it is a hormone that's produced by the primarily the small intestine primarily the distal small intestine and it travels through the bloodstream does a few different things, but one of the things it does is it increases insulin secretion to help cover the glucose that you ate in your meal.

1:46:33And it also signals to the brain to increase satiety or fullness. And that insulin increasing function, which is by the way, glucose dependent. What that means is that GLP-1 only increases glucose secretion, or excuse me, only increases insulin secretion in the presence of elevated glucose. So it only ramps up insulin secretion when you need it the most around a meal. So that's kind of a beautiful thing. That's called an incretin hormone because of that. And there's another one, GIP. So yeah, it's secreted by the gut. And that was originally what got researchers interested in it, like Daniel Drucker.

1:47:28They found that when you put this on pancreatic beta cells, insulin secreting cells, it makes them secrete more insulin. So they said, hey, you know, this is pretty interesting. Maybe this could be a treatment for diabetes. because that's beautiful. If you're trying to increase someone's insulin secretion, especially around meals, which is when they need it the most, that's exactly the kind of thing you want, right? And so they patented this for diabetes treatment. And eventually in 2004, I think it's called Exenatide, was released as the first anti-diabetic medication made from GLP-1. And at the time, you know, the initial drugs did not cause that much weight loss, pretty modest.

1:48:26But what, you know, some of these companies, especially Nova Nordisk, some of these pharma companies got their hands on it, particularly Nova Nordisk, started experimenting with it and started seeing that, well, some variants of this hormone cause a ton of weight loss. And, you know, initially in rodent studies, of course, and this relates back to the fact that GLP-1 is a satiety hormone that signals to the brain that, you know, there's food in your digestive tract, so slow down on your eating. And basically through trial and error, they were able to refine these molecules to create molecules that were much more effective at causing weight loss.

1:49:14And so the first one of these that the first one of the latest generation of these GLP-1 receptor agonists, which is what these drugs are called, to be approved for treating obesity was semaglutide. And just to give you a sense of the magnitude of what effect size this has and how important it is, typical prior to semaglutide, typical weight loss from intensive, like best in class diet and lifestyle programs at one year was going to be in the range of like 5 % to 7%. Weight loss medications were kind of like the better ones were kind of in that range. So maglutide is causing, in randomized controlled trials, 15 % to 18 % loss of body weight.

1:50:10So much larger effect size. And if we use the benchmark of bariatric surgery, which is the most effective weight loss method that we have, that causes kind of like 25 to 30 some percent weight loss. It's like getting up there to almost bariatric surgery levels, weight loss surgery. And then terzepatide, which is approved for diabetes, not yet for obesity, but probably will be, that causes even more weight loss. So that causes something like 20 % loss of body weight. So, I mean, these drugs are just a massive, massive breakthrough. And not only that, but they seem very safe. In most people, the long-term side effects are minor.

1:50:56There's some gastrointestinal stuff, especially at first. It can be actually, it can be rough right at first. But the long-term side effects seem to be really minor. And the biggest side effects are actually positive. Like people get better blood glucose control. They get less cardiovascular events. People with type 2 diabetes have reduced all-cause mortality. And so these drugs are amazing. And drug development is going at light speed right now in this space. And it's just really cool to see. And furthermore, back to the kind of original topic that got us on this, if you give someone semaglutide or terzepatide, initially their insulin levels go up and yet they're losing weight.

1:51:51So they're losing weight, their insulin levels are going up. So this is kind of the opposite of what the carb insulin model would predict. So you have this compound that's these, they act in the brain to reduce food intake. And that shows that this brain mechanism is dominating whatever insulin stuff is happening. And the insulin comes back down over time as they lose weight. So it's not like it's elevated forever, but certainly initially there's an elevation of insulin while weight is being lost. If I'm sort of understanding this correctly, the GLP-1 agonist is acting on the brain to essentially help normalize a dysregulated appetite.

1:52:38Would you say that's, is that fair? I think it is reducing eating drive. And yeah, I think you could maybe argue that it's normalizing, but I think I'm kind of reluctant to use the word normalize because these drugs, some pharma reps will say, you have low levels of this hormone and this is just replacing your hormone. That's baloney. These drugs are ramping up that signal way beyond physiological levels. It's not just a replacement. These drugs are going into the brain and activating GLP-1 receptors way beyond what a normal person would experience. And so, normalize maybe in a sense because you have someone with obesity who has, you know, dysregulated eating habits, maybe excessive eating drive, and then bringing that back down.

1:53:41So, it certainly can feel like a normalization. But I think in terms of the physiology of it, it's not really restoring you to normal physiology. It's having a pharmacological effect that is outside of normal physiology. And do you see that as a drug that someone would continue to take for the rest of their life or would it kind of depend on what's affecting their hunger drive to eat and so some people who where it's driven you know predominantly or entirely by genetics they're going to have more difficulty coming off it whereas others if they could work on sort of behavioral aspects at the same time they might have more success coming off we don't have hard evidence on this so you know to some extent, we'll have to wait and see.

1:54:34But the expectation is that yes, you will have to continue taking this drug. You know, that's certainly a limitation. We would rather have a drug that you take one pill and the obesity goes away forever. You know, like you might take an antibiotic for, you know, a bacterial infection, but that's not how these drugs work. They're more akin to blood pressure drugs where your blood pressure stays lower for as long as you take the drug or cholesterol lowering drugs. You stop one of those drugs and your cholesterol goes back up. And that's what we're seeing in the trials is that when people stop these drugs, their weight goes back up.

1:55:21Now, whether you would see some lingering benefit if someone was on this drug for five years, I don't know. We don't have data on that. You know, would they 100 % return to their original weight or would they stay a bit below? There's some hints that maybe that people might be staying a little bit below even after they discontinue, but we just really don't have answers to that. But again, the default expectation based on diet and lifestyle weight loss is that, yes, if you go off the drug, you're probably going to regain. There you have it, friends. I hope you enjoyed this episode. If you did and want to stay up to date with future episodes, be sure to hit that subscribe button on YouTube and follow on Apple or Spotify.

1:56:11Finally, thank you for showing up and the effort that you're making to take control of your health. I look forward to hanging out with you again in the next episode.