The Pathophysiology of Obesity

Complexity of Obesity and Treatment Approaches

Set Point Variability and Weight Loss Maintenance

Obesity, Inflammation, and Public Health

Next Steps and Future Research

• Investigate the role of pharmacogenomics in predicting individual responses to obesity treatments
• Explore strategies to modify the body’s defended set point to improve long-term obesity management
• Examine the relationship between obesity and neural inflammation, including its potential reversibility with treatment
• Develop more effective interventions that integrate pharmacotherapy, surgery, and behavioural strategies
• Improve public health approaches by incorporating insights from neuroscience and genetics into obesity prevention and treatment

Transcripts are auto generated, if you spot an error, please email enquiries@easo.org

Thank you everyone, so nice to have so many of you to show up to this webinar. So I’ll just first introduce myself so you know who I am. So my name is Bram Berntse and I am one of the EASO ECN board members.

And today I’m joined by another board member, Georgia, and she’ll be later sharing some interesting upcoming opportunities. So for today, you can expect to learn about the traditional perception of obesity, the science underpinning the causes of obesity, and how to convince skeptics that obesity is a disease under the topic of pathophysiology of obesity. So on behalf of the EASO ECN board, we’re hosting these e-learning hub online events nearly every month, except for the summer and the winter breaks.

And we’re doing this to promote knowledge sharing and skill development among students and early-career professionals interested in obesity. The ECN is free to join, and so are the webinars, so please spread the word to anyone who could be interested. We’d just like to remind you that the webinar is being recorded, and the recording will be available afterwards, so you can access it later.

And this is an informal setting, so please feel free to ask any questions you would like to ask. You can either put them in the chat during the talk, or afterwards we’ll have 10 to 15 minutes, and you can also use your microphone, raise your virtual hand, and then ask your question in person. At the very end, we’ll ask you to complete a feedback form, it will pop up automatically after you leave the webinar, it would be nice if you could fill that in so we can improve our future webinars.

I will now hand over to Georgia, who will share some exciting future opportunities. Good afternoon to everybody. So I’m going to mention all the awards and opportunities that are available for the ECN members.

We strongly encourage you to keep an eye on them through the ESO website. So first of all, there’s going to be the ESO Congress, so the European Congress on Obesity, which is going to be held in Mallorca and Spain, and it is going to be between from the 11th to the 14th of May. So this is an amazing opportunity, there is still the chance to apply for late-breaking abstracts, the deadline is going to be February 28th.

But let’s move to the awards and travel grants you can apply for. Actually, the deadline for some of those is already expired, but we encourage you to keep an eye on the ESO website because those are going to be available every year. For example, we have the ESO Novo Nordisk Foundation New Investigator Awards.

The applications, again, have been closed and the applicants will be notified soon. We thank everybody who applied already. There is the ECN Best Thesis Award, for which the applications are closed now, but we encourage you to apply for this coming year.

So we thank everybody who applied already. The applications these years have been very, very competitive, very, very high quality, and it was very hard to make a decision. We also have two different types of grants available, travel grants that can be used by ECN members.

We encourage you to check on the ESO website. I’m going to share all the links for these specific awards and travel grants. Then there are other important opportunities that are training and career development opportunities.

Some of you may already have participated to the ECN Winter School this year, where there was also Professor Miras that was really, really appreciated by the audience. The next year, there’s going to be a similar opportunity. This time is going to be named ESO Masterclass.

So it is not going to be called anymore ESO ECN Winter School, but it is going to be called ESO Masterclass. This year, it will be held from the 20th to the 22nd of November 2025. Again, keep an eye on the website.

I’m going to share all the links that are necessary for you to follow all the updates. We recently launched also the ECN Exchange Programme. All accepted participants will spend three to five days in a specific research centre where they can exchange useful information concerning research or specific skills.

So all activities that may support their career. Applications for 2025 are now closed, but we encourage you to apply for this coming year, so for 2026. We also have an ECN Spotlight where we regularly interview ECN members about their research and share their information, their specialties with the obesity community.

So if you are interested to be interviewed, please get in touch with us. We also have a WhatsApp group for quick updates. Most of you may be already part of it, but we encourage you to take part of it in case you’re not.

And last but not least, please, if you are interested in joining the ECN board, you can apply through the ESO website. The deadline for application is going to be April 4th, 2025. If you are interested in taking an active role in the organisation of all the ECN activities during ECO and not only this, but also the one that I mentioned.

So thank you very much. I’m going to share all the links. All right.

Thank you, Georgia. So back to today’s presentation. So today we have Professor Alex Miras, who is affiliated with Ulster University and a member of the NICE Obesity Management Guidelines.

He will present on the pathophysiology of obesity and the fundamentals of obesity as a chronic disease. Thank you so much for joining us. The floor is yours.

Good. Thank you, Bram, Georgie and Lisa for the invitation. It’s good to see so many people and also some suspicious characters whose name I recognise.

So what I’ll do is share my screen first. So it’s late where I am. It’s late probably where you are as well.

So I don’t want, even though this is quite science heavy, I think we should try to enjoy it and have a nice discussion. Can you see screen and everything? Yeah, I can see it. Okay.

So it would be good to have good questions at the end. Now, I’m going to talk about the pathophysiology of obesity. And I’d like to start by saying that I’m not going to give you all the answers that you want because I don’t have those answers.

But what I’ll try and do is I will try to tell you the story from my perspective, the story around how the narrative about obesity has changed, the understanding of obesity has changed. And what I’ll do is I’ll try to do that with the best evidence that we currently have. The evidence that we have is still pretty primitive in regards to obesity as compared to other diseases.

But nevertheless, this is as good as it gets, I think, now. And I will try to tell you that story so that hopefully you can also use it when you’re speaking to colleagues or, as I was saying, other skeptics who will challenge you that obesity is not a disease and it is the person’s fault. And trying to convince skeptics is not easy because understanding is limited.

So these are my disclosures. Let’s go back to the 1400s and talk about another disease. And we will make parallel to that disease as we move through the talk.

This is the disease of epilepsy. And what you see there is… This is a real painting, of course. This is the patient having an epileptic seizure.

This is the mother very upset. These are the very smart doctors at the time who thought that it was the demon in the patient’s head that was causing them to have seizures. That was the hypothesis at the time.

And as a result, what they did is they invited the priest here to exorcise the demon, to remove it from the patient’s head in order to treat their epilepsy. Well, guess what? That didn’t work, unfortunately. The person continued to have seizures.

It took about 500 years before someone challenged that hypothesis and said, hang on a second, maybe we are wrong here because this exorcisation doesn’t really work. So, someone used an EEG and bingo, here we’ve got the pathophysiology, or at least part of the pathophysiology of epilepsy, which is abnormal firing of neurons in the brain. And it is only after you understand the disease that you’re actually able to treat it.

If you keep exorcising the demon, well, you’re not making much progress. So, now that we have understood the disease of epilepsy very well, it is a perfectly treatable condition in the vast majority of patients. People take their pills, and you’ll see there’s many of them, and they don’t have seizures.

They live an almost normal life. So, the typical perception that we have in medicine about diseases is that usually, not always, but usually, we know the organ that causes the disease, like epilepsy. The mechanism is abnormal firing neurons, electrical firing, and it is only the manifestation of the disease, which is the seizure, which is what we observe.

Let’s talk about the traditional perception of obesity. And what has always been considered is that this was not a biological issue. There was no organ causing the problem.

It was the individual’s fault, indulging in overeating. It was that that caused the manifestation of the disease, which is excess adiposity. But, of course, we were very comfortable in accepting that this excess adiposity contributes to all of the numerous conditions that are associated with obesity, that we very much respect as complications, and usually we separate them into medical, functional, and mental health.

Right. So, what everyone, or usually what the skeptics would say, is that suddenly, in the last 100 years, our environment has changed. And therefore, the BMI has moved, the BMI curve has moved towards the right, yes? So, the BMI in B13 now will be 25-20 previously.

But what I would like, this is obvious, I think. The change in the environment causing the shift is obvious, and we need to address it and do things to try and minimize its effect. But that’s easy.

What I would like you to do is to think about this in a different way, and just concentrate on what happened 100 years ago. Don’t compare it to what’s happening now. And what you’ll notice is that even though when food was not as easily available, it was expensive, and it was certainly not as tasty as it is now, even then there were people that managed to develop obesity.

So, the question, my question, is why on earth wasn’t everyone thin or underweight, right? Considering the environment that people lived in. Moving now to 2025, forget about 1925, and we are all, certainly in the Western world, pretty much surrounded by the same environment. We do live in small micro-environments that might be different, but pretty much our environment is the same.

We’re surrounded by the same cues. So, despite those, not everyone has developed obesity. Surprisingly, there are people that are of normal weight, there are people who are underweight.

So, my question that I would ask usually when we would be in a live audience, I would say, in the same environment, what are the factors that are controlling body weight? Because in the same environment, you cannot blame the environment. That’s the same. It has to be something else.

And this is where things get interesting. So, let’s go to some old studies now. You might have seen this picture many times, but this picture tells us many beautiful stories.

So, these were twins, fraternal twins that share some of the DNA, and identical twins share a lot of the DNA. They were raised in different families, different environments, for whatever reason they were separated at birth. And then they were brought back together just for the purposes of the study.

And what you see here in the fraternal twins is that they have different heights and they have different weights. And the question is, is it the biology that caused that or is it the environment? Well, it’s impossible to say because both were different. So, we cannot draw any conclusions from this.

But if you go here to the identical twins, what you’ll notice is that they have got very similar heights and very similar weights. In fact, the correlation, so the similarity in their heights is approximately 80%. And the similarity in their body weight is approximately 70%.

So, this together with other studies that have been performed in the field of genetics are now telling us the heritability of body mass index being somewhere in the range of 70%. And let me put this heritability number into actual, a meaningful number. What I mean by that is that 70% of where we are in this range of BMIs that I showed you earlier depends on biology.

It depends on our genetics. So, it depends on factors that we cannot control. Sometimes when I say that people get very upset because they think it’s depressing.

Well, it is as depressing as learning that it’s not the demon that’s causing epilepsy and it is abnormal firing in the neurons. Because if we understand the disease of obesity better, we will be able to treat it better. So, let’s try to go through this story.

So, most people that you will see, perhaps in your clinical practice, if you see patients who are going to have this kind of obesity, which is polygenic, it means they have got a lot of, a big number of genes, right? That are known to cause obesity. Each one of them contributes to obesity by a small amount, say one or two kilograms. But if you have got a lot of those genes together, you get the phenotype.

There is another more rare form of obesity, which is monogenic. And in that one, you have got usually one gene that causes the problem, but it is a really big effect size. A good example being melanocortin-4 receptor deficiencies.

Let’s get some evidence about the contribution of genes and our biology to body weight. This is a really good paper. This is a Framingham cohort that was studied in the US.

About 2,000 or so people. And they tracked their… They did two things. They tracked their weight over the first 25 years of life.

But then what they also did is that they genotype the participants. And they counted the number of genes that are known to cause obesity. And people got a high polygenic score here, a medium polygenic score, and a low polygenic score.

So here we are high, medium, low. Now, what you need to appreciate is that the mixture of environments in these three curves that I’m showing you was similar. So people were raised in good neighborhoods, bad neighborhoods.

They were raised in good schools, bad schools, different parents, etc. So the environment was equally spread between the three curves. So we cannot blame the environment for what we are observing.

So have a look at what’s going on here. For the first eight years of life, you will see that the three lines, the three curves are pretty much on top of each other. It is only after the age of eight that they start to diverge.

And you’ll see in the dark blue line here, the high polygenic group ends up weighing about 12 kilograms more or so compared to the low polygenic group even within the first 18 years of life. If you now follow these people up for longer, this is again the same study, what you notice is that the high polygenic group goes up to develop about a 16% rate of obesity as compared to only 1% in those with a low polygenic group. So this is a really powerful study demonstrating the point.

Again, now if we were in a live setting, I would ask you, okay, so if we think that genes play such an important role, where do they work? We all have the same genes in all of our organs, in all of our cells. Where do these genes wake up? And normally I would hear the answer would be, oh, you know, it’s in adipose tissue, it’s in the brain, it is in endocrine systems or the gut. And these are all perfectly reasonable answers.

And this is again another beautiful study that demonstrates exactly that point, that these genes express themselves in a number of organs, as you see here, but the place that is dominant in terms of their expression is the central nervous system. It’s not exclusively, but it is dominant. Okay, so these are the risky genes working in the central nervous system.

The next question that I was going to ask you was going to be, where in the central nervous system does it happen? Where do these genes wake up? It should not be a surprise to us that they wake up in the areas that we’ve known for decades control our body weight. This is a complex network of areas, but to put it simply, we’ve got two key areas that control our body weight here, the hypothalamus and the brainstem, the nuclei here in yellow. And we also have got the reward system, but also the system that responds to external cues.

We’ll talk about that in a sec. But these are the two key areas, and they have got three ways of controlling our body weight. They can do that by changing hunger, fullness, and energy expenditure, okay? And remember, these are nerve cells.

We’re working in the brain here. This is not adipose tissue. It’s not endocrine tissues.

This is brain. So this is where the biology takes place. Now, we should not forget that, even though I said that about 70% of our body weight is regulated by factors we cannot control, we have got environmental cues here in blue.

And even though their role is not as high, it’s not as big as we previously thought, they are still there. And these are things that we can manipulate if we want to prevent obesity, but also reduce obesity in people who have it. So we’re talking about stress, emotions, etc, etc.

We’ll talk about some of those things in a sec, but I would like to focus a lot on the biology aspect of things, which I think is dominant. So we said that these cells have got abnormal genes that contribute to obesity. This is, again, a slide of the brain demonstrating to you that, again, we’re working in nerve tissue, in neural tissue.

But let’s be more specific. We’re working in the white matter parts of the brain. Again, it’s too late.

This is not a neuroanatomy or neurophysiology lecture. But remember, we’ve got two types of matter, white matter here and gray matter here in the cortices. This is the matter that helps us think, go to the university, make decisions, and perform higher function.

The white matter of the brain is involved in more automated stuff. So to give an example, the Mandela-Blongata here, you may remember from your physiology, is involved in controlling our respiration, our respiratory rate. So let me give you the typical example I give to make this more interesting.

Hopefully, imagine that someone comes to you and says, well, I’m going to give you 1 million euro if you stop breathing. Then your cortex here is going to think, well, that sounds like a pretty good idea. I wouldn’t mind having a million euro.

It would help me do a number of things. And what we will do, the gray matter part of the brain will suppress the Mandela-Blongata. It will tell the Mandela-Blongata, stop breathing.

And indeed, you will be able to do that for a number of seconds. But at some point, the signals from the periphery, the oxygen levels, your CO2 levels, et cetera, will start to change. The Mandela-Blongata will realize that, will sense it.

And it will eventually override what the gray matter is telling you to do. It will override what you are asking the Mandela-Blongata to do, because it is, from a revolutionary perspective, not very smart. And you will start breathing again.

So when we tell people with obesity to eat less and more and lose weight, well, it’s not as if they haven’t thought about it themselves. And what happens is that the gray matter parts of the brain in exactly the same way tell the hypothalamus and the brainstem that control body weight to keep quiet. We’re going to lose weight.

And as a result, our health is going to improve. But what happens is that, unfortunately, typically, when weight is lost through caloric restriction, and to be clear about that, when weight is lost through caloric restriction, there are a number of changes that take place, more specifically coming from the periphery, a little bit like oxygen and CO2 here. We’ve got hormones amongst other factors that contribute to the signaling from the gut and the adipose tissue to the brain.

When leptin goes down through weight loss, we have got increases in hunger, decreases in fullness that we will talk about in a sec. So let me go back to this slide again and tell you that, which is something that people find provocative, is that I consider obesity not to be a metabolic disease. I consider obesity to be causing metabolic diseases, but I consider obesity to be a neurological disease.

Because here is where everything happens. It is within the nerve cells. And therefore, by understanding this, we will be able to address this more effectively, hopefully.

And indeed, this is happening at the moment. So this is the modern perception of obesity. Hopefully, you will agree with me, is that finally, we have understood that the dominant organ, not the only organ, but the dominant organ that causes obesity is the brain.

It is the brain that causes overeating. Overeating is the mechanism of the disease. And by the way, I cannot find, I hope this is not stigmatizing, I couldn’t find a better figure of overeating.

If you can find one, let me know. So overeating is the mechanism and the manifestation of the disease is exosadiposity. The disease of obesity doesn’t live here, in the same way that the disease of diabetes doesn’t live in glucose.

The disease of obesity lives here, in the brain. This is just the manifestation. So again, people think this is a little bit disappointing, a little bit depressing.

Okay, so what happens? How can we try to work through that system to cause positive changes to our patients? Well, let’s talk about set point theory or set point probably fact, I would say. It’s more than a theory. The set point theory is one that tells us that our body weight throughout life is, again, as I said to you earlier, determined by a very substantial degree, predetermined by our biology.

The environment is there, but the dominant role is that of the biology. And what happens is that the body will do everything possible to defend that set point if we try to change it through behavioral means. What do I mean by that? Let me give you an example.

We’ve got two ways that we can do this. Either one way, when we are putting on weight, when we’re overfeeding ourselves, or when we’re starving ourselves. So imagine you probably have seen actors that are almost forced to overeat in order to put on weight, in order to play a particular role in a film.

And they do that for a number of months. In fact, what they will tell you is that this is one of the most unpleasant things they’ve had to do, similar to when people are starving themselves. What will happen eventually, however, after the film has been completed, is that these people’s hunger will go down, their metabolism, which means their energy expenditure, will go up.

And as a result, they will go back down to their predetermined set point, despite their attempts to put on weight. If we go on the opposite side, which is what we most commonly are involved with, when people are asked or decide themselves to eat less, just to reduce calories, eventually what happens is that the opposite from what happens with overeating. Hunger will go up, as I have just explained to you.

Energy expenditure will go down. And as a result, their body is pulling them up to the set point that they are meant to be. Are all of these things that I’m telling you my opinion, or is there any evidence behind them? Well, let’s have a look.

This is a superb study. It’s now 30 years old. And in very controlled experimental conditions, the two participants, they made them eat a lot, and they put on 10% of their body weight.

Then they made them eat less, and they returned to their initial weight during the course of the study. Then they ate even less. They lost 10% of their body weight, and then they lost even more, 20% of body weight loss.

And what they did as part of this study is they measured people’s energy expenditure. And what you see here is that the change in energy expenditure, this graph is change, you see that there is no change. Initial weight energy expenditure change is zero.

Look what happens when people put on weight. There is a very significant increase in energy expenditure trying to sabotage what these guys are doing, which was trying to eat more. When they have lost here, when they have gone to their initial weight, right? Here we are here, energy expenditure goes back to what it was.

When people now going there on the other direction to eat less, the energy expenditure will do exactly the opposite. It will go down, and the same will happen with 20% weight loss, and it will go down trying to pull them up. So I’m showing you here the biological mechanisms that are involved in trying to pull us back to our set point.

So that’s energy expenditure. What happens to appetite regulation? Well, this is another beautiful study done by Priya Smithon from Australia. It’s now 14 years old, published in the New England, and what they did in that study is they gave people a rather severe caloric restriction for a few months, and then what they measured was appetite regulating hormones, hormones like ghrelin that control hunger and increased hunger, and these other hormones, PYY, CCK, amylin, that are involved in body weight regulation, and they’re considered to be satiety hormones.

And what you will notice during a meal, a fixed meal, was that ghrelin levels went up during caloric restriction. PYY, amylin, CCK levels, satiety hormone levels went down, and if you ask those people, they will tell you that they were more hungry and less full when they ate. They were more preoccupied with food, and they were also more preoccupied with energy-dense food.

So these counter-regulatory mechanisms are illustrated very nicely in The Biggest Loser competition and the follow-up from that show. You might have watched it, or you might know about it. I believe it has been replicated in a number of countries, but this is from the US show, and what they did in that show, if you remember, they took people with a pretty high body weight, 140 kilograms as an average, and they really had a big go at them.

They were shaming them, caloric restricting them, and exercising them in a rather aggressive way. And as a result, well, unsurprisingly, people lost weight. They lost about 60 kilograms of their body weight, which is fantastic.

That was within the first 30 weeks of the show, and then the show ended. But then what they did, the study group here, is that they met these people for experimentation six years after the show, and when they met them again, first of all, unsurprisingly, they had put on a very significant amount of weight back on, not all of the weight back on, but a significant amount. And look what happened, more interestingly, in their energy expenditure.

This was their energy expenditure when they started on the show. As I have just shown to you, there’s going to be a reduction in energy expenditure when people lose weight, and therefore, as expected, that was their energy expenditure in week 30. But unfortunately, when these people were studied again, six years after the study, instead of their energy expenditure recovering and going back to pretty much what it was when they started, it stayed low.

What does that mean? This metabolic adaptation, which is disadvantageous, means that by doing this, so by just caloric restricting people, we are not just, we’re not only not helping them, but we’re actually doing harm. Because if you think about it, if you have a lower energy expenditure, next time that you want to lose weight, it is going to be even harder. So we need to be very careful as to what we tell people, because we may actually be doing them a disservice based on the science that we have.

So this is probably the most important slide of this presentation and possibly of any of the presentations that I give, which demonstrates a pretty basic concept. The concept can only be basic because our understanding is basic, which is that this system that controls our body weight is extremely sophisticated. If you think about it, it is deeply located in parts of the brain that are difficult to be affected by trauma or other insults.

So the body really protects the system because it is important for survival. So it’s a very sophisticated system. When we tell people to just eat less and exercise more, well, unfortunately, that advice is not usually sophisticated enough.

But the good news, and that’s why I don’t want people to leave this depressed, the really good news is that by understanding that this is the case and by understanding that it is not the devil or the demon that causes the person to overeat, we will be able to treat the condition better. So finally, we have got nutritional therapies, psychological therapies, physical activity therapies, pharmacological therapies, and surgical therapies that are sophisticated enough to work in that system. And they will only work on that system if they address the pathology, if they work in the neurons that control body weight.

And by working in the neurons, they increase fullness, they decrease hunger, they reduce energy intake, and therefore the patient loses weight. And I think a very good example of these advances, certainly the last few years, I’m sure you will agree, is the introduction of pharmacotherapy. And pharmacotherapy works exactly in those centers, that’s why it’s so effective.

We’ve known that actually for years because bariatric surgery for the last 60 years has been and still is the most effective treatment for obesity. And it works by changing the signals, some of the signals that I have shown you earlier on, from the gut to the brain. And again, it works directly on the pathology to reverse the symptoms of the disease.

So, finally, I would like to finish off by saying and discussing this issue about prevention and treatment. Because there is a school of thought that this is a fully preventable disease and all of the money and the resources should be going there. There are other people who think that we need to be doing more treatment.

But again, it’s always important to take care parallel from other diseases. Imagine that, in fact, let me start again, by saying that stopping smoking or not smoking in the first place is a very good way of preventing the disease of lung cancer. But imagine if someone came to your clinic with established lung cancer, a new diagnosis of lung cancer, and you told them that their treatment was prevention.

So their treatment was to stop smoking. Well, they’re not going to be particularly thankful. In fact, you will get into trouble because this is not the treatment for lung cancer.

The treatment for lung cancer is chemotherapy, radiotherapy, surgery, etc. Of course, it is very helpful to tell people to stop smoking because it’s not going to help the disease. But this is not the treatment.

The same with HIV and AIDS. And wearing a condom is a good way of preventing the disease. But if someone comes to you with a diagnosis of HIV, you don’t give them a condom because that’s not their treatment, right? You give them a condom to prevent the disease from spreading.

But their treatment is HIV pharmacotherapy. HIV is another, or was rather, a very heavily stigmatized disease. With years, we understood the disease better.

And now again, HIV is a perfectly treatable condition in the vast majority of patients through very good pharmacotherapy that we have. So the mistake that we make with obesity is that, first of all, we either say that this is only prevention or only treatment. And for any other disease, we don’t do just one or the other.

We do both. But that’s really obvious. But the other mistake that we make is when people come to us, certainly in the clinical setting, having established this disease of obesity, then we frequently tell them that their treatment is prevention.

That doesn’t make much sense. Now, there is, of course, room, as I said earlier on in the talk, there is, of course, room to manipulate the environment, to change things in order to treat. So the environmental changes can act as treatment in terms of stress, sleep, emotional eating, accessibility to food, et cetera, et cetera.

But I think what we also need to appreciate, considering the very dominant role that biology plays, is that we need to be treating both the biology and the environment The biology is very strong. We should not be forgetting that at all. And at the same time, we should be changing the environment to reduce the number of people developing obesity in the future.

So that’s it from me. This is the email that you can find me at if you have got any specific comments or questions. What I would like to do now is I would like to stop sharing and get back to you.

Let’s see how we’re doing with time. We’re not doing too badly. So I think we’ve got a reasonable amount of time for questions.

Thank you so much, Alex. We have plenty of time. It was a really clear overview.

Thank you. Even I could follow as a public health professional. I appreciate that.

So feel free. Everyone is available to ask questions. Let them come through.

I can ask the first one to kick us off if people are not ready yet to ask. So when you describe obesity as a neurological disease, I’ve been to some talks where they are debating whether there are multiple obesities. And so would you think that it could also arise in other organs initially? Or would you think that it’s more the physical manifestation of multiple different diseases, so to say, where it starts as a neurological disease and then trickles down to different and expresses differently in different people, right? Or do you think they could be different obesities actually in themselves? That’s right.

There are different obesities and we are now gradually discovering them. As I said, unfortunately, our understanding is primitive. But at the same time, it looks as if, despite the number of obesities available, it looks like the final common pathway for most, not all, but for most, the final common pathway tends to be the brain.

For example, people are taking… There’s a lot of drug-induced autogenic obesity, as we call it, right? So there are medications that people take, antipsychotics, steroids, etc., that are a specific form of one of those obesities that you have mentioned. But at the end of the day, the common final pathway from these medications is to increase hunger, decrease fullness, and cause overeating. They will also have additional effects on adipose tissue, I’m sure.

But I’m trying to demonstrate that our understanding so far is that the brain is the dominant organ involved in the development of the disease. But this leaves, of course, room for other conditions that we’re going to learn more over the next few years. And then, by understanding that, we will be able to treat these obesities differently in the way that we treat epilepsy differently, depending on the type of epilepsy, people.

Yes, thank you very much. Well, I see a hand raised, so I’ll let the people with raised hands go first. We also have a couple in the chat.

So please, Oziliki, go ahead. Hi, Alex. Thank you very much for your talk.

The set-point theory, I know there’s been a lot of discussion about that. People who have been on the pharmacotherapy and have managed to lose weight and then they come off the medication, how do you explain the proportion of people who remain with a low weight, despite coming off the medication? How do you keep that set-point? Yeah, no, that’s a very good question. And one that I’ll actually observe myself.

Now, we need to make it clear to people, of course, that the percentage of people in whom that happens is rather small. Yeah. So what we are referring here to someone saying, taking a medication, losing 15% of their body weight or 20% of their body weight, they stop the medication and they manage to maintain it.

And I don’t think that there is some, these people are special in terms of their intelligence or in terms of their engagement. I think, and again, that remains a bit of hypothesis, is that the range around people’s set-point can vary. So remember that if you go above or below a certain range, the body starts to sense that and starts getting annoyed and sabotaging what you’re trying to do.

That is if your range is narrow. If your range for somebody is wider, and you lose weight within that range, it is less likely that your body is going to kick up a fuss if that happens. And therefore, these are some of the people who are able to maintain the weight without the medication, probably because this is what has happened.

I’m not saying this is the only explanation because there are many environmental factors involved, potentially, in doing that. But I’m trying to give you the more biological, the best biological explanation I can. And in those people, in fact, actually, you might think that these people never needed to have pharmacotherapy because if you gave them, just if you told them to eat less, caloric restriction, they will be able to do it, no problem.

But it’s a small number. Right. Peter, go ahead.

Hey, thanks for the great talk. So my question is, in one of the slides where you mentioned the places where the mutations are in the brain, there was the ventral tegmental area, which is known as the part of this reward system in the brain that is very connected to addiction and with the dopamine pathways. So there is this thing like food addiction, but it seems like it is mainly researched in the context of eating disorders.

So in the context of the obesity pathophysiology, how big of a role exactly does addiction and reward play? There seems to be rewards in it. Yeah. We need to be careful here.

I remember I’m an endocrinologist. We need to be careful here with the terminology that we’re using because the psychologists around us might start getting upset. But in terms of addiction, this has been explored in the context of obesity.

It is indeed the case that many of the pathways involved in the rewarding value of food are also involved in the rewarding value of recreational drugs, alcohol, etc. However, the forms of obesity that we see do not strictly fit the definition of an addiction in most people. The closest that you can get to an addiction state is through, for example, a binge eating disorder, which is what you have kind of alluded to.

So eating disorders. And it is in that specific situation where the dopamine system seems to be overactive. Now, studying those things in humans is extremely difficult.

I did my PhD in functional neuroimaging of the brain. And I can tell you the technology is pretty primitive, as fancy as fMRI sounds. So we don’t have any convincing evidence from neuroimaging studies that people with obesity have a higher reward response to food compared to people without.

The literature is all over the place. But what that probably means is that if you take a group of people, like Bram talked about the obesity, if you take a group of 100 people, you’re not going to see an effect because they have got different obesity. But if you take the subgroup of people that have got more of an addictive type of eating behavior, then that plays much more of a role.

And it means that we can address it potentially differently. The good news, and I’m just going to talk briefly about pharmacotherapy, the good news is that our pharmacotherapists for obesity these days happen to sometimes hit those areas in terms of signaling. And therefore they can be quite positive adjuncts in treating obesity associated with some of the binge eating disorders.

All right, thank you. All right. We have a couple of questions in the chat.

So Kerry Wardle asks, what is the significance of the age the genetic influence really becomes apparent around eight years old? And can this be used in terms of targeting preventative approaches? Yeah, I don’t know why that starts at eight years old, why the graphs start to deviate at that age. Is it because the genes decide to wake up then? And if they do, why would they decide to wake up at year eight? I don’t know. Or is it that at year eight there’s a set of environmental interaction with the genes to cause that to happen? But it looks like this is the time when the lines start to deviate.

And it might be useful. And again, I don’t know if there are any pediatric people involved with children here. It might be useful to see if we can start, well, predicting who will develop obesity later on, even by small changes in body weight between the ages of eight onwards.

I don’t know if anyone has done those studies or not. But that is certainly plausible. And in fact, there are now studies that are assessing even earlier infant changes as a predictor of obesity later on in years to come.

OK. Then we have another question from Thomas Curtis. Is hypothalamic inflammation involved in the pathophysiology of obesity? That, yeah, that has been a difficult question to answer, both in certainly humans, for sure, but also in animal studies.

Because what we don’t know is whether inflammation precedes obesity. So whether inflammation causes dysfunctional neural signaling and therefore causes obesity, or whether just the obesity causes neural inflammation in the hypothalamus, like it causes inflammation in many other parts of the body. So the cause and effect has been a little bit tricky to prove.

Most people would probably stick with the hypothesis that this is a complication of obesity itself, rather than the cause. Usually what happens when we treat obesity, hypothalamic inflammation improves. But I don’t know if there is a causative link, but I don’t think I have seen one.

But it’s certainly there, and it is something that can also be addressed therapeutically. All right. Thank you.

So then Claudia Correa says, thank you for the great and clear presentation. For cases of patients where medications don’t work on reducing hunger and the food noise, would bariatric surgery be the only way? Or is there a risk of the bariatric surgery not to be effective as well? Yeah. Well, again, as I’ve said many times, if I knew the answer to this question, I would be very rich.

So the reason is that we don’t know, forget about what the next treatment is, we don’t even know why there is this heterogeneity of response to any treatment for obesity. Not just medications, nutritional therapies, physical activity, psychological therapies, always a Gaussian distribution. And we don’t know why that happens.

We suspect that with pharmacotherapy has to do with pharmacogenomics and the way that the medications interact with the receptors in the brain and our receptors can be different or slightly different in the brain. Therefore, one medication works perfectly well for one person and not for another. So what would be the next step? Well, the next step can be anything, because even if the patient doesn’t respond, say, to a GLP-1 receptor agonist-based treatment, that does not exclude the possibility remote as it is, that they might respond to a time-restricted eating intervention.

There is no evidence to or against that. It’s a possibility that they might. And there is also no evidence that, and that is important to say, there is yet no evidence that suboptimal response to medications means suboptimal response to surgery.

Because the reason being that, as you know, surgery changes not just one hormone, but a number of hormones and a number of other mediators involved in body weight regulation. If someone hasn’t responded to usually one hormonal treatment, it doesn’t exclude that they might respond to the many hundreds of molecules that change after bariatric surgery. So it certainly remains an option.

All right, Tietere, go ahead. Hi, Alex. Thank you for the very interesting talk.

And I would like to go a bit more deeper into the narrative surrounding obesity. Because as you say, I sometimes have discussions with my friends who are mostly skinny and drinking beer and eating lots of pizza that it’s all about lifestyle behavior. Now, I’m training for a marathon at the moment.

And I’m losing some weight. And my friends are actually quite cynical about that. They say the whole story you’re telling me is completely wrong.

Because now you’re just doing some more sports and you’re losing weight. How can I counterfeit them without maybe going too deep into the biology of disease? Because I probably lose them when telling them about it. OK, so the question is, you’re losing weight because you are training for a marathon.

Yeah, it’s just like you’re moving more. It’s the old idea of if you eat less, move more. So you’re back.

That’s the solution to your health problem. Yeah, and the answer is that you can do that. You can run marathons.

Good for you and good for everyone that can do marathons. But the problem, again, is that the more you start shifting away from what your set point is meant to be, the more your body will kick back. Again, it doesn’t happen in everyone.

So there will be people that do marathons and are able to lose weight and be skinny, etc., etc. And that is because their body weight regulation allows them to do that. So I would say to them that, and to say that quite, to make a point in layman’s terms, people who are thin are lucky and people who have obesity are just unlucky.

So you can tell them that they may not necessarily agree with you, but to a certain degree, it’s not far from the truth. I’ll do my best. Thank you.

Then we have still one more question in the chat from Melanie Smuk. She says, medications for obesity are allowed for two years only. I guess that depends on the country.

Should it be lifelong instead? Yeah, I mean, I think us in the field here, it is becoming now gradually a very obvious thing, right? So if we’re saying that we have got a major biological contribution, and the biological contribution is not going to disappear. You cannot do anything about, you know, it’s going to stay. You need to address the biological contribution with biological methods.

And just because in the UK people have decided that obesity can be treated in two years doesn’t mean that that is scientifically correct. And now, actually, this has now changed with the latest medications that are allowed to be used long term. At the same time, what you do in addition to the biological drivers that you are addressing with medications, or surgery, et cetera, you’re also addressing the environmental drivers.

But you need to remember that if you are addressing the environmental factors, you are not completely eliminating biological factors. You’re just suppressing them, OK? You’re putting the lead on, but you cannot eliminate. Thank you.

OK, we’ve got, oh, do we have time for one more question? Last one. Cornelia Pottery says, thank you for an informative presentation. From a public health perspective, how can this understanding of the pathophysiology of obesity inform obesity prevention efforts? Yeah, so we just need, the narrative now is changing.

We understand what we have just discussed. And then we’re saying, fine, we understand at least the magnitude of the effect, right? We understand that the environment is important, but it’s not, you know, it’s not everything. It doesn’t cover the whole picture when it comes to body weight regulation.

And it means that we need to get, I think what it means is that we need to get better with our public health interventions, because people from my side that are more on the treatment side are usually very cynical, and they will say, well, public health interventions don’t work. But that’s unfair, because just because we have tried some of them and it didn’t work doesn’t mean that there are not others that may work. In the same way that when we have medications that didn’t work, it doesn’t mean that medications in general don’t work.

So what we need to do is we just need to get better in our public health interventions and try different ones and use the ones that are actually effective. Now, I’m not going to tell you what you’re going to do in your public health interventions, I don’t know, that’s not my thing. But at least we appreciate the effect side, we appreciate what effect it’s going to have on people, and we appreciate that if people don’t respond to that, that is fine, we just treat them like we do for many other conditions.

All right, thank you so much. With that, I would like to end the session. I would like to thank you, Alex, for your presentation and sharing your insights.

It was really, really great. And thank you, everyone, for coming today. It was a well-visited webinar.

So thank you so much, and hopefully we’ll see you next time. All right, have a good night. Thank you.

Bye-bye. Bye, thank you, everyone. Bye.

Bye.