The UK Launch

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So, Andrew, what’s your opinion of this new, relatively new theory on weights and set point? So, weight set point theory, I think, is something that really explains what our patients are describing to us. This feeling that their weight is set at an unhealthy level and that when they try and diet or exercise their way out of it, the weight just comes back to this setting and it’s almost, they seem set in stone. You can’t run away from it and you can’t diet away from it.

And the theory suggests that each individual has their own weight setting and it’s dependent on your genes. So, some people are from families that suffer with obesity. It’s from this new area of epigenetics.

So, what happens when we’re in the womb? They have signals changing our DNA and it’s also dependent on our food environment. So, the types of food, whether it’s ultra-processed foods and stress as well. I think it’s a great theory and I think it does fit in with what patients experience.

They can lose weight on a diet, but then they increase weight back to where they were before. But actually, also, they say they go a bit higher. And my take on that is that you’re signaling to your body that you’re in some sort of starvation, famine environment.

So, when the food comes back, when you come off the diet, the body’s got that message. There may be a famine in the future. Let’s just put a little bit extra energy storage in there.

That’s why they end up even higher than when they went on the diet in the first place. Many of our patients who are living with obesity try and get out of their problem by what we tell them to do, go on a diet. How does that affect their bodies and their metabolism? That’s something we see all the time in the clinics.

I don’t think there is a right or wrong diet. A diet that works for the individual works the for them. I feel that patients we see in the clinics, they’ve got strong willpower because they are putting themselves through dieting and dieting all over again.

We see them in the clinic, they say, I’ve been dieting all of my life. And they actually show amazing willpower being able to do that over and over again. But as you know, going into weight loss, going into starvation mode, that slows down your metabolism and essentially weight loss plateaus.

What tends to happen afterwards is patients will lose motivation, will lose the psychology and they will stop and they will weight regain. And sometimes the set point will be higher than it was initially. And they will end up gaining more weight than before they actually started dieting.

Yeah, I agree that as you lose weight and go further away from your weight set point, your body wants to pull you back to that set point. And the reaction of the body is twofold. One is it wants to encourage you to put energy back in.

So you get these hormones from the intestine, GLP1, PYY ghrelin. These are all changed around to give you a voracious appetite and actually decrease your satiety. So you keep on eating, you never feel full.

And then the next one is that your metabolism is decreased. So you feel very lethargic. So these signals really change the way you feel and the way you behave.

They’re very powerful in changing behavior. So willpower of people on diets has to be amazing. I am amazed when they can lose two, three stone on the diet and the body’s trying to pull them back.

So yeah. We see a lot of studies now done looking into very low calorie diets. And as you know, a very low calorie diet means there’s less than a thousand calories per day, which is really difficult to follow, particularly over prolonged periods of time.

But these lifestyle interventions don’t work long. They tend to fail. And as you very nicely explained, the reason for that is that our bodies will try to counter this stress environment for them, you know, the starvation environment, the diet environment, and it will slow down basic metabolic rate, diet-induced thermogenesis.

And as we lose weight, that set point is actually changes. And it’s actually the tendency to go back to the normal. And higher.

And higher. Yes. And I think there’s some evidence that if you go on a very low calorie diet, even after you’ve regained the weight, when you’ve finished the diet, your appetite hormones are higher than before.

So this is what a lot of people who have been on diets recurrently say, I seem to be getting much hungrier and hungrier and hungrier. And my willpower needs to be stronger and stronger and stronger because it’s, you know, it’s working against you. So diets, I think, work against you.

Exactly. It’s your body’s counter-regulatory mechanism to avoid you from moving from the set point. So it produces appetite-increasing hormones, ghrelin.

It reduces the release of appetite-suppressing hormones, like GLP-1, PYY, oxandamodulin, and many others. And you’re bound to go back to your original set point. It’s really hard.

And it fails. And I’m sure you see a lot of these patients in your clinic. I see them as well.

It’s almost like you’re tied by a post, that’s your set point, to an elasticated band, you know? And you can run away from it. And the further you get away, the stronger the pull back. And then you lose incentive to be on a diet, which just comes back, snaps back.

But the further you get away, the more difficult and the more severe the reaction. George, what do you think happens within our bodies when we go on a low-calorie diet and start to lose weight? So obviously, we take less energy in and we start losing weight. But as we described previously, we’re bound by the set point theory.

So our bodies will prevent us from continuously losing weight. And they will try to counter this situation by reducing the release of certain appetite-suppressing hormones. So they will make us want to go back to our usual weight.

There will be release of ghrelin, the hunger hormone, released in the stomach by the G-cells. And there will be less release of appetite-suppressing gut hormones, like GLP-1, released by the L-cells with oxytomodulin, PYY, and polyhistokinin in the duodenum. And that will reduce our satiety, a feeling of satiety.

And then we will gradually weight plateau and start gaining weight. So the efficacy of the intervention will be hampered over time. What do you think changes during a diet? I agree.

I think you get this complex interaction of all these little hormones that actually produce an increased appetite and decreased metabolism. But I think the master controller of that is leptin. So this hormone that comes from your fat cells, when you start to lose weight, actually immediately when you’re on a diet, your leptin level goes down.

And your brain senses this and thinks, well, OK, the tank is becoming empty quite fast. And then the hypothalamus, the weight control center, acts to produce all these hormonal changes that would then give us behavioral changes, signals on how to behave. And these hormones and peptides, they control us.

There’s a difference in the way we act from being a child to a teenager to an adult to an old person from a sex hormone point of view. Massive differences. And these differences, I think, they change our behavior massively.

It’s not your character. It’s actually what the body wants, how it’s controlling you. Yes.

We’re bound to biology. And what changes to energy expenditure happen during this process? Yeah. So I think on the basis of decreasing your basal metabolism, so the amount of energy that you use before you move, that can be very dynamic.

And you can almost turn down that dimmer switch of energy. And I think that’s produced by changes in your autonomic nervous system. So this is the nervous system that we learn in medical school is the fight or flight response.

So when you get in a situation where there is a threat, you get this stimulation of the sympathetic nervous system. Fight, you feel strong. Or flight, you want to run, but you can run really fast.

And then on the other aspect is when you’re relaxing and you feel very relaxed, your blood pressure’s down. So we’re taught that that system is for survival. But actually, the secondary aspect of that system is to preserve or use up energy.

So when you go on a diet, you will go into that parasympathetic response. You won’t use up much energy. Your pulse is low.

Whereas when you overeat, you’re going to be your blood pressure’s high, over-metabolizing and getting rid of that extra food that you’ve eaten to try and keep you back at the set point. So what you’re saying is essentially that as you lose weight, your energy requirements drop, your basic metabolic rate is lower. So in order to continue losing weight, you have to reduce even further the amount of food you eat, which is extremely difficult, especially if you’re on a very low calorie diet already.

I had a patient who had been living with obesity for many years. Maybe she was 25 stone. And she did really, really well with willpower and went down to 1,200 kilocalories a day.

But she was on it for a year. And she went from 25 stone to 16 stone. She came to my clinic because she was still overweight.

And she was complying with 1,200 kilocalories a day. But her weight was totally stable at 16 stone. Her body had adapted to the low calories.

Exactly. What do you think we’ve learned from this episode, George? I think we very clearly demonstrated that we’re bound by biology in a specific weight range. Our bodies are predetermined to reach.

This is due to genetics, epigenetic changes. And it’s really difficult to move that set point despite interventions, lifestyle interventions and pharmacotherapy or other interventions of weight loss. What is your view, Andrew? So I think we’ve learned that the weight set point theory is probably not a theory.

It’s probably true. And that it explains exactly what our patients are telling us. They can yo-yo down and up in weight, but they’re always at this particular set weight.

And that set point is determined by our genes, epigenetics, this new science, but also the environment and the quality of food and of highly processed food that we have or not. Not the calories. Obesity.

The big truth.

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We sort of have this very simplified understanding of obesity. People living with obesity are stigmatized and sort of blamed for their condition and it’s sort of not really widely understood to be a disease. But there’s a lot of science behind it.

What’s your sort of take on the science of what causes obesity? Andrew, thank you for bringing this up. A great campaign has been going on on changing the language of addressing obesity. There is a lot of work going on into the obesity stigma.

But I agree with you, we’re missing the science. And I think it’s easy to miss the science because obesity is a very complex disease, a multifactorial disease driven by many different parameters. But I think the key molecule, and you agree with me, I think, is leptin.

So leptin resistance is probably the biggest driver of the obesity pandemic and the effect it has in the signaling between the gut, the brain and the adipose tissue. And this leptin resistance is fueling insulin resistance and further weight gain and suppression of the gut peptide hormones. This is, I think, the main driver along with genetic and epigenetic changes.

Yeah, I mean, I think probably just to clarify what leptin resistance is. Leptin is a hormone that’s produced by the fat cells and it’s supposed to act as a signal to your weight control center in your brain, to tell your brain how much fat you’ve got on board, how much energy you’ve got on board. The problem is when that stops working, the leptin signal gets blocked by insulin, but also inflammation.

What’s your take on inflammation and obesity? Is it an inflammatory disease? Very good point. So the adipose tissue releases more than leptin, it releases pro-inflammatory cytokines as well. So I think, as we know, obesity is associated, linked to chronic low degree of inflammation.

And that’s in part due to the release of pro-inflammatory cytokines like TNF-alpha. But I think the food choices in today’s society may be influencing this. So obesity itself causes inflammation, but actually some of the foods that we eat, some of the processed foods also cause inflammation.

And the more fast food and processed foods we have, the more the ratio of two essential fatty acids in our diet, omega-3 and omega-6, will balance each other on the ratio. Depending on the intake in your diet, and they are essential fatty acids. So the omega-6 coats every cell in our bodies.

And when you get a preponderance of it compared to omega-3, that affects insulin signaling in itself. So by having a Western diet, not only taking in refined carbohydrates, which are going to cause insulin, but also taking in too much fast food, vegetable containing food, you are profoundly affecting all of your cells in your body. So insulin doesn’t work properly.

Again, getting into this massive vicious cycle of too much insulin in the body, blocking leptin, and then these signals and the symptoms of the disease, starvation, feeling of hunger and lassitude. When we have a Western diet, we have a lot of omega-6, which is inflammatory. So the diet itself, the Western diet, fast food and processed food and food that sits on a shelf is pro-inflammatory.

So that combined with the fact that obesity itself is an inflammatory condition, these two things block leptin and the signal doesn’t get through. So you have a situation where a patient is with high leptin levels, but because of the inflammation, the diet and the insulin, that signal is not getting through. We know that obesity causes type 2 diabetes.

What effect does that have on insulin signaling? Do you need more insulin with type 2 diabetes? Yes, it is a vicious circle. Overeating doesn’t cause obesity. It is actually obesity that causes overeating because of all the mechanisms you explained.

So early in the onset of diabetes, the beta cell, the organs producing insulin, the pancreas are preserved. Their function is preserved. But over time, that deteriorates.

At some point, insulin is inevitable. But then again, more insulin fuels more resistance to insulin and that fuels more hunger and more weight gain. So it is a vicious cycle.

Nowadays, a lot of patients with uncontrolled diabetes need to have bariatric surgery in order to improve their cardiometabolic health and also improve their health through weight loss. We have a multidisciplinary approach to managing patients with obesity. What is your view on that? Are there benefits to treating patients with different treatments? Obviously, trying to tailor treatment, but different modalities, like blocking different pathways? Well, I’m going to defer the medical treatment to you in a minute because I know there’s a lot of new, really exciting treatments coming out that are actually quite effective.

I’ll talk about bariatric surgery in a second. But I think if we understand obesity, and just as we’ve explained it, it is a condition caused by the type of food that we’re consuming, not particularly the calories, but actually what that food does to your body. If we understand that, then actually by encouraging people at a very early stage of obesity or overweight not to go on diet, the problem is a lot of people don’t learn how to cook.

So they’re at the mercy of our big supermarkets with all the processed foods in the middle of them. So that would be my advice for someone struggling with overweight, don’t go on a diet. Going back to our weight set point theory, when you do, for instance, gastric bypass, their weight set point is here.

Overnight, their weight set point has gone back down close to the normal range. But they’re finding the signals are pulling them actually to just being slightly overweight. And it’s a really nice feeling for them.

They totally feel in control. I’m sure you’ve seen them before. What about the medical treatment of obesity? So I like combining treatments to treat obesity.

And we try to do that in our unit. I know other units do the same. So I think the manipulation of gut hormones is the main medical modality.

And this originates from the outcomes of bariatric surgeries. We’re living in the era that the physicians, in which the physicians are very privileged to have the options of treating patients with other than advice. So I think the main treatment options are GLP-1 receptor agonists, which, as you know, by giving them supraphysiological doses of what is essentially missing, as we described earlier, and we are helping them improve their satiety, increase their satiety or reduce their hunger.

But there are other options. There are different options. And blocking one pathway is not really the way forward.

There’s no one right answer to treating obesity. So we have different treatments, dual agonists, ghrelin enzyme inhibitors, other treatments, GIP, PYY analogs. And also we have oxyndomodulin analogs and other medical treatments.

But I think the key message is that we need to tailor treatment. We need to combine treatments to get the most out of the treatments we have. Yeah, I mean, I think the whole change in the understanding of obesity comes from this realization that actually the stomach and the intestines are what we would call an endocrine organ, as well as a digestive organ.

What we didn’t understand until recently was that the intestine and the stomach produces these hormones that change our behavior. And also the fat, going back to leptin. So I think it’s fascinating that you guys now are being able to prescribe particularly one hormone, GLP-1, which mimics that hormone going from your intestine, which sort of appears about half an hour after eating, which is supposed to be the signal for you to stop eating to your brain.

But actually we can give that by injection under the skin. And it stops that pullback of voracious appetite when you lose weight. So I think that they’re great treatments.

Since we have been speaking about leptin resistance and leptin being the main driver, what is your view on replacing leptin? Is that a viable pathway moving forward? Can we give leptin because of the resistance to leptin? So I mean, that’s a fascinating subject. And as you probably know, years ago when leptin was discovered, I think there was a pair of sisters who were leptin absent. So there was no leptin signal.

When the scientists then gave them leptin, their weight normalized. And this was like, we’ve got it. We’ve cracked obesity.

But then actually when the scientists gave leptin to people who don’t have a natural leptin deficiency but just have obesity, they’ve already got a lot of leptin in their system. So to give them more didn’t work because the leptin is being blocked. So it was quite an exciting time in obesity research.

But that was before we realized leptin was important and crucial in weight regulation. But that’s before we understood leptin resistance. So George, a lot of people will say that obesity is linked with food addiction and the fact that our highly processed foods are really, really tasty and people get addicted to them.

This addiction is driven by biology rather than by choices. We go back to what we have been discussing all day today. So it’s going back to the adipose tissue and the gut, the effects of leptin and resistance to leptin, the effects of gut hormones to appetite regulator, the hypothalamus.

And the fact that these patients have blunted signals when it comes to appetite and satiety. So they feel hungrier, they tend to overeat and that fuels further overeating. So obesity drives this process.

Yeah, I mean, I think I agree that once you’ve developed leptin resistance, obesity caused by leptin resistance, the behavioral signals from your hormones will give you this voracious appetite. And you have a voracious appetite, that’s hormonal behavior that’s imprinted in you in an environment where the food industry produce food that people really want to buy and go back to. So we know that, for instance, sugar has the same signaling pathway, actually, as opiate drugs.

So it gives you a similar reward to a much lesser dose, but it does give you a similar reward when you have sugar, it’s like a drug. So I think that there is a degree of addictive, perceived addictive behavior. These people are ravenously hungry because they’re leptin resistant, which is the biology of obesity.

And you have hedonic food around you. So it’s almost preordained that you’re going to become a bit addicted to that. If the right choices are made with regards to their diet and their lifestyle, are we solving everyone’s problem with doing that? If you are just overweight and want to lose some pounds, I think if you follow really good lifestyle changes, learn how to cook, eat two or three healthy meals a day, over time, maybe over a couple of years, your weight would settle down or your weight set point would settle down towards normal weight.

However, those people who are suffering with more severe obesity, even if you have those great lifestyle changes, the leptin resistance is going to stay there to a degree. And it doesn’t matter how hard you try and get out of that, it’s still going to be there. And this is where this group of patients suffering with proper obesity benefit from bariatric surgery.

And it’s such a powerful tool to change the way the guts are configured. And that therefore then changes the signals from the guts to the brain to give this seamless satiety, lack of appetite, normal metabolism. And this, your weight set point just automatically decreases towards a healthy level.

So I do think there is a fairly large subset of people suffering with significant obesity, who even with lifestyle changes, they need more. I think for people suffering obesity throughout their lives, just increasing, increasing, increasing throughout the years and decades, their weight, bariatric surgery is a really good option. I mean, the two main operations that we’re doing are the gastric bypass and the sleeve constrictor.

And both of those really affect that signal from the stomach and guts to the brain. There’s another old fashioned or older fashioned operation called the gastric band, which is basically like a sort of plastic type ring with an inner tube that you can tighten that is above the top of the stomach. Now that produces weight loss basically by stopping you eating fast.

But the problem with that is as you lose weight, it doesn’t change those signals. So Andrew, we’ve spoken a lot about the etiology of obesity, the complexity of the disease and the management. We haven’t spoken a lot really about another metabolic disease, which is closely linked to obesity, type 2 diabetes, which as you know, is another pandemic.

So a modality that is used more often nowadays is metabolic surgery to treat type 2 diabetes. Some of these patients achieve remission of diabetes, though, without weight loss. So what is your view on the weight loss independent metabolic benefits of having bariatric surgery? I think that’s a good question.

And yeah, we do see people who have type 2 diabetes. So unlike type 1 diabetes, where there’s a shortage of insulin, actually early type 2 diabetes, there’s too much insulin. And actually that’s why that then blocks leptin and you get this vicious circle of obesity and type 2 diabetes.

The really good thing about the gastric bypass in particular is that as food goes from ingested food, it goes through a small little stomach pouch. And then through that, it goes straight into the intestine. So within five minutes of eating, food is in the intestine, which is the small intestine, which what the body perceives that to be, you’ve overeaten.

So it produces this hormone that’s supposed to stop you eating, GLP-1. But also it actually has an effect on insulin function. So it improves significantly the sensitivity or the effectiveness of insulin.

So overnight, you’ll see some people who maybe they’ve been diagnosed with type 2 diabetes over the last two, three years. You do a gastric bypass and suddenly they don’t need any treatment. The diabetes has gone straight into remission because GLP-1, because of this change in the plumbing of the intestines, has increased significantly, caused insulin to be much more effective again and reverse the diabetes.

And the great thing, the great knock-on of that is well, obviously, you don’t need as much insulin to work. So certainly the leptin signal is getting seen because the obscuring insulin has gone away. And GLP-1 also is a satiety hormone.

You don’t feel hungry. So all of these things just nail your weight set point much further towards normality. Obesity is a complex, multifactorial disease requiring multimodal approach to ensure better outcomes.

It is a relapsing disease. So patients need to be educated on the long-term changes required even after bariatric surgery. Metabolic surgery is a very effective way to treat type 2 diabetes by improving the signaling of insulin, leptin, gut peptide, hormone release, improving satiety and therefore causing weight loss as well.

So I think the take-home points from this episode are the fact that obesity is caused by leptin resistance. Leptin is the hormone that comes from the fat that’s supposed to signal to us how much energy we have on board. And that gets blocked by insulin and inflammation.

High insulin levels come from the Western diet, sugar and refined carbohydrates. Inflammation comes with obesity itself but also is contributed to again by fast food and processed foods with the omega-6 in there. And this all causes this cascade of the leptin signal not being read.

And the fact that metabolic surgery is actually really good to deal with this whether you’re on it or not. I think the takeaway messages are that leptin resistance is a key driver. It hampers insulin release and insulin sensitivity and the effects of insulin centrally but also the release of gut peptide hormones and thus causing obesity along with the Western diet.

And I would say that metabolic surgery is a key modality to treat type 2 diabetes mellitus primarily when it’s early onset and not complicated. Education around obesity as a disease is missing. Healthcare professionals should increase their awareness of obesity as a disease and the complexity involving etiology and management.

I think to understand obesity appropriately we need to get away from that simplified energy in energy out equation as the primary cause of obesity. And think much more along the lines of what processed and westernized foods actually do to our bodies to encourage it to gain weight. In a way, obesity is an appropriate response to a Western diet.

Lifestyle interventions have been unsuccessful previously and currently in maintaining metabolic health. So you mean the more you diet the more difficult it becomes to lose weight. The more efficient your metabolism is the way you rebound back up.

So I think we have a much better understanding of weight regulation now how our weight is regulated really by leptin and how signals from hormones in our stomach and guts GLP1, PYY, ghrelin signal how much energy to take in and then leptin itself acting on our metabolism signal how much energy to expend. And this usually keeps us on an even balance until we get to this problem with leptin resistance which causes obesity. Genetic, epigenetic and environmental changes bind us to the weighted standpoint and predetermine our response to different modalities and the effect these will have on coexisting complications of obesity.

We are living in the era of tailored medicine and within the NHS we have scarce resources to treat patients with obesity. So finding the right treatment for the right patient at the right time is key to optimising benefits and outcomes to patients with obesity. Predetermining response to treatment through the use of multi-omics, miRNAs, exosomes is key to determine response and outcomes.

Multi-modal approach is key for ensuring best possible outcomes for our patients. Obesity. The big truth.