Regulation of Energy Balance and Body Weight


This session includes information on the impact of genes on body weight, an overview of the interplay between energy intake and expediture and information on metabolic adaptation during and after weight loss. Key speakers: Professor Giles Yeo MBE, Dr Alessio Basolo, Dr Silvia Bettini


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Lovely, so thank you everyone for joining us. Sorry for the slight technical delay this evening. We have three fantastic speakers with us.

The first unfortunately can't join us in person. Giles is in the Netherlands, but he has sent us a fabulous presentation. So I'm going to put his bio in the chat and then start his presentation.

So I will share my screen with you and hopefully you'll be able to see Giles's fantastic presentation. So just there we go. Okay, can everybody see that? Is that working for everybody when that plays? Can somebody let me know if that's coming through when I press play on Giles? I couldn't hear the speaker when you started the video.

Yeah, me neither. Okay, let me try again. Is that working? Hi folks, I think I'm recording.

Thank you very much to the organizers for a lot. Thank you very much to the organizers for allowing me to speak and I apologize. I cannot be there in person, so I'm not going to share my screen.

Put on the show. So I'm here to talk about the genetics of obesity. So I'm a geneticist by trade and I think that's a perfectly upstanding thing to do.

My mother-in-law still speaks to me, that's a fantastic thing. But when people ask what I study and I tell them body weight, of which obesity happens to sit on one end of the spectrum, immediately I become the bad person. And I become the bad person because I'm perceived as giving bad people, overweight people, people living with obesity terms I do not use in any pejorative fashion an excuse.

Which I think philosophically has always been an interesting take for me, because if I was studying the genetics of dementia, the genetics of cancer, the genetics of arthritis, would I suddenly be giving those people suffering from those conditions an excuse? No, I'd be trying to understand biology, mechanisms, God forbid, I might be trying to help somebody. But yet, when we talk about body weight, yet when we talk about obesity, suddenly it becomes imbued with its choice, its bad lifestyle, it's a habit. Okay, and I want you to, I want to take the next 20-25 minutes or so to rebut that, that it is not, that A, I'm not giving anyone an excuse, and B, that it is not a choice at all.

I have a rather cryptic title, Genetics of Obesity, Can an Old Dog Teach Us New Tricks? And now there are two dogs in the story, there's an actual dog who will appear and you'll see it, but there's also a metaphorical dog, which I will point out when we actually get to it. So, hello, very pleased to be here. This is, in very many ways, why I'm thought to be a bad person.

I think we've all seen this energy balance scales of justice thing. And it's otherwise known as the first law of thermodynamics, right? So you can't magic calories from thin air, and you certainly can't magic them away. Look, the only way you can gain weight is to eat more than you burn.

And the only way, therefore, to lose weight is to burn more than you eat. And I know what you guys are thinking, sorry, what? We've come to this seminar to listen, to eat less and move more? Yes, because it's physics. Our body weight has to be a function of physics.

How can it not be? Because it's a fundamental law. It's the how we get to how we are. But that is too simplistic, because where the complexity and biological variation and interest lies is in the why.

Why do people behave so very differently about food? How come some people respond to stress by eating, whereas some people respond to stress by not eating? It's exactly the same hormone, cortisol, yet there's diametrically opposite responses to it. Some people love food. I love food.

Other people use food as fuel. Some people take more food to get fuller. Other people feel hungry all the time.

These are not imagined. These are actual behaviors that influence the physics, the why of how we behave around food, make more driven to it, therefore making some people eat more. Therefore, we are small, medium, and large in the environment we live in.

So we now have a general understanding of food intake control. I've put here a simplistic architecture. Our brain needs to know two pieces of information in order to influence our food intake.

It needs to know, A, how much fat we have. Now, this is important, because how much fat we have is how long we would last in the wild without any food. So if your sources of food stopped today, how long would you live for? So it's a pretty important integer to actually hold in your head.

But your brain also needs to know what you have just eaten and what you're currently eating. These signals are going to come from your gut, your gastrointestinal tract. So these long-term signals from fat and short-term signals from your gut circulate in the blood and signal to the brain, which then responds and translates to these signals and influences your next interaction with a menu, with a refrigerator, and with your supermarket shelf.

Critically, there are genetic modifiers that run throughout this entire process. And geneticists such as myself can harness these genetic modifiers to understand pathways, to understand biology. And today, I want to focus on one specific pathway, and it is the fat sensing pathway.

And this fat sensing pathway is the so-called leptin melanocortin pathway. Leptin is produced from fat to signal the amount of fat you have. It signals to the brain, a part of the brain called the hypothalamus.

Within the hypothalamus, it triggers a set of neurons called the POMC, or pro-opioid melanocortin neurons. These are processed into melanocortin peptides, hence the name, which signal to the melanocortin 4 receptor, influencing food intake and metabolic rate. This is the first ODOG in the story, the metaphorical ODOG, and it's the melanocortin pathway.

And why is it an ODOG? Because we already know all the major components of this pathway. And we know this because genetic disruption at every single level of this pathway, every single level of this pathway, results in severe obesity. There was a golden period of time between 1997 and the year 2000, turn of the millennia, in which we identified, we and many others within the field, identified mutations within every single stage of this, resulting in severe obesity, whether or not you have whiskers and a tail, or whether or not you don't have whiskers and a tail.

And why am I here talking to you guys about work that was all worked out before the turn of the millennia? Well, I want to argue that this ODOG, worked hard on this, is going to be able to teach us some new tricks. So I'm just going to give you some examples throughout and highlight where the new findings have actually emerged. So let's start at the very beginning.

Leptin deficiency. Now, leptin, as I said, is a fat hormone, is a fat adipokine, and it circulates in the blood in proportion to the amount of fat you carry. So the more fat you have, the more leptin, the less fat, the less leptin you have.

And it is the key signal from fat that signals to the brain how much fat you have. What happens when you don't have leptin? So this is a child, three-year-old weighing 42 kilograms. Okay.

And this is work done by my colleagues, Professor Stephen O'Ratley, and he was the one that led the study way, all the way back when, and his at the time clinical fellow, Sadaf Ruki, now Professor Sadaf Ruki. And Steve asked the question, you know, what happens if a human being didn't have leptin and they found some kids with leptin deficiency? And this is what happens. So this is a child who clearly is severely obese, three years old, as I said, 42 kilograms.

And this is clearly not just being mildly overweight, he is severely, severely obese. I mean, I have a body weight of 75 kilograms. So this is a three-year-old who was born at two thirds my body weight.

And this is what happens if you don't have leptin. Suddenly there's a disconnect between the amount of fats you're carrying and what your brain senses. In fact, because you have no, because this child has no leptin, your brain can't sense the leptin.

And so for all intents and purposes, the brain senses no leptin. And when do you not have any leptin? When you're starving. Okay.

Because without leptin, you don't have fat and you don't have fat when you're starving. And so the brain, in spite of the body habitus of this child, this child has a brain who thinks he's starving, therefore making him eat ferociously. Okay.

Hence the body habitus, hence the amount of fat. Now, Steve then asked the question, well, if fat is a hormone, and if you take the analogy of type one diabetes, you replace insulin to manage your glucose homeostasis. Can you inject yourself with leptin to manage your fat homeostasis? Lo and behold, you could.

So this is the same child now a few years later, but with daily injections of leptin, and you can see that his body weight has normalized. And that's because his brain now senses that there is fat in the body and normalizes his feeding, his feeding behavior. Leptin is there not to tell your brain, I just want to be clear how not to tell your brain that has too much fat, but to let your brain know it has enough fat and then to act when it doesn't have enough fat, it turns on the starvation response.

Now, as I said, leptin then signals to the part of the brain called the hypothalamus, where it triggers a population of neurons called the POMC neurons. Now at this stage, I could show you pictures of kids with POMC mutations and the knockout mice we created actually in order to understand the mechanism. But I thought I would focus on, haha, a real dog.

And this is a work that was actually done in Labrador Retrievers. Now this work was led by a veterinary surgeon colleague of mine, Eleanor Rafferty. And I'm sure a number of you out there own Labradors as pets because they are the most popular pet dog in the North America.

Why? Because they have a wonderful temperament. But aside from that, however, all of you who own Labradors know keep your compost bin shut because the Labrador will in with a shot to eat anything that's in there. It is probably one of the most, if not the most, food motivated dog.

And Eleanor was interested in understanding why. Okay. And so she threw the genetic book at these Labradors.

And to cut a long story short, a percentage of Labradors have deletion in POMC. Now if you actually do a percentage, not all of them, so you can do what we call a genotype-phenotype correlation where we match wild type is no deletion, heterozygous one copy, homozygous two copies. And if you plot that against body weight, then what you can see is you can see that each deletion allele is worth two kilos or so in body weight, such that homozygous dogs for the deletion are four kilos heavier than the wild type dogs.

Now that doesn't sound like a lot, but Labradors only get to around 30 to 35 kilos. So four kilos is an awful lot of dog. And when we do the same analysis, but this time with food motivation, you see exactly the same pattern.

So this increase in food motivation with the deletion is probably driving the obesity phenotype that we see. And so this is what I said. It's a couple of kilograms per allele or 0.3 of a standard deviation of body weight, but not all Labradors, that's roughly for those of you who follow the FTO biology, which I worked on for quite a while, is three times the effect size of the FTO-Quisk allele.

Now, not all Labradors have it, as I said. In fact, 75% of Labradors are actually wild type. It's only 20 to 25% of Labradors that either carry one or two copies of the deletion, but yet 95% of Labradors are highly food motivated.

So Eleanor Raffin is now welcome funded in order to try and answer some of these questions about key genetic drivers. That are there, but this is not the end of the tale because not only are Labradors really have a wonderful temperament as a family pet, they're also very, very trainable. In fact, they're still trainable.

They're primarily used as guide dogs for the blind. Now, guide dogs are trained within an inch of their life because they're about to be given a human being to look after for the rest of life. And the pyramid is very steep.

There's lots of failure and the ones that fail become pets. So you end up with the pinnacle, the few, the proud, the guide dogs, and they are trained using Pavlovian techniques with food. And so much so that if you look with food, so if you actually look at the successfully trained guide dogs, certainly in the UK, we find that 80% of them carry the deletion for POMC compared to 25%.

So here's the concept. Imagine I'm the guide dog and I'm bringing back visually impaired Mr. Smith, say a chicken ran across the road. Okay.

What are the chances of chicken for dinner? 50-50, 80-20, doesn't matter. The guide dog is trained that it will have a 100% chance of getting dinner if he brings Mr. Smith's safety back home. And so we started off by looking at food motivation, which is what we still study, but then went into this whole world of trainability because of the selection pressure that was actually placed on the dog.

So if you actually go back home to look at your Labradors and you see they've got big googly eyes and says, look, Fido loves me. Fido doesn't love you. Fido is hungry.

Anyway, we made it onto the cover of the journal. This is Alanor, who still needs to study. And this chocolate lab is Jasper, one of the participants.

And so now you'd be unsurprised to know that if you actually have a mutation in the MC4R, which remember leptin, leptin, pump C, pump C, the melanocorticoid 4 receptor. So it's the same pathway. And if you have a mutation in the melanocorticoid 4 receptor, you end up with severe obesity.

And this is where I actually began chronologically speaking on the scene in 1998, old dog, as I said. And we find that actually it results in severe obesity. But a couple of interesting things about the MC4 receptor.

First of all, it's not a binary system. It's not on or off. So we now know that it is that mutations in the MC4R are actually quite common.

How common? I'll reach out. I'll come back to you in a few in the next slide and tell you how common. But we now know of a few thousand mutations, and some of them are more severe and so therefore are completely dead in a functional study we do with tissue culture in the lab.

Whereas others are more subtle, anywhere from 30 to 70% function, you know, slighter changes in the protein. So this is work, just to be clear, that was done by me using recombinant protein in a lab in 2003. It's quite a while ago.

On the right hand side is clinical research done by my colleague, Professor Siddhartha, and she analyzes the feeding behavior of children. Now if you actually look at the right hand bars over here, these are studies done within a buffet breakfast scenario, where everything is measured in and out and the kids are allowed to eat what they want. So you get a measure of how much they eat.

Now focusing on the two red bars, you'll see that this is the biggest bar here is leptin deficiency, the child, the very, very first child I showed you. And the other red bar, the smaller red bar, is treated leptin deficiency. And you see this huge drop off in feeding once the child has been given leptin.

Squash sandwiched in the middle are the kids with MC4R deficiency. Now Siddhartha, Professor Farooqi, analyzed these kids as they came through, but only divided them up into these categories after I provided the tissue culture lab experiments. And we were able to predict how much the children were going to eat in a buffet meal based on the percentage of function of their receptors in an in vitro study.

So it's a rheostat. It's a tunable system rather than an on and off system. And I said it was more common.

So how common? So this is what we've done with the Avon longitudinal study of parents and children, ALSPAC, run by my colleagues in Bristol. And it's a birth cohort. So pregnant women between the years of 1990 and 1992 around the Bristol area who went to the Bristol hospitals to give birth and were recruited to the study.

Their kids were then followed longitudinally. And I say kids, they're not 30 years old, obviously. But they were followed through.

And we have other data. We published this work last year. We have other data about the longitudinal effects of MC4R deficiency.

But I just wanted to highlight a couple of things. First of all, we found that 0.3% of kids within the ALSPAC study, people within the ALSPAC study have pathogenic mutations, demonstrably pathogenic mutations in the MC4 receptor. So 0.3% extrapolated to the whole UK population is 200,000 people.

Extrapolate that to the USA, a larger country, for example, that's more than a million people potentially with mutations in the melanocorticoid 4 receptor. And what is the functional output of this? Well, at 18 years old, I took, I took the, we took the age as they became adults. At 18 years old, if you carried one copy of a loss of function MC4R mutation, you are on average nearly 18 kilograms heavier.

That's 40 pounds. Okay. That's also five BMI points, 20 to 25, 25 to 30.

And of that 18 kilos of added weight, 15 kilograms of which are fat. Okay. That's a lot of weight because of a, of a lack of function and 200,000 people in this country.

But the really exciting thing about it is we now have a treatment that targets the, that targets the system. So this is the group that actually identified the first POMC deficient child. I didn't show you the picture.

And this is the group of Heiko Kruder and Annette Gruters from the Charité hospital in Berlin. And working together with Rhythm Pharmaceuticals, they they have used a compound called set melanotide to treat POMC deficient kids. And so this was the very first study 2016.

And you can see the two POMC deficient kids here. Okay. Patient one at 18 years old is 160 kilograms folks.

Okay. And patient two is 145. And you can see that patient one has been treated for 40, 42 weeks and has lost 50 kilograms.

And patient two has been treated for 12 weeks and has lost more than 20 kilograms. We have not seen this level of pharmaceutically assisted weight loss since the leptin was given to the original leptin deficient child. And it has really excited and energized and energized the field.

Now, if you start to think about the fact that 200,000 people potentially in this country have it, and you begin to look in other parts of nature, you begin to realize not only is the pathway of the leptin melanocortin pathway conserved, genetic tweaks, genetic variation within the pathway to influence feeding behavior is also a conserved mechanism throughout nature. So let's take a look in agriculture. Just one example.

Okay. There are some pigs, okay. That have a particularly favorable fat to lean mass ratio and are good for bacon, for example.

Okay. That have mutations in the MC4 receptor. Why? Because farmers don't, this is not a genetically modified pig.

The farmer has selected a specific trait growth rate, you know, fat to lean mass ratio. As I said, they just happen to have mutations in the MC4R because it has resulted in that trait. And this is not a mammalian specific thing.

Okay. No, let me introduce you to the blind Mexican cave fish, which begs two questions. Why are they blind? And why are they Mexican? So that giant asteroid that actually smacked into the, and killed all the dinosaurs 65 million years ago, hit in where is now the Gulf of Mexico.

Okay. Hence they're Mexican. Now, when they actually hit, they formed cracks in the bottom of the ocean, which filled with water and became underwater caves.

And some fish were stuck in these underwater caves. So in these underwater caves, there's no light. So over the millions of years that have since passed, the eyes of these fish evolved the way, hence they're blind Mexican cave fish.

But why am I telling you about this? Because not only are these caves lacking in light, they're also lacking in food. There's very little food down there. So any fish that was remotely blasé about the plankton that was floating by and didn't snap it up immediately, became an X fish.

All of the blind Mexican cave fish, they have mutations in the MC4 receptor. It has kept them alive. Let me ask you this question.

Where is the choice? Where's the choice? This is a fish caught in the wrong place at the wrong time, or the right place at the right time, depending on how you want to look at it. This is a pig. The Labradors were being selected for by humans.

200,000 people in this country have hardwired feeding behavior, ladies and gentlemen. This is not a choice. It's a hardwired genetic response, genetic adaptation to the environment we're actually in.

Now, in the last five minutes, I just want to touch on polygenic body weight, polygenic obesity, because the vast majority of our body weight is not determined by single genes. It's relatively rare. Not super rare, as I've talked about, 200,000 people, but relatively rare.

And we now have a good idea about and a good understanding about what we call polygenic obesity. This is a Manhattan plot, which is a way of looking at polymorphisms. These are not mutations, just to be clear, within genes.

Now, I have studied a gene called FTO for the past 17 years, and it's not a polymorphism because half of you listening to me will carry the risk factor for FTO, making you on average a kilo and a half heavier than the person sat next to you who's not, and 25% more likely to end up with obesity, half of you. All of you will have some mix of these genes, but I just wanted to highlight two of them for you. There is POMC of Labrador fame, and there's the MC4 receptor.

Blind Mexican cayfish takes 200,000 people in this country. It's the leptin melanocortin pathway. So while severe mutations result in severe phenotypes that I've showed you, very, very subtle polymorphisms influence where we sit on a normal distribution of body weight.

And you can now create these polygenic risk scores. If you actually add up all of the different risk alleles together and plot it against the MI, what you see is a linear relationship, which begs the question, can we actually find people with high polygenic risk scores and predict if they're going to end up with obesity, do something about it? And the answer at the moment is no, because while a lot of companies, such as 23andMe, are out there making predictions, all of them fundamentally misunderstand the difference between population level risk and individual predictability. So we can't equate one to the other, certainly not yet.

So listen, am I giving anyone any excuse? Let's go to those two questions I asked at the very beginning. Am I giving people an excuse? No. You got to consider your genes like a hand of cards in poker.

You can have good hands, you can have bad hands, and the only people you can blame them, the only people you can blame are your parents, which is who gave you the genes to begin with. But it doesn't matter if you have a bad hand at poker, you can still win. It is just more difficult.

I'll give you another analogy. I will never, ever run as fast as Usain Bolt, okay? And there's my genes and I'm sticking to it. But it doesn't mean that if I train, I won't run faster than I do now.

So people who study, people misunderstand what you can do with genetics. Genetics does not give you a point in space and time. It does not determine who you are, okay? Genetics, of course, brackets a set of possibilities.

Why am I bald? Because of my genes. Why do I look Chinese? Because of my genes. But within that bracket of possibilities, you can move up and down, okay? Are you rich or poor? Do you have kids or not? Do you commute to work? Et cetera, et cetera, okay? That is what geneticists are trying to do to understand the bracket of possibilities.

So my final thoughts, how about obesity being a choice? Are we all sinners, given the rise in obesity? What is a sin? I'm not a religious person. What is a sin? A sin is something you choose to do, even though you know it's bad. And this is me choosing to eat a slice of pizza.

And I say body weight, food intake behavior is not a choice. And you're saying, well, of course it is. You're choosing to eat a slice of pizza.

Listen, folks, we do not gain or lose weight overnight. We just don't, okay? Our body weight is the function of thousands of different feeding events that have happened over the past few years. But just imagine that because of your genetic hand of cards, you are 5% less likely to be able to say no to the slice of pizza.

One in every 20 times you said, hang it, I'll have the slice of pizza. 5% over thousands of feeding events is hundreds of thousands of calories, which is why some people are small, medium and large in the environment. It doesn't change the physics.

We still need to eat less to lose weight. But until we as a society understand that for some people, it is always more difficult than others, that people with obesity are not bad, morally bereft, slothful, but are fighting their biology. We will never ever fix this global pandemic of obesity.

And this is me choosing to eat a piece of broccoli. At that, I want to thank my colleague, Steve Arathi, Tony Hall, the guys, my team are in bold here and the rest of the team. I'm funded by the Medical Research Council and WPSRC.

And for those of you who want to listen more, I also have a podcast called Dr. Chow, so you'll choose the fact where you can get from all your normal Spotify, Apple and other places you get your podcasts from. It's a pleasure to speak to you. I'm so sorry I couldn't do this live.

Thank you very much. OK, so did that work for everybody in the end? OK, everybody here, Giles, nice and clear. Fantastic presentation.

Yes, thanks. It was really excellent. Yeah, he's fantastic, Giles, and he has offered to answer any questions.

So if anybody would like to send anything over to me, he would, I'm sure, be happy to answer any questions. He's really apologetic that he can't be with us today. He had to go to work, but he's here to help us.

Planned to be, but is fortunately or unfortunately, probably fortunately, stuck in the Netherlands. So he's having some difficulties with travel at the moment. So yeah, his podcast is definitely worth listening to.

And his books are fantastic if anybody would like to read them at any point. OK, so we are next going to pass the floor over to Alessa. So just let me put your bio, Alessa, in the chat here.

Can you hear me? Yeah, that's perfect. OK, cool. I'm sorry I lost my voice for some reason, but I will do my best.

Lovely. Not completely, but. You sound fine, nice and clear, thank you.

OK, cool. So welcome. Thank you so much for joining us.

If you would like to share your screen and get started. Yes, let me see the questions at the end. Can you see something? Yeah, it's just loading now.

Yeah, perfect. If you can just pop it into presentation mode for us. Can you see right now? Yeah, perfect.

OK, good afternoon, everybody. I would like to thank the organiser to give me the opportunity to speak today and I will talk about the interplay between energy intake and energy expenditure. This is the outline of the presentation.

I will touch some of the introduction we can kind of just heard about in the fantastic previous presentation. And then I'm going to talk about the measurement of energy expenditure, the regulation of energy balance from static to dynamic model, the energy sensing mechanism and some of the metabolic phenotypes. This is the first slide everybody knows, I guess, in this webinar, the obesity is now a global epidemic.

And then these are our recent data from the WHO in 2022, showing that there is an estimation of 50% of adults are living with overweight or obesity. And on the right side of the panel, almost a quarter, 23% of adults in the European region are living with obesity, as we can see here from this nice graph. There are many factors influencing obesity, which is not a single disorder, but a heterogeneous group of conditions with multiple causes.

So body weight is determined by an interaction between a lot of different factors such as genetic, environmental and psychosocial factors, acting through the physiological mediators of energy intake and energy expenditure. So today we'll talk more about the metabolic rate and the food intake, as we can see over here. Now, as we saw in the just heard about in the previous presentation, obesity can be described as the result of a long term imbalance between energy intake and energy expenditure.

And that's how I will focus today on this crosstalk between these two components. Sorry to disturb you. Can you pop your presentation into full screen? I think some of the attendees are struggling to see it.

I think it's in presenter mode rather than full screen. Like this one? What? No, wait, let me. I'm sharing this.

Let me see. What about now? No. I'm not sure.

Now? Yeah, that's better. I'm not sure what's the problem that you cannot see the slides or. Yeah, no, that's perfect.

I think it was just coming up in a slightly, slightly too small. So in the full screen, it just makes it clear. Oh, so is this fine now? Yeah, that looks good to me.

Thank you. Sorry. That's fine.

Can I go on? Yeah. All right. So.

So I was saying that we will talk about the interplay between energy intake and energy expenditure. So I want to show you this picture is the first paper published in 1986. This is the first paper actually showing the determinants of the 24 hour energy expenditure in man.

And these are the original pictures from the first metabolic chamber, which is still in Phoenix. And this paper was published by Eric Raussing on the left side of the panel and Clifford Bogardos, which is the actual branch chief still in Phoenix. And these are the old pictures of the chamber.

And the Phoenix respiratory chamber based is based on the principle of open circuit indirect calorimetry, which we are going to show you in a minute. I am happy, actually, to show you also this one, which is the one that we just built with a lot of difficulties in Pisa, the University Hospital of Pisa. And this is the one that we are running right now.

What's the what we are going to measure in the chamber and how does it work? So basically, it's kind of simple. The subjects as the human being, you know, enters in the chamber and then, of course, breathe. So we consume oxygen and then we exhale CO2.

And what the chamber is going to do, actually, is the is the calculation between the hair, which is going to go inside. And then at some point, you know, there is an indirect calorimeter, which is going to measure also the expired hair, which is the one that is inside the chamber, mixed with the expired hair that the subject is going to throw out. And everything is going into a computer.

And then what we have out as a calculation is the respiratory question. I'm going to show you in a minute. And the energy expansion, of course, everything is controlled by airflow controller for, you know, the air going into the chamber and the air going out of the chamber and the software.

It's called color cue, which is the one who that is going to calculate and pull out all the results. So, again, while we measure, this is one of the most important thing, I guess, in the measurement of the energy expenditure also for the total one. And then it's called the respiratory question, which is the ratio between the oxygen, the CO2, the volume of the CO2 of the subject and the volume of the oxygen is also very important because it's an estimate or it's measurement of the ratio between carbohydrate and lipid oxidation in humans, as we can see here from this cartoon.

We have we use values from zero point seven, as we can see here, when we have a pure fat oxidation and then zero point eight, zero point nine, when the protein we have pure protein oxidation. And then we have the values of one value of one, which is the value when the fuel carbohydrate are carbohydrates are oxidized. But why it's really important, the respiratory question, because we do the mean for the measurement of the energy expenditure.

We do the mean of the oxygen and CO2 over 24 hour that the subjects consume. And then we use the 24 hour O2 and CO2 to calculate the 24 hour RQ, as I just said. And using the last formula, there are a few formula, but we use the last formula we put in this equation.

And then from this equation, we have the measurement of the total 24 hour energy expenditure. The 24 hour energy expenditure is composed by different components. We have the resting energy expenditure divided in in turn of cost of being arousal and sleeping metabolic rate, which counts for actually 60, 70 percent.

And then we have the thermic effect of food. So basically the energy that we need to digest and absorb nutrients, which counts for five, 10 percent. And then lastly, we have the physical activity, which counts for 20, 30 percent.

And this is what we measure inside the chamber over 24 hour. And this also is just a representation, is just like a trajectory of one real person inside the chamber. And then, as we can see here, we have the little increase of energy expenditure after breakfast.

And then we have an increase during lunch, goes down and then goes up again during dinner, during snack at 7 p.m. And then goes down when the subject is sleeping. Now, when we talk about the energy expenditure, I guess this is the most important thing from again, the first paper on this argument, which is the paper of Robinson in 1986. And then in this graph we have in the X axis, the fat free mass.

And then in the Y axis, we have the 24 hour energy expenditure. And as you can see here, this is a positive, strong, positive association between these two components. This means that the fat free mass is the major determinant of 24 hour energy expenditure, explaining almost 70 percent of its variance.

And then we have some other variables such as fat mass, gender age and ethnicity, additionally account for the five, for five percent. Now, how is regulated the energy balance? So at the beginning, we, as always been described as static model. But then let's see how we move on the dynamic model.

So the static model suggests that a chronic positive energy balance leads to an increase in body weight and development of overweight, obesity due to the storage of energy surplus as body fat. So basically, this means that if you eat more and then compare that to what you spend, you increase your body weight. But this model assumes that variations in caloric intake and physical activity independently modify the components of energy balance.

In our obesogenic environment, which everybody lives today, I guess, such a perfect matching is not is not simple to achieve. Right. So actually, it's barely achieved.

So the adipose organ, the adipose tissue serves as dynamic energy depot that constantly conveys signals to the central nervous system, as we so heard about in the previous presentation, to communicate the amount of energy stores and to elicit compensatory response, trying to protecting against the unavoidable deviations from the balance equation. And that's why we kind of move now to the dynamic model of energy balance and the energy intake and energy expenditure now are dependent on each other and are regulated by a more complex and intricate model, which aims to maintain the body weight and body energy stores within a definite range. So basically, the conservation of energy equilibrium can be considered a dynamic process in which variations of one component, which can be, of course, energy intake or energy expenditure, cause biological and behavioral compensatory change in the other part of the system.

So basically, this means that, you know, if you have an increase in energy expenditure, your body trying to increase the energy intake and vice versa. And the same thing in the other end is that if you have a decrease in energy expenditure, you need more food, you know, to do your things all over the day. But how this can be described.

So I will talk a little bit about the energy sensing mechanism, because it's important to show that from an evolutionary point of view, the link between the energy demand and caloric intake would guarantee an adequate food intake in a variable life context through this energy sensing mechanism that aims to preserve life and reproduction. So that's why recent studies I will show you in a minute have hypothesized that energy expenditure as reflective of the body energy demand plays a role in regulating food intake by conveying peripheral signals to the central nervous system to modulate anger and satiety signals and so on. But to understand this mechanism, we need to kind of go back in 1988.

This is again, Eric Robinson in 1988. In these landmark papers showing the association between the resting metabolic rate and the body with the body weight change, in this case, gain. So basically what they did in this paper was group this Native American population.

It was on this paper was done in Native American population. So basically, they divided these subjects in three groups, low resting metabolic rate, middle resting metabolic rate and high resting metabolic rate. And as you can see here, what they showed was that people who add low resting metabolic rate, as you can see here in the black squares, they add higher percent of body weight gain over time compared to the other two groups.

So middle one, middle resting metabolic rate in the white circles and high resting metabolic rate in black triangles. So basically, this was one of the most important paper showing that the reduced rate of energy expenditure was a risk factor for body weight gain. But the thing was that it's kind of apparently opposite result showed by Luke in 2006, analyzing or evaluating Nigerian lean population.

And what he found was actually the opposite result. So the resting energy expenditure was positively associated with the weight change per year, as we can see from the main figure of the paper. Now, and the question now is, is it therefore possible then that a relatively higher energy expenditure may increase hunger, even leading maybe to a greater than necessary intake and eventual weight gain? I will show you some data from the NIH group of Jonathan Krakow.

So basically, this one, the first one from Christopher Weiser in 2014, who evaluated the relationship between body composition, 24 hour energy expenditure and food intake in 127 individuals non-diabetic. What we found, what they found here was that the fat free mass index was positively associated with the caloric intake. This study was, the food intake was measured in ad libitum with the vending machine.

So fat free mass, positively associated with the caloric intake. And on the other side, the total energy expenditure of these subjects was positively associated with the caloric intake. So both of these two measurements, fat free mass and total energy expenditure, were both associated with the caloric intake.

And Piaggi in 2015 found another interesting thing because he wanted to evaluate these relationship altogether. So the relationship between fat free mass, energy expenditure and energy intake. And this paper was done in 107 subjects with obesity.

And what was the results of this study? So he performed a mediation analysis trying to quantify the effect of fat free mass on energy intake, the direct effect, but also the indirect effect through the energy expenditure. And what was found here was that indirect effect of fat free mass on energy intake through energy expenditure. So basically this graph, this part of the graph right here accounted for 80% of the total effect of fat free mass on energy, on energy intake, compared to just 20% of the fat free mass directly to ad libitum food intake.

And the conclusion was the higher 24 hour energy expenditure rather than fat free mass induced greater diet and intake when food was provided ad libitum, kind of confirming this energy sensing mechanism. Now, the efficiency of this feedback is challenged by the clear evidence that most people in this obesogenic environment increase their body fat stores beyond what is considered physiological and healthy. And then in the same population of Native American, we had some follow up.

It was kind of two years, if I remember correctly. But what we found here was that this positive deviation from the energy expenditure food intake relationship is associated with weight gain. So in this graph, you can see on the X axis, the ad libitum food intake adjusted for 24 hour energy expenditure.

So basically counting the energy expenditure of each subject. And as we can see, it was a positive association with body weight change. So basically, people who eat more, the increase in body weight when you count the energy expenditure of those subjects.

So then the focus of the researchers or scientists was to try to understand the adaptive response of one component to change of the other constituent of the energy balance equation. And the next question was, are some people more susceptible to weight gain due to their energy expenditure phenotype? The answer, I think, is yes or maybe yes. And we need to try to get back the thrifty genotype phenotype hypothesis, which was an ancestral concept.

So the thrifty phenotype encompasses the idea that it was beneficial for body weight preservation to conserve energy, lowering the metabolic rate for, for instance, the hunter gatherer populations. But in today's environment, the thriftiness is no longer beneficial and would lead to excessive accumulation of energy stores that will never be dissipated. And assessment of the metabolic thriftiness may be better evaluated than during energy balance disequilibrium, which is actually difficult to measure in free living condition because, you know, we require careful control of food intake and precise measurement of energy expenditure.

But what they did was evaluated this disequilibrium under specifically controlled condition or extreme dietary interventions such as 24 hour fasting and overfeeding diet. And these studies, I will show you those in a minute, led to the identification of energy expenditure phenotypes that predispose to weight gain or loss based on change in energy expenditure during these kind of acute dietary interventions. These two papers, one from Chris Weyer and Martin Reinhart in 2001 and 2015, again showed these two different metabolic phenotypes, spent thrift and thrifty phenotype.

In this cartoon, we have here the 24 hour energy expenditure, we have the energy balance, and then we have the overfeeding diet and then fasting. So what are these two phenotypes? So the spent thrift phenotype or subjects are subjects that have a smaller decreases in energy expenditure during fasting, as you can see here, and larger increases during overfeeding. Compared to the thrifty ones, there is an energy efficient phenotype and these subjects are characterized by a larger decrease, as you can see here, in energy expenditure during fasting, a smaller increases in energy expenditure during overfeeding, as you can see here.

So we have two different phenotypes, metabolic phenotypes. I'll show you each study. This is the one of Martin Reinhart, so six weeks of caloric restriction in patients with obesity.

So basically, the reduce of 50% the energy need. And then, as you can imagine, you know, after 42 weeks, the percent each subject lost weight, as you can see here from this graph. And then, what he did, he divided these people into a group based on the median of the response of energy expenditure during fasting.

So basically, thrifty one in yellow and spent thrifty one in green. So basically, what he confirmed was that the thrifty one showed a larger decrease in energy expenditure during fasting, which was associated with the less percent of weight loss. Compared to the spent thrifty phenotype, who had the smaller decrease in energy, smaller decrease in energy expenditure during fasting with higher percent of weight loss and spent thrifty subjects also lost more fat mass and higher total energy deficit.

So the other one was done from Tim Alstein also in 2019, evaluating the six week low protein overfeeding diet. So basically, 50% more of the energy need for these subjects. And again, as you can imagine here, we have an increase in body weight after a few weeks of overfeeding diet and pretty much the same concept.

So basically, the thrifty one here, so people who had larger decrease in energy expenditure during fasting had an increase in weight gain and spent thrifty one, they have a less increase in weight gain. And the other thing is the spent thrifty subjects gain also more fat free mass. In conclusion, so the energy intake and energy expenditure are dependent from each other and are regulated by a dynamic model.

Energy expenditure act as a regulator of food intake through an energy sensing mechanism that allows to adjust the energy intake to the energy needs imposed by change in the environment. And then I guess we have two different metabolic phenotypes. So the thrifty one, which is an energy saving phenotype more prone to increase in body weight development of obesity and spent thrifty one, which is a wasteful phenotype more resistant to weight gain.

I'm not saying that the static model is not true anymore, but I think I guess it's a lot of different factors which can lead to the obesity development. Now, this is, I think, a good thing to say different mechanism in the research point of view. But I guess that in clinic, what we do is trying to help people to lose weight because obesity has a lot of comorbidities and we need to help those people.

We have some strategies. Of course, lifestyle is the most important thing, exercise, nutrition. We had a lot of different options right now.

We have a therapeutic approach with some drugs and stuff, and then we have also the bariatric surgery. But I think that we need to be careful because the weight reduced state elicits a complex response of anger, increased metabolic efficiency and reduce energy expenditure, which together may favor the way to gain if the subject is not taught to do a good lifestyle, which is, I think, the most important thing, because this mechanism is called metabolic adaptation. It's really important.

And Silvia Bettini is going to talk in a little bit about this. I guess I will thank you all and I'm happy to take any questions. That's lovely.

Great. Thank you so much. Do we have any questions for our second speaker there? We can either raise your hand or pop them in the chat, whatever's easier.

We do try to keep these webinars quite informal, so please feel free to unmute and ask away if you do have a question. Lisbeth, should we come to you first? Hi, Lisbeth, go ahead. Hi, thank you so much for this excellent presentation.

I was wondering, as you probably are aware of the biggest loser studies where people lose like 40 kilograms of weight or 60 kilograms of weight and regain after six years 40 kilograms again. And also the metabolic adaptation plays a role, probably also due to lowering of the resting energy metabolism. However, those who regained their weight were not the ones who decreased the most in their resting energy metabolism.

Do you think your whole hypothesis and the data you showed on the thrifty phenotype and spent thrifty genotype might be also related to this? That maybe it's more, of course, these numbers are on average, that it should be divided more in subtypes to understand. Do you have an explanation, another explanation for it? Well, yeah, thank you for the question. I think that, well, there was excellent study, the biggest loser.

Also, there was a metabolic adaptation after six years, but I think that maybe Sylvia is going to talk later on. I don't know, but I think that it can be maybe related to this type of different phenotypes. Based on what you just said, because I think this is kind of genetic thing, you know, like it's kind of these people, we don't know actually why.

But based on this study, which, you know, we conducted in Phoenix because I spent five years in Phoenix. So this is all the studies from the group of Jonathan Krakow was kind of tricky because you don't really know why, you know, these are two different phenotypes. If you ask me what I think about the metabolic adaptation after this weight loss, I think that it can be related to that, but I cannot give you some other explanation because I don't know.

I don't think anybody knows actually. Yeah, still mystery. Yeah, thank you so much for your data.

It's excellent work, which you showed. Thank you. Thank you.

Any other questions from participants? I guess we can always come back at the end as well and see if there's any general Q&A after the next presentation. Okay, so can you just, we'll just get you done and then we'll get the next speaker on. Lovely.

So I put your speaker bio in the chat already, just because I'm conscious of time this evening after my technically slow start. So Sylvia, I'll pass the floor to you. I'd just like to show you something.

When you're ready. Thank you. Okay, can you see the full screen? Yeah, looks good.

Lovely. Thank you. Okay, perfect.

Okay, good afternoon, ladies and gentlemen. Thank you for the invitation. I'm delighted to be here.

The topic of my presentation is metabolic adaptation during and after weight loss. It was demonstrated that weight loss is accompanied by a reduction in energy expenditure, not accounted for the changes in body mass composition and difference between observed and predicted energy expenditure predicted by fat mass and free fat mass values. It's called metabolic adaptation or metabolic glowing.

Metabolic adaptation has been observed both in patients with and without obesity after voluntary starvation experiments, after diet and exercise, and after biopsy surgery. Today, we'll focus on the last two items. In this study, as we can see before, the authors investigated resting energy expenditure changes in 16 people with severe obesity undergoing an intensive diet and exercise intervention as part of the biggest loser televised weight loss competition.

The participants rapidly lost massive amounts of weight. Resting energy expenditure was substantially reduced at the end of the competition, indicating a large degree of metabolic adaptation. And despite a significant amount of weight regain at the follow up, six years later, resting energy expenditure remained suppressed and metabolic adaptation persisted.

Despite bariatric surgery being considered the most effective therapy for inducing and maintaining long-term weight loss, several studies described a reduction in long-term resting energy expenditure after both laparoscopic sleep gastrectomy and Roux-en-Y gastric bypass. In our previous study, we investigated body composition changes and resting energy expenditure before and one year after sleep in 154 patients with severe obesity. A predictive equation for resting energy expenditure before sleep was computed by using the baseline body composition, free fat mass and fat mass values, and by entering the individual post-surgery body composition values in the predictive equation, a predictive post-surgery resting energy expenditure was then calculated.

The metabolic adaptation was defined as the difference between measured and predicted post-weight loss resting energy expenditure. We demonstrated that resting energy expenditure was reduced after one year, indicating a degree of metabolic adaptation, calculated as the difference between the measured and the predicted resting energy expenditure. Also in this study, Chu and colleagues demonstrated a significantly decreased of resting energy expenditure and the presence of metabolic adaptation one year after both sleep and gastric bypass.

In the same way, Tam et al. analysed metabolic adaptation in 40 patients treated with gastric bypass and in 13 patients treated with sleep and found a greater than expected reduction of resting energy expenditure not explained by changes in body composition at six weeks after surgery in both groups and the suppression in resting energy expenditure after sleep and gastric bypass remained up to two years, even after weight loss plateau. On the other hand, other studies demonstrated no metabolic adaptation occurring after surgery.

In this study, not significant changes were observed in resting energy expenditure at years 1, 2 and 5 after bariatric surgery, in particular gastric bypass, probably due to patients maintaining a greater fat-free mass with a high metabolic rate. However, in this study, patients did not present severe obesity. As you can see, mean BMI is 28 and they substantially maintained weight.

It's worth noting that at present, very few studies have investigated whether the metabolic adaptation persisted a long-term follow-up after bariatric surgery, showing conflicting results. Indeed, it was demonstrated that resting energy expenditure declined precipitously at six months after bariatric surgery, but these changes were no longer significant after two years. Thus, the aim of our study has been to evaluate the changes in resting energy expenditure and to calculate the degree of metabolic adaptation occurring five years after sleep gastrectomy and speculate about the possible involved mechanisms.

Thus, we reassessed 47 out of 154 patients who participated in our previous study with one year follow-up and we collected all parameters of body composition, resting energy expenditure, physical activity, biochemical parameters in 37 patients. Thus, the final study was conducted in 37 patients. These are the characteristics of the 37 patients in the three time points, B1, one year after, and B5, five years after.

Patients displayed a weight loss of 30% at one year with a total weight loss of 22% five years after. Fat mass and free fat mass both showed a significant reduction between B1 and B5 one year after. However, while fat mass showed its light for the increase at B5, free fat mass remained unchanged.

Considering physical activity, activity increased significantly between baseline and B1 with more patients practicing activity in line with the current recommendations. In line, I mean, as you can see, according to physical activity guidelines for Americans. Followed by a relative maintenance in the long follow-up with some patients all practicing activity over current recommendations.

In particular, at five years, we were able to collect the intensity of the physical activity in a metabolic equivalent mass. As you can see in figure A, measured resting energy expenditure displayed a TH1 reduction one year after leave with a corresponding decrease of predicted resting energy expenditure of about 20%. This data showing a greater reduction of measured than predicted resting energy expenditure after weight loss and confirmed the presence of metabolic adaptation at B1.

The difference between measured and predicted being statistically significant, as you can see in figure B. On the other hand, no difference between measured and predicted was observed at five years, thus metabolic adaptation vanished. So, what are the mechanisms underlying the presence and the persistence or resolution of metabolic adaptation? The mechanisms underlying are still under investigation and several questions remain unanswered. The most likely suggested mechanisms are decreased circulating lip-lactin levels, negative energy balance, decreased thyroid hormones due to sympathetic nervous system activity, decreased catecholamine associated with weight loss, changes in substrate oxidation, contribution of beige adipose tissue and browning, and insulin resistance and degree of metabolic impairment.

Due to time constraints, we will consider only some items. The first, several reports suggest that in lean human subjects and patients with obesity, plasma-lactin concentrations decrease during caloric restriction out of proportion to the decline in total body weight or fat mass, and increase with refilling or long-term different insulinemia. Knuth et al.

compared the changes in lactin energy expenditure in 13 patients underwent either gastric bypass or participated in the biggest loser weight loss competition and demonstrated that metabolic adaptation was related to changes in lactin. Another important item is insulin resistance and degree of metabolic impairment. We previously showed that patients with pre-diabetes and diabetes showed a slightly higher measured resting energy expenditure than patients with normal glycemia at baseline.

As the previous speaker said, Paggi et al. described a positive association between glycemia and resting energy expenditure. The increments of resting energy expenditure described in subjects with high insulin resistance can be correlated to an increase in fat oxidation rate and gluconeogenesis induced by high free fatty acid concentration in blood.

Nevertheless, in our population, we did not find significant changes in respiratory quotient that represent an estimate of fat oxidation. We suggest that the improvement of glycemic control after sleep induced weight loss may cause a significant reduction in resting energy expenditure in measured resting energy expenditure. In fact, we divided patients according to their metabolic profile and we showed that metabolic adaptation was present only one year after surgery in patients with pre-diabetes and diabetes only and five years later metabolic adaptation vanished.

Furthermore, we noticed a correlation between metabolic adaptation and excess weight loss as you can see in figure A, but no correlation was seen with weight gain in figure B. Lastly, as you can see in figure A, we divided patients into two groups. One, those who were classified as sedentary or practiced physical activity under current recommendation in the figure and two, those who did physical activity in line or over with the recommendation in line in the figure. At WU1, so one year after sleep, we described a higher metabolic adaptation in patients who practiced physical activity under current recommendation and patients who practiced physical activity in line with current recommendation.

Moreover, in figure B, focusing on metabolic adaptation at WU5 and having data on MET at WU5, we divided patients in those with MET less than medium and those with MET higher than medium and we highlighted those patients who practiced less physical activity showed higher metabolic adaptation. Now, interestingly, we demonstrated that patients who practiced more physical activity more or in line with the current recommendations presented less metabolic adaptation both one and five years after the weight loss. This finding can be in contrast with the results observed in the biggest loser participants who showed metabolic adaptation despite high levels of physical exercise and we suggest that weight loss obtained by bariatric surgery associated with the lifestyle changes and increased physical activity may prevent the metabolic slowing.

Finally, I'd like to conclude by saying metabolic adaptation or metabolic slowing is expected after a lifestyle program, both in a short and in a long period. Most of the data demonstrated a metabolic adaptation after bariatric surgery in a short follow-up. Very few studies investigated whether the metabolic adaptation persisted in a long-term follow-up after bariatric surgery, showing conflicting results.

Our study demonstrates that metabolic adaptation is present only one year after surgery and only in patients with metabolic impairment, pre-diabetes and diabetes and disappears five years after and weight loss obtained by bariatric surgery updated with lifestyle changing and increased physical activity may prevent the metabolic slowing. Thank you very much for the attention. Lovely, thank you so much for another fantastic presentation.

We've had three really great speakers this evening. Do we have any questions from participants? I think I've not seen any come chat. Anyone's welcome to unmute and ask a question if they would like.

The biggest loser stuff's really interesting, isn't it? I think, do you think you would, if you had a patient come to you, do you think you would recommend them doing that type of camp slash intervention? I imagine it's a big talking point, isn't it? There's a lot of those types of things that you can go off and do these sort of camps and lose lots of weight in a very short space of time. Do you get people asking you for recommendations on things like that, patients in clinic at all? I don't know, excuse me, can you repeat your question? So I wondered with those that are working in clinics, whether they have patients, you know, ask for camp recommendations like the biggest loser sort of style approach. I just wondered how often patients ask to be, you know, sort of referred on to a similar sort of programme.

Whether that's sort of a popular question. From patients in clinic. Does that make sense? Yeah, can I go? Or was for everybody or for? Yeah, just generally.

Yeah, that's, that's a good thing to say. I mean, that's what I was trying to say in one of the last slide of the presentation, because I think that we have a lot of strategies now, you know, drugs and dietary intervention. But I think that if the patient at some point is not switching the brain, you know, to understand that he needs to do some, you know, strong physical activity, maintaining the fat free mass and all of that.

I guess it's kind of, you know, physiological to get the weight gain, the weight back, you know, so and then the thing is, in this case, I guess, the metabolic adaptation is still this kind of gap between the energy intake and energy expenditure, which at some point, long term, whatever it is, it kind of go back and some of the weight loss is going to, you know, to go up again. So I think the lifestyle actually is one of the most important thing. Of course, we cannot fight obesity just with that.

But I think it's one of the most important thing to, you know, to count. Yeah, so do I, if I can add, we can see that we want to emphasize that five years after the liver gastrectomy, patients get plenty of physical activity, because as I showed you, the mass median is over 2000. Considering that four mass get assigned to the time spent in moderate activities, patients trained over recommendation.

So our population, that so this factor can be explained probably because patients were encouraged to meet the physical activity guidelines. And we suggest our patients to meet lifestyle changes, diet and and physical activity and a balanced diet. It's very important, not starvation, a balanced diet.

Okay, we've had a question come in on the chat that says, I don't know which one of you would like to take this. But it says, could it be the slowing of RMR six years after weight loss in the biggest loser to be due to the participant was in negative energy balance for two weeks before the two sorry, two weeks before the six year examination, participants were asked to do a daily weight measurement for two weeks before the six year examination. So they may have reduced their energy intake and therefore slow their RMR.

Yeah. I guess I am. I said before, our, our finding is in contract with the drug, the results observed in the biggest loser participants.

And we suggest that weight loss obtained by bariatric surgery associated with lifestyle changes may prevent the metabolic adaptation that was just present in the biggest loser competition, nevertheless, the diet and the extreme physical activity. But the real mechanisms underlying the important difference between the biggest loser and the participants of this surgery, our surgery program, it's not clear. Now, we didn't know the mechanisms of metabolic adaptation.

And according to us, the mechanisms can be the metabolic impairment, so insulin resistance, and the presence of not only diabetes, but also polydiabetes. And it's very important to preserve fat to mass with physical activity. Probably the combining of the two mechanisms.

Yeah. Okay. Thank you.

Is there anything else to add before we close this evening? I don't see any other questions in the chat there. Is there anything either of the speakers would like to add? Are you quite, quite happy? Yeah. Okay.

So just a couple of housekeeping things before we close. Obviously, thank you so much to the pair of you that are on live and also to Giles for the presentation. They've been fantastic and a really another interesting topic.

I will share the recording on the SharePoint afterwards so everybody has access to that as part of the comms network. And also hopefully you've all received an email about the comms summit in September. It's the first one we're doing back in person since 2019.

So hopefully we will see a lot of you in Istanbul in September. I did send an email earlier in the week because we are offering funded accommodation places. So if you have any questions about attending that, if you just let us know, that would be great.

And the NAF or DISA survey for Andrea is also still live. So if any of you haven't completed that, that would be much appreciated. And we've got lots going on at the moment with the comms, but we are also looking to really expand these webinars and this platform to really promote all the centres talking to each other and sharing all of the fantastic expertise that we have.

So if you do have any ideas, anything you think would be helpful, any feedback or anything you'd like to share, please do drop me an email. Any ideas would be welcome. I know everybody's very busy, but it would be great if we could get the centres and the network as a whole working a bit more collaboratively together when we've got all of these excellent brains.

It would be a shame not to be using them all. So yeah, I think I'll close there for this evening. Thanks again to the fabulous speakers.

And the next one of these webinars is on the 28th of June and Maria will be going through the ASO's medical nutrition therapy recommendations. There'll be a section on adults, a section on children, and also a small section on methodology and how they put those recommendations together. So hopefully that will be of interest.

And we are then going to break for the summer. So there won't be a webinar in July or August because we're conscious it's a time of year where everybody needs to wind down and have some well-deserved holiday. So the webinars will then resume again in September.

So September's will be around the theme of the summit. So hopefully we can do some live streaming from there as well so people can have access for those that aren't able to travel. So thank you very much.

Good evening and I will speak to you all again soon.