Hello, my name is Elizabeth Bauer. I'm an endocrinologist at Mayo Medical Center San Diego, and I'll be talking to you today about obesity pathophysiology, one of my favorite things to talk about. I have no disclosures, and today we're going to be reviewing a couple different things, but we're going to be going over the definition of obesity and its prevalence. We're going to be discussing how complex the disease is and the many components that are interacting together, and we're going to try to understand the challenges for weight maintenance after weight loss has been initiated. So starting with a definition, if you don't have time to listen to my lecture and you just have a couple seconds, this definition encompasses what I'm going to be talking about. Obesity is defined as a chronic, relapsing, multifactorial, neurobehavioral disease wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences. So it's a mouthful, but it really goes into just how complex the disease process of obesity is. The prevalence of obesity worldwide in 2020 was estimated at 15%, and it's projected to rise to 18% by 2030. However, the average prevalence dramatically does change based on country, with some countries having a much higher prevalence, including the United States, whose average obesity prevalence is over 40% and in an upward trend. It is multifactorial and involves interactions between many different systems, and it's the result of defective regulation of energy balance and body weight, rather than a defective eating control. And so we're going to go in and discuss some of these interactions. So we're first going to talk about genetics, since it's a very common question that patients ask, and it's incredibly fascinating. So most people are correct when they say, it's in my genes, because hereditability of obesity is somewhere probably between 30 and 85%. The problem is that it's not a direct cause and effect. So that means that just because you have a gene associated with obesity, it does not mean that you will have obesity, and vice versa. So bear with me as we go back to medical school and talk a little bit about genetics. So when we're talking about genetic variation, we are talking about a relatively large differential. You can have changes to the DNA itself, or you can have changes that affect the creation of DNA, meaning the translation and transcription of it. So there is no question that a mutation causing a loss of function in genes that directly affect energy balance, such as leptin or melanocortin pathways or chromosomal rearrangement will cause obesity. And this is usually because of hyperphagia, along with other endocrine effects, such as low thyroid and testosterone. But overall, these mutations and resulting conditions that are known as monogenic obesity are overall very rare and account for less than 5% of obesity. Syndromic means that there's an additional phenotype that creates a syndrome. And some common examples are Prader-Willi and Fragile X. And they usually have other conditions like cognitive delay, in addition to the hyperphagia and obesity. We now have hormone replacement for some of these conditions, but not all. Polygenic obesity or common obesity is heavily affected by the environment. And this is through interplay between polygenetics and the obesogenic environment. Genome-wide associated studies, or GWAS, has identified many genes and single nucleotide polymorphisms, or SNPs, that are associated with obesity. These variations are involved in pathways affecting the neural circuits, including appetite and satiety regulation, insulin secretion, and energy metabolism, among others. But despite the identification of hundreds of these genes associated with obesity, they only explain about 5% of variants of a VMI. So in other words, there's a lot that we do not understand, but it is apparent that there's a strong genetic component that is underlying the large inter-individual variations in body weight. And this determines how people's response to the obesogenic environment. So this may cause some to store energy as fat while others do not. It is also likely that some of these genes need to be turned on by the environment before they create the obesity phenotype. Epigenetic modifications are environmentally induced chemical changes of DNA and histones that do not affect the DNA sequence. So some of these mechanisms are modifications prior to or post-translation, and it regulates gene activity without affecting the genomic sequence. Exposures in the mother can also affect the fetus. So for instance, in animal models, maternal obesity caused an increase in leptin gene expression, and this was through epigenetic modifications in the fetus. And the two most common ones are DNA methylation and histone modifications. So if you take an individual who's genetically predisposed to obesity and you place them in a calorie-restricted environment, these genes are protected because they're trying to maintain the energy needed to survive. However, if you place them in an obesogenic environment with not only an abundance of foods, but foods that are calorie-dense and many times engineered with ultra-processed ingredients to stimulate high caloric intake, and you combine this with less activity and higher stress, they will have an easier time gaining weight and a harder time losing weight. So a genetically predisposed person in our obesogenic environment will do unfavorably with increased caloric intake. Genetics and epigenetics are just one contributor, though. They have done many different studies showing that individuals who do carry these obesity-related genes are modifications, and you can still have the modifications done with the environment, and you can show that doing different behavioral modifications can actually cause improvement in the epigenetics. So, for instance, physical activity has been shown to reduce the genetic predisposition to obesity for those with the FTO gene. Genetic associations with obesity based on 32 BMI variants was stronger in those who had a higher intake of sugar-sweetened beverages. But high-protein diets and low-fat, hypocaloric diets did have beneficial effects, and they were able to lose weight and improve their body composition in those that had, you know, alleles that were related to obesity. So just having the gene doesn't mean that you cannot lose weight. It most likely means that, in this type of environment, you're predisposed to gain weight faster or easier and more difficult to lose weight based on different energy dysregulation. And so going into the processes that are in place to regulate our energy storage, we're going to talk about the central and peripheral nervous system, which have a very close relationship and need each other in order to receive appropriate signaling to determine where our energy stores are. So normal physiologic CNS regulation of food consists of incoming input from the peripheral long-term and short-term energy storages and adjusting the signaling to maintain an appropriate energy balance. So a positive energy balance from a high food intake should activate pathways that would decrease food intake, such as decreasing or inhibiting the rewarding properties of food or increasing satiety. Similarly, if there is a negative energy balance, the reverse should happen, right? And you should have an increase in the hormones that stimulate hunger and increase rewarding properties of food to stimulate intake. So first talking about the peripheral side, these peripheral signals come from enteroendocrine and pancreatic hormones, adipose tissue, and the gut microbiome. And there is a whole host of enteroendocrine and pancreatic hormones, but we'll go over some of the main ones. Ghrelin, which is the one that most people are familiar with, is the main eryxogenic hormone, and it's produced in the stomach, and it increases in production prior to a meal to stimulate food intake. Other intestinal hormones, such as GLP and GIP and PYY, they regulate food intake by slowing gastric emptying and increasing satiety. The newest FDA approved anti-obesity medication, terzapatide, is actually a GLP-1 and a GIP receptor agonist. And in the clinical trials, there is upwards of 15% total body weight loss seen on average in the studies using this medication. These hormones in the peripheral system go back to the CNS and they indicate, they tell the body if energy storage is neutral, positive, or negative. But these same hormones can be dysregulated in obesity, resulting in less of an effect. So, ghrelin, which is supposed to go down after eating to indicate satiety, is less suppressed after a meal in those with obesity. Adipose tissue, we used to think, was just for energy storage. Energy storage in the form of triglycerides, and that's all it was for. That's what we used to think, but now we know that it's its own metabolic organ and it produces many paracrine and endocrine hormones, known as adipokines, with important effects on metabolism and immune function and is also detected at the brain level. Leptin and adiponectin are the two main ones that are produced by adipose tissue. And leptin effects are supposed to decrease appetite and increase energy expenditure, but as adipose tissue increases, the same effects are not seen, and this is likely due to leptin resistance. Adiponectin functions to improve insulin sensitivity and decrease inflammation in healthy tissue, but as adipose tissue goes up, the concentrations are decreased, and this leads to increased inflammation and insulin resistance and many downstream metabolic effects. The location of the adiposity also makes a difference, with less inflammatory effects seen in those that have subcutaneous fat compared to visceral fat, and that is partly why weight by itself oftentimes is not enough to determine metabolic risk, but if you combine it with abdominal circumference, it gives a more accurate assessment of their disease profile. So a person with the same amount of adipose tissue, the same weight, the same height, but if one is concentrated in the central and upper body, they will have more unfavorable changes related to metabolic complications, and that is because of the changes in the adipokines, the inflammation, and the downstream effects that happen. We now know that there are over 200, and actually somewhere around 236, different complications of obesity, and these are the metabolic conditions that most people are familiar with, like diabetes and hypertension, the biomechanical ones, such as obstructive sleep apnea, but there are also 13 different types of cancers, and these are common cancers, like ovarian cancer, breast cancer, colon cancer, prostate cancer, that are increased in individuals with obesity. So centrally, we talked about peripheral, now centrally, there's also overlapping brain circuits that help maintain energy and homeostasis, and the main regulator is the hypothalamus, and the hypothalamus is receiving these incoming peripheral signals, and it's gauging fuel availability, and then sending signals back to control food intake and energy expenditure, and this is what is happening physiologically in all of us, and this is referred to as homeostatic regulation. Under steady state conditions, all the energy consumed is metabolized to maintain our basal metabolic rate, our thermogenesis, and our energy expenditure. The excess fuel is stored to be used later, and it's required for human survival during times of starvation. The problem is that these pathways are now operating under conditions of sustained positive energy, and the body's efficient storage of fat can lead to obesity. So the body is always trying to stay in an energy-neutral state, but it's conservative for fat, and so if you have sustained balance, then it becomes inefficient. It starts to store fat, and then it leads to obesity. The second major player is the hedonic or mesocortico-limbic system, and this is located in our basal ganglia, and this is what we call our reward or motivation system, and it was important evolutionarily because strong food-seeking behaviors and motivating people to eat was critical during times of food deprivation. The system is regulated mostly by dopamine, dopamine, which is triggered also in response to many other things, including stress and emotions, cravings, external cues, and this can lead to increased food intake. Also, in this modern food era where we have commercials and advertising of food that is concentrated, ultra-processed, and very highly palatable, it can promote hedonic overeating, which is eating in the presence of metabolic satiety, meaning you feel full but you continue to eat because it tastes so good. They've done studies where they've used functional MRIs and have shown that people with obesity have increased activity in areas of the brain that drive anticipatory feeding, but decreases in areas of reward likely from decreased dopamine receptor. So what that means is that people with obesity need more food stimulus to achieve the same level of dopaminergic response to achieve the satisfaction. So obesity drives the wanting of food, but not the contentment, so they need more to reach that satisfaction. The third central regulator of food intake is our prefrontal cortex, known as the executive system, and this integrates the cost and benefits of our actions and it selects kind of the best deal. So some of the costs and benefits it considers are conscious, and those are things like, what is the future impact of your waistline if you eat this pastry, or calculating if you can afford this meal that you're about to buy. But the conscious, you're making a conscious decision, but a lot of it is subconscious, and in many animals, including humans, it appears that we are wired to value calories above other food properties, and the easier the calories are to get, the more we want to eat. And this becomes a liability, again, in a world where calorie-dense foods are more convenient than ever to purchase, prepare, and consume. It also can get very tiring to always have to be using your executive system to make those decisions. You're surrounded by all these foods, and you're having to sit there and be like, that food looks absolutely delicious, but it's not good for me, so I'm going to choose this food instead. You can do that, but over time, it is exhausting. So we talked a little bit about just how incredibly complex obesity is and all the factors that are in constant interplay, including genetic inheritance, central nervous regulation, and our environmental influences, but in the end, obesity is a result of disruption in energy homeostasis, resulting in pathophysiologic processes that produce and maintain an increase in body weight. And this can make it very difficult to lose weight, and more importantly, sustain the weight loss. So now we're going to talk a little bit about when to lose weight, some of the systems that go into effect to promote weight regain. In larger studies of patients who were taught lifestyle modifications, including nutrition, exercise, and behavioral modifications, only 20 to 25% of these people can continue to keep the weight off over the course of several years, so it's difficult. In this meta-analysis of 29 long-term weight loss studies, more than half of the lost weight was regained within two years, and by five years, more than 80% of lost weight was regained. So why is it so difficult to lose and keep weight off? We will talk about some hypotheses, such as the body weight set points, metabolic adaptation, and then the neurohormonal adaptation and behavioral changes that are most likely contributing, but it is not one theory for all. Everybody is different, and some of these theories can be a little bit difficult to prove because they are either tested in animal models or in small cohort studies. And because we are so complex as human beings, one person can have one adaptation and another person not. And so most likely, each of these are contributors, but it doesn't mean that if you have obesity, this is what's happening. But we'll go into some of these hypotheses. So the first is the body weight set points, and this is the hypothesis that the body will defend its highest fat mass. The sustained positive energy that occurs when you have excess adipose tissue causes the body to reset to a higher weight set point. And so when there is weight loss, it triggers this change where you have this change in neuroendocrine factors to promote weight regain. So in one study, they found that for every one kilogram weight loss, their total energy expenditure did go down by about 25 kilocalories per kilogram. However, it also promoted an increase of about 95 kilocalories per day of energy. And so although there was an energy expenditure decrease, people ate more because of the effects that went into place, such as increased hunger. So the body will strongly defend against weight loss, and it weakly defends against weight gain. There is neurohormonal changes that happen after weight loss, and this happens when there's a decrease in food intake and an increase in physical activity that's creating a negative energy balance. And so in this study, you can see that there was 50 individuals with overweight and obesity without diabetes, and they were followed for 10 weeks on this very low-energy diet. And on average, they were able to lose about 13 kilograms after 10 weeks. And they measured different hormones before initiation of weight loss, and then they did it again at 10 weeks and then at 62 weeks. Here is just showing three of the hormones, but they also measured leptin and quite a few others. They found that ghrelin, for instance, as an individual lost weight, their ghrelin levels increased. And even over a year later, their ghrelin levels were still higher than they were at baseline. Same thing with GLP. So ghrelin is a rixigenic. It tells you you're hungry when it's time to eat, and then GLP and PYY are satiety indicators, so make you stop eating. And these were decreased at the same time, even up to a year later. So the hormonal response changed to promote weight regain, and this was even after one year of weight loss. Metabolic adaptation is another hypothesis of why it's so difficult to keep the weight loss in effect. And this refers to the process by which the body adjusts its metabolism in response to energy intake or body mass. And there are several open debates in the research world about the actual magnitude of it. It can be a little controversial, and it's mostly because there have been different studies showing that it's a very large effect and others that have not shown as big of an effect. We do know that resting metabolic rate is related to our body mass, so the less mass that you have, the lower your metabolic rate should be. However, in patients who undergo weight loss, they have a reduction in resting metabolic rate out of proportion to the reduction in body mass, and that's what metabolic adaptation is. It's saying we know there's decreased RMI because they lost weight, but this is out of proportion of what would be expected for that amount of weight loss. This was particularly shown in a study in obesity in 2016, where they followed 14 of the 16 contestants on the Biggest Loser competition that was televised. And they found that although a substantial weight regain occurred six years after the show ended, the resting metabolic rate remained suppressed at the same average level at the end of the competition. So the mean RMR after six years was 500 kilocalories per day lower than they expected based on the measured body composition changes and increased age of candidates. And so 500 calories less than what was expected. Going into a little bit of the details, the weight loss after the end of the study was about 58 kilograms on average. Six years later, 41 kilos of that had been regained. Right after the study ended, 610, the resting metabolic rate was 610 kilocalories per day less than was expected. But even six years later, if you looked at the metabolic adaptation, so 704 below baseline, and then the amount of weight that was regained after doing those calculations, it was still a net average of almost 500 kilocalories per day lower than expected six years later after the weight loss. They also found that individuals that lost the most weight and were able to actually keep it off had the most amount of metabolic adaptation. And so it is thought that it is not necessarily a marker that it's bad. It's a marker of a changes in weight loss. They also think that because in Biggest Loser, the physical activity component was one of the very high or main treatments in addition to the low caloric diet, that this most likely is part of the reason why the metabolic adaptation was so much higher in this study compared to this next study, which I will talk about. So in this team, they looked at 171 sedentary overweight women who on average lost about 12 kilograms in their study where they were eating 800 kilocalorie diet. And they didn't do the testing. They did the testing, but it was after four weeks of weight stabilization. So after the weight had come off and they were trying to achieve a BMI of 25. So once they met that criteria, four weeks later, after weight stabilization is when they initiated kind of the testing from baseline and then when they did the post-testing. They found that one year post weight loss, 52% or they had regained about 52% of the lost weight. In two years, 83% of the lost weight had been regained. And when they looked at the resting metabolic rate, they found that yes, right after weight loss, there was a statistically significant amount of metabolic adaptation of about 50 to 60 kilocalories per day. But at one year and two years, they did not find a difference. And they did not find a notable difference based on weight as well. So their conclusion was that metabolic adaptation at the level of resting metabolic rate is minimal when measurements are taken under conditions of weight stability. And it does not predict weight regain up to two years after follow-up. So you can see this is very different from the previous study that I showed you where there was still a very high 499 kilocalories per day of metabolic adaptation. Different behavioral changes is also a contributor to the difficulties with weight maintenance. And it's for many different reasons. There are four common behavioral kind of adaptations that I know that I do and I'm sure a lot of us have done before. But commitment amnesia, it's kind of the forgetfulness of the degree of change in effort that is required to achieve initial weight loss success. So you know, when you lose weight, and then later on, you forget how difficult or what you actually had to do in order to lose weight. And you fail to do those same mechanisms. So the dietary changes, the increase of physical activity. As we go through life, we have altered priorities. These can be different life circumstances, changes in health status. We can get priority fatigue. So a lot of things are in our life, we have to prioritize, you know, job, family, all these different things. And it's not making healthy body weight a priority. Resorting to previous nutritional or physical activity habits after achieving initial weight loss success. So that means when you lose weight, you kind of revert back to your bad habits instead of maintaining those same habits that allowed you to lose weight in the first place. And then set point fallacy is the mistaken belief that once achieved, maintenance of weight loss will persist. And that is irrespective of, again, the behavior and nutrition and physical activity changes. So you know, an example is, I know if I could just get the weight off, I could keep it off. And we've already gone over, that's not true, and it's difficult, and it's definitely a marathon and not a sprint. So all of these changes make it difficult, but not impossible to lose weight. However, it does give you an appreciation of the complexity that is obesity and why a multidisciplinary team is needed to get the best and most sustainable outcomes. In some of the future lectures, you will learn about some of the medications that can treat obesity. And this is by targeting the central and peripheral processes that are dysregulated, the ones that we talked about. And so they target them. And it ends up making it easier for an individual with obesity to lose weight. This is one table from the American Association of Clinical Endocrinology, ACE, the Clinical Practice Guideline 2023. And you can see the mechanisms of these medications, how it is kind of targeting those central and peripheral processes that help regulate energy expenditure. So we are in this together. Thank you for taking the time to learn about obesity and for all the time and effort you put into caring for patients with obesity. Continue the good work efforts that you are doing, and thank you for listening in. Have a good day.

obesity

pathophysiology

genetic factors

energy homeostasis

environmental factors

weight loss

pharmacological interventions