So I am trained as an endocrinologist, but I've spent most of my career in the cardiometabolic space. And I've spent a lot of time doing research in obesity. And like with kidney disease, there's a lot of excitement. There was nothing much happening in the obesity space for 20 years, kind of like with the kidneys. And now all of a sudden, lots happening. Obesity is a disease. And that's the thing that I want to get across today. We accept diabetes as a disease, kidney disease as a disease, and we treat it. But we don't accept obesity as a true disease. And we don't treat it like it is. And so our patients are not getting fair treatment. There's a lot of bias and stigma in this field in this area of obesity. And until we can all accept the fact that obesity is a true disease, we're not going to get anywhere. We can have all these great medicines, but these medicines won't be available to our patients. One is because our patients don't accept that they have a disease. The providers, which is you, don't accept it. And the people who pay for care won't accept it. So I'm going to do something a little different today and talk about obesity in the brain to try to help convince you that, yes, obesity is a disease and it needs to be treated, just like we treat other chronic diseases. Let's move on. So actually, I'm going to back up for a minute. So part of what I'm doing here is wearing my hat as the incoming president of the Obesity Society. The Obesity Society is a big organization in the United States, but we have a global touch as well. And my campaign as president is going to be raising awareness about obesity as a disease. And here we go. Here's my start. So here are my disclosures. The objectives. We're going to talk about the complex regulation of food intake and how it's dysregulated in obesity. We're going to discuss the importance of higher brain centers. Yeah, we're going to talk about the brain. I'm not a neurologist, so some of this is beyond me. But we'll help try to convince you this. And then how does this relate to the disease and its potential treatment? And we're going to talk about how these treatments may impact the brain. All right. We're going to start with a case. 36-year-old woman who wants help with weight loss. That's the first barrier. She wants help. She reports a slow, gradual change in her weight, a weight gain over 10 years, especially after two pregnancies. Most of her family members are overweight or have obesity. So this might be a genetic predisposition. She says, my metabolism must be low. She's tried every diet out there. She's lost some weight, but she always regains it. She doesn't eat at all, she says. You do a 24-hour recall, and it suggests that she doesn't eat much. She says, I'm not hungry, so I don't eat out of hunger or emotion. She denies snacking or ingestion of liquid calories like sodas or juices. She works out, goes to the gym two, three times a week. What else can I do, she says, in much frustration. This is someone I see almost every day. All right. A couple of things come up with this case. The first is, she says she doesn't eat much. And your history suggests that she doesn't eat much. But you know she must be eating more than what she says or reports, or else she wouldn't be gaining weight. It's all about energy balance. Is she lying to you? Is she embarrassed about how much she eats? Or is this her true perception? Maybe she doesn't sense how much she's eating. Maybe she's eating things that she doesn't realize. I think this is part of the disease of obesity. She doesn't eat out of hunger. So does she not feel hunger or satiety? These are very subjective feelings. And if I asked every one of you what hunger is, you will give me a different answer. And some will say, I get really hungry, and I eat in response to that, and not others. So if she doesn't feel hunger, then what signals her to eat? What tells her to stop eating? Again, this might be part of her disease. Why is she not adapting physiologically? She's gained weight. So why is she not downregulating her energy intake, like our other hormonal controls? Are her homeostatic or physiologic mechanisms at fault here? Again, is this part of the disease? Now, she loses weight when she tries, which most people do. But then she regains it. Why is that? So what promotes weight regain when we go on a caloric restriction? Is this, again, part of the disease? And how can we help her maintain long-term weight loss? That's the most important. So I started off by writing on the title of this slide is, is obesity a disease? Question mark. And I decided, no. There's no question about it. Obesity is a disease. So there are many definitions, but here is one proposed by the American Medical Association for a disease. It is an impairment of normal functioning of some aspect of the body that's associated with characteristic signs or symptoms and associated with harm and morbidity. Think about obesity. Does it fit these criteria? The answer is absolutely yes. Obesity, as I'm going to talk about, is associated with appetite dysregulation, abnormal energy balance, and endocrine dysfunction. And it's associated with increased body fat, a characteristic, pain in joints and altered metabolism, sleep apnea, and others, and then clearly associated with harm and morbidity, increased development of type 2 diabetes, cardiovascular disease, cancer, osteoporosis, sleep apnea, et cetera, et cetera. Over 200 organ systems are impacted by the disease of obesity. And we're trying to change the narrative to say, obesity is not a risk factor for these diseases. It causes these diseases. These are complications of obesity. All right, let's spend some time on this. So body weight is regulated, clearly, in animal models. This is in rats. If you feed rats and you let them be in the blue line in the middle, they just gain weight over time, and then they start plateauing before they die. If you do an experiment where you overfeed rats, that's in the little red line, they gain weight. And then when you let them eat normally again, their weight comes down to exactly where they would have been if you never overfed them. If you do the opposite experiment, you underfeed rats, they lose weight. Then at time two, you let them have free access to food, they regain the weight exactly to where they would have been if you had not put them on a caloric restriction. So clearly, there's something regulating this in animal models, and we believe that there is this same regulation in humans. So how is energy balance regulated? One is on the energy expenditure side. We have a resting energy expenditure, thermic effect of feeding, and then physical activity. We have substrate metabolism, which is very important. So fat oxidation, nutrient assimilation, the gut microbiome we know is very important. And then we have regulation of energy intake or appetite. So appetite modulators, there's also cognition and behaviors that are important. And let's focus on this side of it. So what regulates energy intake? Well, we have physiologic mechanisms, and I divide them into two types. Short-term signals that are meal-to-meal, hour-to-hour, and then you have long-term signals that are adiposity-related. Then we have many non-homeostatic mechanisms, and we'll talk more about these in a minute. So this is kind of a model. Here we have the brain. The brain is what controls all this. We have anabolic pathways in the brain that tell us to eat. They stimulate hunger and actual behavior of eating. These same pathways inhibit energy expenditure. We also have pathways in the brain that are catabolic, that inhibit food intake, tell us to stop eating, and those same pathway enhance energy expenditure in the body. So if we eat more than we burn, we are in positive energy balance. Those calories have to go somewhere. Where do they go? They go to be stored in adipose tissue. Now, as endocrinologists, we like feedback loops, right? Well, we knew for many years that there was some type of signal that went back to the brain to tell you to stop eating and burn more calories. And in 1994, the hormone leptin was discovered, a hormone made by adipose tissue that feeds back to the brain to tell you to stop eating and burn more energy. We also learned that insulin, while it's not made by adipose tissue, is higher in people with excess adiposity because of insulin resistance. Insulin feeds back to the brain as well, and it enhances the catabolic pathway. So it tells you to stop eating and burn more energy. Then we learned later, in the end of the 21st century, is that what it's called? 1999 or so, 2000, that the intestinal tract is critical. And the hormone ghrelin was discovered. From the stomach, again, tells you to eat. It was, quote, the hunger hormone. But then other hormones like GLP-1, PYY, and others, so incretin-based hormones, feed back to the brain to tell you to stop eating. So a satiety signal. All of this is assimilated in the hypothalamus of the brain. So NPY neurons, POMC neurons, control hunger and satiety. Peripheral signals like ghrelin stimulate NPY and tell you to eat. But it's not the hypothalamus that ultimately tells you to eat. It's second-order neurons in the brain that actually gets you to make that behavior. Then you have your satiety signals like GLP-1, PYY, and our adiposity signals like leptin, which stimulate the POMC neurons, which then stimulate satiety and those behaviors in second-order neurons. So in the perfect world, you overeat. That puts you in positive energy balance. That leads to weight gain, fat mass gain, but also lean body mass gain. That should feed back to the brain to tell you to stop eating. That's what happens in our animal models. But obviously, that's not happening, or else we wouldn't have the obesity epidemic or pandemic that we currently have. So what's going on here? Well, we could learn from some genetic models. So leptin deficiency causes severe obesity. So certainly the OB-OB mouse is deficient in leptin and has severe obesity. The DB-DB mouse has a deficiency in the leptin receptor. It also has severe obesity. And we've learned that humans with leptin deficiency also are, and with leptin receptor mutations, have severe obesity. If we give them leptin, we reverse that obesity. And these individuals with leptin deficiency have completely different neuronal activity in their brains compared to people without obesity. And when we give them leptin, we normalize that brain activity. It's quite dramatic. Other genetic models would be mutations in the melanocortin pathway. Again, melanocortin in the hypothalamus being critical. POMC mutations and melanocortin-4 receptor mutations are both associated with severe obesity. Good news, we now have a drug, set melanotide, which is an MC4 receptor agonist that is magical to these patients. Look at that little boy losing all that weight based on that medical therapy. We're talking 30, 40% weight loss for these individuals. So clearly these examples are extreme, but they really emphasize the importance of the physiology. But what about in more common forms that are non-monogenic? Our polygenic obesity that we have, how does that work? Well, let's look at people with obesity. What's happening to their hormones and their appetite type behaviors? So we did this study where we took individuals who were very lean and genetically not prone to obesity, and then took people who were prone to obesity based on family history and other markers. And what we found is if you were obesity prone, you had more leptin, but you already had more adiposity. Ghrelin was actually lower, and that's been shown a number of times. Lean individuals have more leptin. That's counterintuitive. Ghrelin tells you to eat, yet they have less obesity. End of the day is, do our people hungry? And is there a difference there? And the answer is no between these groups. So despite having more leptin and less ghrelin, these individuals who are prone to obesity have just as much hunger and the drive to eat than the person without obesity, telling us that there must be resistance to leptin and also an issue with how ghrelin is working centrally. And this is a model that I think that makes a lot of sense about the polygenic common obesity, that genetically we haven't changed in hundreds and hundreds of years, right? So people who were prone to obesity genetically 100 years ago in a resistant environment, they didn't have obesity. Those are the people on the left here. But those same individuals who are genetically prone to obesity who are now in our obesogenic environment, now the phenotype comes out. They have obesity. So it takes this interaction between our genetic predisposition with the environment to really produce the obesity that we see. To further worsen this, the hypothalamus develops inflammation just from overeating, especially higher fat food. So this is out of a review. In the top part of this figure, it's animal data. If we overfeed rats, they develop gliosis in their hypothalamus, which impairs their ability to regulate their energy balance. Now there's evidence in the bottom part of this figure that this happens in humans. First from cadaveric trials that people who have died for other reasons, those with obesity had more gliosis in their hypothalamus. And now we are doing MRI studies that show more inflammation in the hypothalamus. Question is, is that reversible or not? But we know that inflammation causes a worsening of appetite regulation. All right, weight loss is a further drive to weight gain. It leads to powerful compensations. So first, as we lose weight, we lose lean mass as well as fat mass. We all know that. And our energy expenditure goes down by about 15 calories per kilo of weight loss. So it's expected that our resting energy expenditure would go down. And at the same time, leptin goes down, so does GLP-1 and ghrelin goes up. All the signals tell us to eat more. And these are very powerful. And we start eating more, we regain the weight. So what are the problems here? Is that our biologic signals are really more powerful and designed to protect us during times of undernutrition. When food is scarce, you see it, you gotta eat it because you may not get food for the next week. Signals drive us to eat when we're in negative energy balance. All those signals are upregulated. There's clearly a genetic component and predisposition where the right environment then leads to obesity. So really, there may be resistance to these hormones that are peripherally signaled, such as leptin resistance, but way more complicated than that. We also know about this hypothalamic inflammation, which may be a critical piece to this whole puzzle. At the end of the day, it's also very much more complicated, especially in the human model. Because in humans, much more important, and this is related also to the environment, is our non-homeostatic regulation of energy intake. So I divide these into two different buckets, per se. One are internal inputs. So reward is very powerful. Cravings, and we know there are very much similarities to substances of abuse are similar to eating and food behaviors. Just thinking about food and restraint, the opposite of wanting to eat, cutting back on what you wanna eat. Learn behaviors. Attention. And then we have these external inputs. We have the environmental cues, like the seeing of food, I know it's there, I know it's available, I know it's good. I smell it, mm, yum. And then I taste it. Availability and portions. If food's not there, you don't eat it. If it's there, we tend to eat it. If the portions are bigger, we eat more. Those experiments are pretty clear. Social context. Do we eat more when we're around people or when we're alone? There are a number of variables there. And then finally, time cues. We live in a world where we wake up, we have to eat for breakfast before we go to work. And then we're given a break in the middle of the day. Oh, we gotta eat lunch. And then we come home and it's late, and now we're eating dinner much, much too late, right? So we're forced into this just based on our daily lives. It's not that we were meant to eat three meals a day, right? We are being pushed into eating three meals a day. So those are important. So to kind of summarize the biology and the interactions with the environment is we have these biologic or homeostatic mechanisms, many of which are genetically determined. Like adiposity signals like leptin, metabolites are important, the gut peptides as we talk about, even gastric distention. These all work through the hypothalamus and then higher order neurons in the brain to impact energy intake. But then we have these non-homeostatic mechanisms, internal inputs, external inputs, that might have you eat regardless of what your homeostatic mechanisms tell you to do. In the United States, we have Thanksgiving coming next week, and I'm gonna eat a lot of food on Thursday. And my biologic signals are gonna tell me to stop eating. I'm gonna feel full, I'm not gonna wanna eat anymore, but then we're gonna bring out the pumpkin pie. I eat pumpkin pie once a year and I love it. So I'm gonna eat it, even though my biologic signals tell me not to eat it, I am gonna eat pumpkin pie. And not only am I gonna eat pumpkin pie, I'm gonna put whipped cream or vanilla ice cream on it. And so that's a drive to eat that's not controlled by our biology at all. But the reality is all of this interacts in the brain. So both of these work together like how we work with the environment. And I believe that these non-homeostatic mechanisms overpower our biology, and that ends up feeding into the obesity rates that we have. All right, so let's spend a minute, talk about the brain. And this is gonna be a lot of the research that I've done over the last, whatever, many years with colleagues at the University of Colorado, people who are much smarter than me, who do all this analysis of looking at brain imaging. So we use functional MRI or fMRI to evaluate the activity in the brain in response to food signals. Primarily we use pictures of food because it's just an easy way to do it. It's very robust in its effects and it's very consistent. If I do these studies here in Dubai, or if I do them somewhere in China, where I do them in the United States, we see the similar findings across the board. Very easy. And the sight of food is so important to initiate us to eat. So we look at different networks in the brain that are turned on, activated, when we see pictures of food, and we start by doing it when people are hungry. And what we see is a network of brain activities turned on. You can squint, the exact places aren't as critical. But these are all very important areas in the brain as it relates to eating behaviors. These are areas that relate to attention, so you have to have attention, and reward, motivation, memory. So this is our brain when we're hungry. Then we have these people overeat for three days. And these are normal weight individuals. What happens to all that activity? They're still fasting. We show them the same pictures of food, no activity. Complete suppression. It's pretty surprising. So you go from all that activity to no activity with just three days of overfeeding. And in fact, we can show this reduction in activity with just a single meal as well. So then the question is, what about people prone to obesity? Are they different than the people who are not, or are resistant to obesity and are normal weight? And the answer is robustly yes, very different. And here I'm just showing an example of what areas are different in people prone to obesity compared to those not. And in the boxes underneath those lovely blobs of brightness in the brain are more quantitative values. And what you see in the green, those are the obesity-resistant individuals, normal weight individuals. The brain activity goes down when you eat. So when you go from fasted to fed, that is the normal response. Now we look at the obesity-prone individuals, we see a completely different response, the opposite. The activity went up in response to eating. That's pretty fascinating. And then we also looked at people who were reduced obesity. So they had lost seven to 8% of their body weight, and we see the same signals. That normal weight individuals get a reduction in activity when we feed them, and those with reduced obesity, we see an increase in activity. Opposite of what we had, so clear big differences here. Now not only are there differences in the response to food signals, there are differences in the brain overall. There's an activity in the brain called the resting network. So when we sit here, and those of you who have fallen asleep because I'm boring you, your brain is still active. It's still turned on. And that's called the default or resting network. And it's three main regions of the brain that are activated when we're doing nothing. The medial prefrontal, the lateral parietal, and the posterior cingulate. Those things don't mean a whole lot to us, but those are important. And what we found is that there were big differences between people who were prone to obesity and those who were resistant to obesity. Where those who were prone to obesity had greater activity in these brain regions. Why is that important? It's important because when you go to do something, your brain has to shut down the resting state to be able for you to focus on something else. People prone to obesity have higher resting state. It's harder for them to turn that off to be able to focus on another signal. So this may be an important part of the obesity disease. Not only is functional activity different, brain structure is different in people prone to obesity and in a number of important brain regions. Again, data from our lab. So that's great. We can show that there's differences. But I hope that is convincing that there is a physiologic difference between these individuals prone to obesity compared to people not. The question is, can we do anything about this? And the answer is yes. This was a study done by other investigators where they just did a behavioral intervention and they showed that they could impact the activity in the brain just by doing a behavioral intervention. Pretty fascinating. I don't have the data to share today, but we did an intervention where we took pictures of food and we paired it with disgusting things like severe trauma and just horrible things. It was subliminal. The people did not see the disgusting things. And when they saw those pictures of yummy food, but then it was paired with something disgusting, their liking of that food went down. And the brain activity changed as well. So we can, with behavior modification, alter the brain activity. We did a study, and these are the results, with an exercise intervention. Six months of chronic aerobic exercise. And that was associated with significant reduction in the activity in the brain related to food signals. This, again, would be considered a good thing from an appetite regulation perspective. Exercise also altered the resting state. You know, we said that the resting state is overactivated in people prone to obesity. Exercise actually improved that and reduced that activity. What about appetite-related peptides? So just a summary of a number of studies. Leptin restores the normal response to visual food cues in people who are leptin deficient. I mentioned that earlier. But another study was done, which is interesting. So if I take someone with obesity and have them lose weight, their leptin levels go down. If I give them leptin, that enhances their activity, improves their activity in their brain. PYY and GLP-1 infusions have shown important impact in brain regions. And so has ghrelin, has caused a reduction in hunger centers in the brain, excuse me, an increase in hunger centers in the brain. And here's a study that infused GLP-1 or PYY or both. And what they found is that infusing these hormones mimicked the fed state, which makes sense. These are satiety hormones. So on the far left are people who are fasting and then they're fed in the white bar. So you see their activity goes down significantly. Now, if I give them PYY or GLP-1, you see that their activity is similar to the fed state. Now, if I give both hormones, I completely suppress the activity completely. But these are acute infusions of these hormones. Can we do this with medical therapies that are more long-term? So one study was done with loraglitide, which we know is a daily treatment for type 2 diabetes or obesity. And it was associated with significant reductions in brain activity in similar brain regions that I showed you earlier. Suggesting a couple of things, is GLP-1 probably works all through the brain and not just in the hypothalamus. A study was also done with naltrexone bupropion, which is again approved in the United States for the treatment of obesity. And again, showed significant alterations in brain activity. So we can alter those responses. There's one study that looked at semaglutide in terms of resting state. We talked about how important that might be. And semaglutide did improve or reduce the resting state in the brain all throughout. So this takes us to the last part of the discussion, which is why should we be treating obesity as a disease? Well, because we have known neurotransmitter and neurocircuitry that are abnormal in this disease. We treat people with depression who have similar types of activity in their brain with medicines. So why not consider medical therapy? I'm not saying that medical therapy should be our one and only treatment. Lifestyle interventions, behavior modification are still critical. But I think we need to also consider using obesity medications to treat this long-term chronic disease. So this is a cartoon pulled from a pretty old guideline from 2015 from the Endocrine Society. And it basically points out all the different neurocircuits that are associated with energy balance regulation and appetite regulation. And I've plugged in a number of the drugs that we have today that work on these different mechanisms. So it's not all about GLP-1s. We know that other mechanisms are important. Where GABA is important, so topiramate. We know that dopamine's important, so phentermine might be important. Naltrexone, bupropion. I think we need to use all these treatment options for our patients and maybe in different combinations. So we know that drugs that are incretin-based, like GLP-1 or GLP-1-GIP agonists, leads to significant weight loss. That's pretty convincing when we see that. But even more convincing is we treat a patient and they lose weight with these drugs. We stop the treatment. What happens? They regain the weight. Now, they haven't regained all the weight a year later, but they're on the trajectory for regaining the weight. Now, there's the rare patient who doesn't, but the majority will. Now, if this isn't convincing that this is a disease, I don't know what is. I'll take an example. If we treat someone for hypertension and we put them on an ACE inhibitor, their blood pressure improves. We say, yay, great, that improves their outcomes. Now that their blood pressure's normalized, should we stop their treatment? No, it's a chronic disease. If we stop the treatment, the blood pressure's gonna go back up. We have to start thinking about obesity as a chronic disease that needs a chronic treatment, because this is what happens when you stop the intervention, people regain weight. Why does lifestyle interventions fail? It's because people cannot adhere to the changes in lifestyle long-term. Their body signals tell them to regain the weight, so it's very, very difficult. These drugs are actually very powerful, and even our older drugs, like Phentermine and Phentermine Topiramide, et cetera, two, three, four-year data of weight-loss maintenance. No lifestyle intervention gives you more than a year's worth of weight-loss maintenance, so these drugs are very powerful. Now, what I'm not saying is that someone starts semaglutide and they lose weight, they need to be on semaglutide the rest of their life. There may be other alternatives, newer treatments, or maybe older treatments that are cheaper that might be good to maintain that weight-loss more long-term, so I think we need to get a better sense of what the algorithm is. For many, many years, we've been preaching in the obesity field that weight-loss is one thing, weight-loss maintenance is a different thing. We said it with diet therapy. Use a very low-carb diet. Initially, you lose your weight. Then maybe you go on a low-fat diet for weight-loss maintenance. Same with medical therapy. We use a powerful drug that helps you lose a lot of weight initially. Maybe we use something different for long-term therapy. We have a lot to learn. And the exciting part, emerging pharmacotherapy in the obesity space is impressive. This is just one example of many, many different drugs that are being developed with many different mechanisms of action, not only looking at appetite suppression, but a number of drugs looking at preserving lean mass loss or muscle mass loss, which would help potentially mitigate the reduction in resting energy expenditure, which promotes weight regain. So these are important. There's a lot, lot going on in the field. So the rationale for pharmacotherapy, obesity is a chronic disease, and it's associated with neurocircuitry in the brain that's altered. And so this is critical that we need long-term therapy to reverse that. Adaptations occur in response to energy restriction and weight loss, and these promote weight regain. This makes weight-loss maintenance very difficult for most patients, and again, supports the need for long-term treatments. Obesity medications alter the neurobiology associated with obesity, relating to significant long-term weight loss and improvements of obesity-related complications. Therefore, my conclusion is obesity medications should be considered as a long-term therapy, not a short-term fix or just a kickstart. So to wrap it up, and then we'll take some questions, let's come back to my case. Her genetics and biology probably favor nutrient storage and increased intake of nutrients and storing them. So how do we help her? We need to look for ways to alter her biology. Maybe it's pharmacotherapy targeting these biologic signals. She may be less sensitive to the environmental cues around her. So we can try to change the environment, but that's very difficult to do. We can look at strategies to help her better interpret the external signals around her. We can consider behavioral techniques that might help her deal with the environment. But again, pharmacotherapy may help her be more sensitive to cues. Our patients tell us when they're on semaglutide, terzepatide, that the food noise is gone. That helps them deal with the environment around them. Her behaviors might be at fault. Well, how do we fix that? We can look for better ways to facilitate behavior change. We can treat any underlying mental health or emotionally related behaviors. But again, pharmacotherapy may help her make these behavioral changes, another way these medicines work. So with the brain imaging work, I wanted to acknowledge my collaborators and fellows and students and research assistants at the School of Medicine Colorado before I moved to Charleston. With that, I thank you for your attention. I'll be happy to take some questions.

obesity

chronic disease

cardiometabolic

brain mechanisms

pharmacotherapy

genetic predisposition

stigma