Weighing the Facts of Obesity

I'm thrilled to welcome you to the last Longwood Seminar of 2018. Thank you for being with us tonight. I'm Gina Vild. I'm the Associate Dean for Communications and External Relations at Harvard Medical School. We have been offering this mini med school for 18 years, and it's a success because of your continued interest and enthusiasm. There are so many people who have been attending year After year. You are familiar faces, and a Longwood Seminar family to us. So I want to thank you for your engagement, for attending, for joining our discussion on social media, and

from tuning in from locations all over the world, because I'm really thrilled to also welcome our live stream viewers tonight. I'd like to share with you that this year, the first three seminars were viewed by more than 60,000 people from all over the world, including countries Brazil, Japan, Australia, South Korea, Morocco, and the United Kingdom. So, thank you. We're thrilled to have you be a part of this. And I invite you, if you missed any of this year's seminars, or would like to view any of our past seminars, many of them are Evergreen, please look

at the Harvard Medical School website. I also invite you to access additional Harvard Medical School resources by visiting Harvard Health Publishing website, www.health.harvard.edu, where you will find extensive health-related information, including tonight's topic of obesity and nutrition. We ask that you help us keep our future Longwood Seminars fresh and topical by responding to a survey that we're going to be sending you within a few weeks. We use these surveys to evaluate the success of our seminars and to help us plan future seminars, including topics. We do tend to crowdsource our topics, so your ideas are valued

and appreciated. Now, a couple final announcements. More than 160 of our attendees have earned certificates of completion by attending three or more seminars this year. And, that number, I'm told, may be as high as 200 individuals. So we're thrilled. We're awed by your commitment, and we honor your achievement, so please join me in congratulating all of you. [APPLAUSE] Thank you. If you've already qualified, you will be able to pick up your certificate in the lobby after the seminar, or, we will mail it to your home. We also will be mailing our professional development point certificates

for teachers. Those will be coming to you in the mail in the coming weeks. Our speakers will be taking questions at the end of the talk, so please write your questions On a card that you will see our staff passing up and down the aisle. Just hand them your questions. If you're watching from the live stream, please write your question in the Facebook Live or the YouTube comments section, and we will try to get to as many of those as possible. Now, please silence your phone, but don't turn it off, because we invite you to

join our Twitter conversation using #hmsminimed. Before we formally begin the program, I just want to take a moment to introduce Two members of our team who, and really to express my gratitude to them for all their extraordinary work. They're good listeners. They've listened to everything you've told them. They've tried to really orchestrate a perfect seminar season for you, and they have tremendous attention to detail. So please join me in thanking Barbara Berlin and Elsa Fong. [APPLAUSE] Thank you. Thank you so much. Thank you. Thank you. OK, for this evening's program, Weighing the Facts of Obesity.

Obesity tops the list of acute health challenges in the US. Here are just a few statistics from the National Institutes of Health. Did you know that more than two in three adults are considered to be overweight or obese? More than one in three adults are considered to be obese. About one in 13 adults are considered to be extremely obese. Particularly worrisome as this, the statistics for children, about one in six children and adolescents ages 2 to 19, Are considered obese. But what's the root cause, and why is it affecting children as young as two years

of age? Former First Lady Michelle Obama worked for eight years to raise awareness for obesity. In launching her initiative, Let's Move, she said the physical and emotional health of an entire generation is at stake. You may already know that obesity is not simply the result of too much food and too little activity, but what are the contributing factors? Is there a connection between obesity and genetics? Does being overweight put you at risk of developing chronic medical conditions? And, what positive steps can both children and adults take to shed the extra pounds, and to begin to

rebuild their physical and mental health? We don't yet have all the answers, but we do have is a panel of experts from Harvard Medical School. They're here with us to share their research expertise on the causes of obesity, and possible treatments that could help combat this epidemic. Dr. Frank Scheer is an associate professor Of medicine at Harvard Medical School, and Director of the Medical Chronobiology Program at Brigham and Women's Hospital. Dr. Christos Mantzoros is a professor of medicine at Harvard Medical School, and the Director of Human Nutrition Unit in the Division of Endocrinology Diabetes and

Metabolism at Beth Israel Deaconess Medical Center, and the Joslin Diabetes Center. And first you'll hear from our moderator, Fatima Cody Stanford. Dr. Stanford is an instructor of medicine at Harvard Medical School, and an obesity medicine physician at Massachusetts General Hospital. A nationally recognized expert on obesity, Dr. Stanford has recently been exploring the impact of behavioral environmental factors in the complex process of weight regulation. Thank you for attending, and please join me in welcoming our guest speakers. [APPLAUSE] Good evening, everyone. Let's try that again. Good evening. Good evening. Excellent. Today we're going to learn about weight

bias and stigma. We're going to spend some time learning about obesity and its pathophysiology, and as soon as my slides appear there, because they are here, we will move forward. So I'm Dr. Fatima Cody Stanford, and we're going to spend time talking about weight bias and stigma, and its impact on care. So what we're going to do, is we're going to discern how weight bias and stigma contribute To energy storage. We'll learn about how early life interactions influence weight bias. Then, we'll determine the deleterious impact of weight bias on health outcomes, ascertain how health professionals

harbor both implicit, which is bias that is inside of us that we're not aware of, and explicit, which is bias that we are aware of. And then I'm going to explain how organized medicine organizations have sought to tackle the issue of weight bias. So, we're going to start talking about my childhood. So, I am in this orange here. So, that's me, and this is my sister. So I thought-- I wanted to make sure that we were both included. And the reason why I'm starting here is because I was humbled, and then actually a little bit

perturbed when a colleague of mine came up to me and told me that at the age of five, I came up to her in dance class, which is why you see these dance pictures, and said to her that she was fat. Now, she just told me this about a year ago. She actually is an obesity medicine physician practicing currently, but she said that that influenced her life. And she said that if anyone was-- if I was capable of change with regard to this issue of weight bias, then anyone was capable of change. So that was

quite humbling, that someone that dedicates my life to the care of patients that have obesity-- you will notice I will state the words "have obesity" because this is a condition that people aren't defined by. They have the disease of obesity. So we're not going to refer to patients as obese patients throughout the course of this presentation. Rather, these are patients that have obesity. But you can imagine, that if someone that is committed to this disease process, that it was quite startling that at the age of five I went to a colleague of mine, I guess

our childhood friend, and called her something that had a major impact on her life. It could have been a negative impact. Thankfully, it was a positive impact. But let's think about how, starting at this very young Age, this causes major issues. Now, we've learned about energy balance, and we've learned that it's about just calories in and calories out, the food and beverages that we take in, and the bodily functions, and physical activity. We have stool output, et cetera. But if it were really the simple, I wouldn't have a job. I would not be an obesity

medicine physician scientist. So we're going to learn about why this is indeed incorrect. It's not a lifestyle choice. It is a disease process. And yes, we are interacting with our environment, which Is an obesogenic environment. But we're going to learn about why this is indeed false. So, obesity is a multi-factorial disorder where genetics, environment, development and behavior all play a role in a person's likelihood of having obesity. Now, we're going to start with some really complex information, but this will explain why obesity is a disease process. So what really regulates our weight is the brain,

OK? So the brain is very important in all of this. It helps define our set point, or set range, for our weight. The hypothalamus, which is located here, Gets signals from our fat tissue, our large intestine, our small intestine, our pancreas and our stomach, and then sends signals to your brain to tell us not only how much to eat, but it also tells us how much to store. So let's look at the brain. The brain is getting signals about our diet quality. So I will always ask my patients not about the number of calories they're

eating. I'm asking them about the quality of their diet. Their energy density is important. It's getting information about physical activity. Now, the important thing for us to know about physical activity and the role it plays in regulating weight, is that it helps to create weight stability. However, in January of every year, in the United States and across the world, we go and join gyms to lose weight. When our gym enthusiasm doesn't lead to weight loss, many of us leave the gym. That's important to not do, because we know that physical activity is one of the

best things that contributes to weight maintenance. Not often weight loss. On average, people lose no more than about to two pounds if they're dedicated to their physical activity, but it does have a lot of other positive impacts. Now sleep. Sleep quality and duration plays a large role in how the body regulates weight, and we'll hear about that a little bit later from one of the other speakers. Medications that we prescribe, as physicians, can lead to weight gain. I go through a laundry list with patients, of medicines that can lead to weight gain. I'll go through

that now with you. Lithium, Depakote Tegretol, Celexa, Cymbalta, Effexor, Paxil, Prozac, Ambien, trazodone, Lunesta, Gabapentin, gliperide, glipizide, glimepiride, atinalum, Toprolol, propanalol, long-term insulin, and long-term prednisone, just a few of the drugs that can cause weight gain. And I do do that with every patient. [APPLAUSE] Patients that have circadian rhythm disturbances can have issues with regards to rate. So those pathways that we looked at in the brain are Affected by circadian rhythm. And then, finally, thermogenesis, which is just how much we burn with activity and with rest. A lot of that is genetically determined. So these

things play a role in how the body is regulating your weight, and whether or not you have a propensity to having obesity. Now, this is a very busy chart, and this is something that you can access by looking at the obesity society infographics. But what I love about this chart, is that it explains the potential contributors To obesity that we know of. What you can see there are things that happen inside of the person. There are things that happen outside of the person, that-- and they're contributors or influencers to obesity. These things here at the

top increase how much you take in. These things here at bottom decrease how much you're able to burn, and these things here in the middle affect either how much you're eating, or how much you're burning, or notice there's an unknown here. We just haven't figured it out. But this is how complex it is. Now, we're not going to go through each of these factors here, but we are going to touch on a few of them, just to give you an idea of looking at these contributors or influencers. Now when we look at contributors or influencers

to obesity, they fall within these broad categories of biological or medical. Food and beverage behavior and environment, maternal and developmental, social, psychological, economic, and then environmental pressures on physical activity. Now let's look at some of these contributors that happen inside of the individual, things that might create, then increase Intake or hyper-reaactivity to environmental food cues, delay to tidy, so this delayed idea of how long it takes you to feel full. Disordered eating, we can have decreased expenditure explained by the gut microbiota, meaning the bacteria in the gut of individuals that has obesity is different than

the bacteria of those that are lean. Thermogenesis, we talked about. Physical disabilities, things that might affect your intake and your expenditure may be genetics and epigenetics, age-related changes or mood disturbances. Things that may happen outside of you that contribute to your intake are environmental or chemical toxins, pervasive food advertising, or large portion sizes, things that might decrease your expenditure or our built environment, how our environment allows us to be active, sedentary time, labor-saving devices, and things that might affect our increased intake or expenditure may be weight bias and stigma, which is the focus of my

segment, weight cycling, and/or maternal or paternal obesity. Now when we look at the bias, you know, the other thing that we really pay attention to, Especially here in the United States, is race bias. Now race bias-- I specifically put up this post here, is that if you did a Google search and typed in the term black teenagers, or black teen men, you got mug shots, unfortunately, so nothing positive. If you typed in a white or Caucasian teen, you got these kind of nice, smiling pictures that was featured in The Washington Post. So this is pervasive,

even in our search engines, unfortunately. Google has tried to change their algorithm to combat this. Now when we look at weight bias, we do have these kind of adjectives that are demonstrated here. So you have this very lean individual, and so there are adjectives that might be used to describe her as vain, superficial, ambitious or conceited. For this woman that has obesity on the right, she might be considered to be lazy, insecure, given, undisciplined, or passive. So just by looking at them, we've made judgments on what their qualities are without learning anything about them and

their experience. Now, let's look at when do we really start to exhibit bias? When does this happen? So there was this study that was done, looking at mothers and children, and they looked at children across an age spectrum. And they found that older infants, about 11 months of age, tended to view, or have a preference for, a heavier body type, so a body type that had obesity. Now, as they got a little bit older, older toddlers, so around 32 months of age, instead pervert looking at average-size or leaner individuals. And this was strongly influenced by

the mother's prejudice against those that had obesity. So just as early as 32 months of age, children begin to demonstrate bias. Now, let's look at how parents can influence weight bias in children. This was a big study that was done, exploring the role of parents in the transmission of the stereotype about body size and attitudes. They looked at 279 three-year-old children and their parents, and they asked the parents to complete self-reported body size attitude and dieting Measures, and interviewed the children. Over time, negative attitudes towards large bodies and awareness of weight loss strategies are merged,

but there was a really strong preference, such that fathers that had this significant bias were more likely to convey it upon-- amongst their sons. For daughters, there wasn't specifically that the fathers or mothers had a preference in terms of conveying that information. So, we have to pay attention to what's happening, and our biases, as people that are parents, and how They affect our children. Now this was a great city. This was actually done in Germany, so for my German audience there, this study was looking at weight teasing and weight bias internalization, and psychological functioning, and

they looked at close to 1,100 male children between the ages of 7 and 11 in Germany. They completed surveys on weight teasing, weight bias internalization, restrained eating behaviors, and emotional conduct program-- problems. And here, you can see that BMI is the thing that they looked at. BMI stands for body mass index, is what the World Health Organization uses to define someone's weight status. And if someone had issues with their BMI, they were predisposed to weight teasing and predisposed to weight bias internalization. They also decided to restrain their eating. Now, weight teasing was specifically associated with

emotional problems and conduct problems in these individuals that struggled with obesity, And then internalizing the bias they experienced also affected both restrained eating and emotional problems. So here we are seeing that in these young boys, this is affecting their medical health and also their psychological functioning. So does this really mean anything? Does this translate to outcomes later on? Absolutely. So, this particular study looked to identify whether weight-based teasing in adolescents predicted adverse eating, or weight-related outcomes 15 years later. What they did, was they collected information from Project EAT-IV, which was almost 2000 individuals. And they

did a cohort study, meaning, they started in 1999, and went over all the way to 2015, to see what the impact was of this weight teasing in adolescence was on individuals. So what you found here is that weight-based teasing in adolescence predicted a higher body mass index, and obesity, 15 years later. So people that had a high BMI, then led them to have binge eating, dieting and unhealthy weight control, and affected their body image. Now for the females that were studied, what we saw was that both peer and family-based teasing caused issues, whereas for the

males in the study, peer-based teasing specifically appear to have the highest impact on their BMI long-term. So, let's look at weight bias internalization and metabolic syndrome, and metabolic syndrome is this likelihood of developing obesity. They looked at blood pressure, waist circumference, glucose, which is blood sugar, triglycerides, which is a type of cholesterol, and HDL, which is a good cholesterol measure, And adults with obesity in a weight loss trial. In this trial, you can see that this was predominantly African-American and 88% female, which is pretty indicative of what we see in weight management. And 51 adults,

or about a third of the adults met criteria for metabolic syndrome. And they're higher weight bias internalization, so we're really feeling the impact of the weight bias they experience, predicting greater odds of metabolic syndrome and high triglycerides. And high triglycerides is one of these bad cholesterols. So, the mental health of persons with obesity who experience bias, it causes physiologic stress. It leads to weight gain. It leads to disordered eating, and then maladaptive behaviors, which we see in adult life. So, this particular study looked at about 20 to 2,400 adults that completed questionnaires about weight stigma,

bias internalization and coping strategies. Women, overall, reported higher weight-based internalization compared to males. Black men and women, however, reported less weight bias Internalization than white men and women, and black women were less likely and Hispanic women were more likely to cope with stigma using disordered eating. Black men, however, surprisingly, were more likely to cope with stigma using disordered eating, which was a bit surprising in their findings. So, what happens with medical students who become your physician? So they did a study at Wake Forest, and they looked at 310 third-year medical students between 2008 and 2011.

They took a test called the Weight Implicit Association Test, and in this particular test, they found that a third of the individuals exhibited moderate or strong explicit bias. Explicit bias is this bias that we know that we have to individuals that struggle with weight. But what was more surprising is that 2/3 were unaware of their implicit anti-fat bias, so that they didn't realize that they had this prejudice towards individuals that struggled with their weight. This is a really great study. This is the Medical Student Bias in CHANGES study. And this was a study that looked

at students for 49 US medical schools throughout the country. These were public and private schools, and they made sure that they covered all regions within the United States. They looked at about 1,800 medical students at the beginning of their first year, and at the end of their fourth year, which is the conclusion of medical school. They used web-based surveys to include measures on weight bias, and their medical school experience, and climate. So, in the implicit bias, remember, implicit bias is this bias that you're unaware that you had. They also compared this to the public. So

they looked at about 398,000 persons in the public. And you can see that the weight bias measures in the public are here, and the CHANGES study, which were the medical students, is here in this line. So over the course of that four years of medical school, you saw a decrease in implicit bias within the medical students, compared to the general public. But, let's not be so excited about that, because explicit bias, which is that bias That we know that we have to individuals that struggle with weight, you can see that over the course of those

four-- those same four years, we saw an increase in both the public and within the medical students in terms of their explicit bias towards that persons that struggle with weight. So what did they learn? That medical students may reduce-- or medical schools may reduce weight bias by increasing positive contact between students and patients with obesity, eliminating unprofessional role modeling By faculty members and residents, and altering the curricula to focus on treating difficult patients. So, they did a big systematic review, which means they looked at all of the literature, looking at weight bias in health professionals,

and they found 15 studies with health professional students, and two studies with health professionals. So these are people that are no longer students, people that have finished their training. What they found was that the studies reported changes in health professionals' beliefs and knowledge about obesity And its ideology. However, the evidence of effectiveness is poor, and we don't know much about how long-term effects are, because the studies have really not studied the long-term impact of any of these issues. So, when we're looking at weight stigma and the treatment of obesity, it's important for us to recognize

that weight stigma leads to stress. It affects eating and physical activity behaviors, so we see binge eating, increased caloric consumption, maladaptive weight control, which we've talked about, disordered eating, lower motivation For physical activity. We also see physiologic reactions. So, we see increased levels of stress hormones, like cortisol or c-reactive protein, increase in our blood sugar, and increase in our blood pressure. When patients experience weight stigma, they have poor treatment adherence, less trust of health care providers. They avoid follow-up care. They delay in preventing-- getting preventive health screenings, and they have poor communication with their providers

because they really don't respect them. This also leads to weight gain and physiologic distress with depression, anxiety, low self-esteem and poor body image, and it can lead to poor glycemic control and advanced chronic disease, which is very important. And then we also see lower health-related quality of life. Now when we look at ethnic identity and how it affects implicit bias, there are similarities and differences between African-American and Caucasian women. Overall, African-American women have less explicit weight bias, meaning, we don't specifically go to people and give them information that tells us we have weight bias, But

when they use the Implicit Association Test, which is a pervasive implicit anti-fat bias, African-American as well as non-Hispanic women were found to have implicit weight bias. African-American women that had a lower ethnic identity, so maybe did not as much identify with being African-American, were negatively biased. And non-Hispanic white women who had higher ethnic identity were more likely to be negatively biased. So that ethnic identity and how people relate to their race and ethnicity plays a large role. Now, what-- how does this translate To what happens in daily life in terms of things like graduate school

admissions? They did a study, and they looked at all of these schools, which I've heard is not in the live stream, but the higher BMI significantly predicted fewer post-interview offers of admission into psychology graduate programs throughout the United States. This was specifically worse for female applicants. And, BMI was not related to the overall quality of the applicants, but it did relate specifically to the number of weight-- Stereotypically weight-related adjectives in the letters of recommendation. Higher BMI was related to more positive adjectives in the letters, but overall, they were not being accepted as much into these

schools. And then, there's a lot of bias in employability. So they specifically did a study. They gave kind of pictures of this woman, and they explained-- they rated their impression of her overweight image after learning that she previously Gained and lost weight. So people were really happy that this patient lost weight, but when they found out that this patient had undergone weight loss surgery, they experienced significant bias compared to whether or not-- comparing that to someone that potentially could have lost weight through diet and exercise. When I think about weight loss surgery, I think it's

important for us to recognize that it's a tool in the spectrum of treatments for persons that have severe obesity. So, we should not judge negatively For the people that need to utilize that tool, but just recognize that it's a tool that someone like myself might not need to utilize to achieve and maintain a healthy weight. So, people have heard of this show, The Biggest Loser, and so, how does this affect our weight bias? People might say, "Oh, it improves our weight bias," but they did a study where they looked at people that looked at an

episode of The Biggest Loser and compared those to a control group, which was just a nature show. And what they found, was pretty quickly, that persons that watch this particular show, just one episode, exhibited higher levels of weight bias because it showed the controllability of obesity. Now what most of you guys are unaware of, is that 96% of the patients that go on The Biggest Loser regain all of their weight, because there is the set point that we talked about, which is why we start off looking at the hypothalamus and how it regulates weight. There

is a decrease in resting energy expenditure, and so, when you decrease your resting energy expenditure, Which is how many calories you have to have on board above something like 600 calories, which is where theirs gets dropped to after their very intense exercise and eating programs, they eat 601 calories, their bodies do whatever it can to compensate and come back to where it was previously. So they looked at levels way by using the IAT, the Implicit Association Test that we talked about, the Obese Person Trait Survey which is the OPTS test, and the Anti-Fat Attitude Scale

at baseline and one week later, and you can see that they felt as though this Was more controllable in these individuals, so significant higher bias after looking at the show. So what are we doing here? So as an officer of the Massachusetts Medical Society, I helped write the legislation that recently passed last year, looking at discrimination against persons with obesity. And it states the following: "The Massachusetts Medical Society recognizes that weight stigma in the health care setting leads to a disparity of care and poor health outcomes in patients with obesity, that the Massachusetts Medical Society

will develop and promote educational information to physicians, and physicians in training, about weight stigma, And that the Mass Medical Society will advocate for legislative policies and institutional practices to prevent weight stigma." I also helped draft the language that passed the American Medical Association right before it passed, and actually the year after, the Mass Medical Society. So this just passed last annual meeting, which was last June. And it is as follows. It says that, "Our AMA," which is the American Medical Association, "encourages the use of people first language, meaning that we say patients with obesity, Patients

affected by obesity, in all discussions, resolutions or reports, regarding obesity. That we encourage the use of preferred terms in discussions, resolutions and reports regarding patients affected by obesity, including weight and unhealthy weight, and discouraging the use of stigmatizing terms, including obese, morbidly obese, and fat. And, to educate health care providers in the importance of people first language for treating patients with obesity, equipping their health care facilities with proper size furniture, medical equipment, and gowns for patients With obesity, and having patients weighed in a respectful fashion." So, in summary, weight stigma has a negative impact on

the health and psychological health of patients who struggle with obesity. It's seen as early as infancy, and maternal and paternal anti-fat bias influences children. Weight bias may be mitigated by proper training in health professionals, and that is all. So I want to thank you for your time. I'm going to shift over to Dr. Frank Scheer who will take over from here. [APPLAUSE] Thank you, Fatima, for the introduction. I would like to thank the organizers for inviting me to speak here, and I'm very excited, seeing all you here attending. And, I'm a little bit nervous, because

I hear this is attended by maybe 60 or 100,000 people. But, I will be talking to you about kind of another side that links to obesity and metabolic and cardiovascular disease, which is sleep and the circadian system. And I'm dedicating this lecture to my lovely wife, And my two fantastic sons Bart and Toby, my wife Linda. And, as you've heard, obesity is an epidemic currently in the United States and in many developed countries. This is an image from just about 20 years ago or so. So, the rates back then were about 10% to 20% of

the population in the United States had obesity. But then just in a short amount of time, just 20 years, this doubled to about 20% to 40%, depending on the states you are looking at. So a very rapid increase. And you can see that it's especially True in the southeastern parts of the United States, and I'll ask you to just keep that in mind. So, we heard a lot about the causes of obesity, if you think about an individual level. And so, what are the primary factors, from a biological individual point of view? Well, these are

genetics. So, each person is different, but also your diet and your physical activity. And, of course, they're connected, because your genetics may drive your diet, and may drive and influence your physical activity. But if we ask what of-- which of these factors that really changed a great deal in our recent-- in the recent years which is causing the rapid rise in the obesity epidemic? Well, it's not going to be genetics, of course. Because human species hasn't changed much in the last 20 years. So the focus has been, for many decades, on diet and physical activity.

And this is also why behavioral approaches to prevent or treat obesity have been focused on what we eat and how much we eat, and how much we exercise, And how much we limit sedentary activity. But might there be other lifestyle factors that we can think of that may help us? Because, the truth is, we need all the help we can get, because diet and exercise aren't enough, as is clear from the obesity rates and in the country today. So, one of these factors might be sleep, which is what I'm going to try to convince you

of, and so Toby, my youngest son, actually made me aware of insight by a famous actor who actually recognized that sleep is-- might actually be a super power. So Bill Murray wrote this. He said, "I love sleep, because it's like a time machine to breakfast." OK, so there's already a clear link between sleep and metabolism there, right, and nutrition. But on a more serious note, sleep is a behavior that is really representing one-third of our life, especially, of course, when we are babies and toddlers, we sleep a lot. But even though we sleep less and

less as we age, it represents about a third of our life. And so, that factor by itself has really-- Intrigues many investigators and clinicians. And it was actually Alan Rechtschaffen who is one of the pioneers in the sleep field who actually was-- co-invented the Sleep Scoring System, who very eloquently indicated that, "If sleep does not serve an absolutely vital function, then it's the worst mistake in evolution." So, now this picture of-- the same kind of picture as I showed you before, of obesity, now for short sleep. And, what you can see is that the rates

of short sleep, and here defined as less than seven hours of sleep per night, are between about 25 or 50% of the population. You'll notice, again, that it's especially this same region here that is mostly affected. Now, this is, of course, no evidence at all. And so, now we have to really look at the scientific evidence. And, the scientific evidence, based on epidemiological data, have shown, indeed, that individuals who have either short sleep or disturbed sleep have an increased risk of being obese, having Diabetes, or having cardiovascular disease. And this is one example. Here, you

can see short sleep, as assessed by actigraphy. So, this is a wrist-worn device, motion detector, that can objectively estimate sleep. And, of course, you've all heard of many of these commercial devices, but there are better scientific devices as well. And, in this study, it was shown that as sleep duration decreases, the odds of being obese goes up. And so, for example, here, less than five hours of sleep, it's doubling or quadrupling of the odds of being obese. Now, of course, this is an association. And, we all know that association is not causation. So unfortunately, epidemiological

studies by themselves cannot make that case. So we need to ask the question, what is the causal evidence for the link between sleep and obesity, and is it actually sleep disturbances that cause obesity? Or, might it be that if people have obesity, that this perturbs their sleep? And, there's good evidence for that as well. As you will probably know, the chance for sleep apnea Is greatly dependent on one's body mass index. And so, because sleep apnea influences your sleep, that is a very reasonable reverse causality right there. But there is actually a very strong experimental

data to make the case to link, actually causally, decreased or impaired sleep with adverse health consequences. So, highly controlled in-laboratory studies, experimental within subject, randomized controlled trials, have shown that disturbed sleep or shortened sleep leads to disturbances of those factors involved in glucose control, such as decreases in the release of insulin, Or decreased sensitivity to the insulin, which are both risk factors for the development of Type 2 diabetes. Similarly, although the picture is a little bit more complicated, there is also good evidence for changes in hunger and appetite hormones, also hunger and, if people are

allowed how much they eat of experimentally manipulating sleep duration, and finding that people actually will crave to eat more. And, there's also some preliminary data that when you are not sleeping as well, that you will not exercise as much, which is not hard to understand when you're feeling exhausted and tired after a bad night of sleep. So this provides experimental data to show that, indeed, short sleep or disturbed sleep can lead to increased risk for developing obesity. And similarly, for cardiovascular disease, or changes in inflammation, or changes in blood pressure, an autonomic nervous system regulation

is also tied together, disturbed sleep to increased risk for cardiovascular disease. Now the image actually gets worse, because, as I just mentioned, if you have an increased risk for obesity, and this obesity may disturb your sleep through sleep apnea, perpetuating and aggravating Your disturbed sleep altogether. And, so, yes. So, poor sleep-- there's real evidence that this leads to poor health. And so, this is one of these experimental studies. This is work by Karine Spiegel and Eve Van Couter and colleagues in Chicago, a very nice study showing, in early days, and replicated by many various studies

that already two days of short sleep, four hours time in bed, results in changes in physiology, so an appetite hormone. So, ghrelin is a hunger hormone. Leptin is a tidy hormone that will actually stop you from eating. And as you can see, this balance is such that these people will experience an increase in hunger and appetite throughout their whole wake up as shown. And so, this provides this experimental evidence bit by bit, that, yes. Short sleep can result in increased risk for developing obesity. Now, sleep, for the longest time, Has been viewed as something that

is by the brain and for the brain. And so, the initial studies really have focused on the cognitive consequences of impaired sleep, such as impaired memory and poor cognitive function. And, of course, this is very important, you know, for your school grades, for example, or for traffic accidents, crashes on the road, many severe consequences. But it doesn't stop there, because short sleep has many various effects, also, on the rest of the body. So, I've already been talking about blood sugar control, Hunger, and especially, high-density foods if sleep is disturbed, and decreased physical activity. Of interest,

if you are dieting, and you are restricting your sleep, you actually are impairing the fat loss, and actually stimulating muscle loss, as compared to when you're well-rested. Increases in blood pressure, and even vaccinations against, for example, the flu vaccine, aren't as effective when you have been exposed to short sleep. So, conclusion is that sleep is not just for the brain, but it's also for the body. And I think that the National Sleep Foundation put this very nicely, saying, that "Sleep is as important as diet and exercise, only maybe, easier." OK, so I think we should

add sleep here to the list of behavioral-- considerations for behavioral approaches, where we can tackle obesity and other metabolic and cardiovascular diseases given the existing literature out there. Now sleep is something you typically do at night, and not during the day. And sleep is, thereby, also one of the factors that is controlled by the circadian system that you may have heard of. And so, the question is, is there something specific about the circadian system that has changed over the recent years? And, of course, you get-- you will have heard about many of these examples where

the use of electronics, handheld electronics, iPads, or telephones or computer screens may interfere with your sleep, or people are exposed during the night to external light pollution, or, they may be doing nighttime snacking. So there are many behavioral factors that have changed since the invention of the light bulb and beyond that have really impacted on how we schedule our day. We're no longer purely a diurnal species. And so, what does the circadian system influence? Well, it's not just sleep that it influences, that you will have heard of. It affects basically most, if not all, of

our physiology and our behavior. So, for example, cardiovascular control, immune function, Endocrine system, the autonomic nervous system. And, with the knowledge that the circadian system influences these many aspects of physiology, the question immediately comes up, how might this be involved and also disease states? So pathology. And, of course, we can think about prevention, behavioral lifestyle modification. We can think of diagnostics. If your metabolite or your hormone or your measure of interest varies by time of day, one has to keep that into mind treatment approaches. For example, in the cancer field, the use of chrono-chemotherapy is

something that really has grabbed the attention, also, of the NIH. And we can also think about genetics and personalized medicine, where knowing the interindividual differences between one's chronotype that might be based on clock gene differences may help us in viewing and treating the disease. So, I'm going to take you back in time. We spoke about a time machine before, But now I'm going to really take you back in time, so 3.5 billion years ago, that's a lot of zeros right there. Since when life on Earth has been exposed to the day-night cycle, of course, due

to the rotation of the Earth-- of the rotation of the Earth around its axis. And life has found ways to adapt to this. Because, of course, these are very dramatic changes in the environment, light-dark cycles, radiation, temperature cycles, predation, et cetera. And so, that's illustrated here by this heliotrope plant that opens its leaves during the day and closes them at night. And so, you may wonder, why does this leaf open-- this plant opens its leaves during the day? Might this just be the exposure to sunlight, and then when that is absent it closes them again?

Or might it be an internal clock in the plant? And this very question was a question that was asked 300 years ago by a French astrophysicist Jacques Dortous de Mairin. And what he did, is he stopped the rotation of the Earth, at least from the point of view of the plant, of course. Because he placed the plant in continuous Dim light conditions. And, to his amazement, when he very carefully looked at the plant, he found that the plant was still opening and closing its leaves. It was a rhythm of about 24 hours. So really, the

first piece of evidence that there is such a thing as a circadian clock in living organisms. And, so then, it was quite, for a long time in the circadian field. But then, the next question was, OK, we have an internal clock, and there was more evidence coming after that. But where is this located? And so, the first question that was asked was, to us in the mammalian system. And the approach that was taken was to look at different brain areas. If you would remove those brain areas, if the animal would become arrhythmic, if it lost

its circadian rhythmicity. And it was found that there is one particular area, very small in the hypothalamus, called the suprachiasmatic nucleus, that if you remove that specific area, the animal becomes Arrhythmic, but no other areas. So that indicated, well maybe, this is a key area that is the master clock. But there was not enough, because maybe it's just a path through, something is passing through the suprachiasmatic nucleus. Maybe that's not the real clock. So the next question was, if you now move this superchiasmatic nucleus in a Petri dish, can it still be rhythmic? And this

was done, of course, much later. But it was shown that even in a Petri dish, This tiny structure, a cubic millimeter, is able to generate this beautiful 24-hour rhythm in a dish when it's completely separated from the rest of the body. So it's not only necessary, it's also sufficient for circadian rhythm generation. So for the next 20 years or so, that was the overarching model, that we have one clock in our brain, and this dictates all our 24-hour rhythms. But then, about 20 years later after this, it was recognized that the same property is true

for virtually every single cell in your body. So if you take a heart cell, a liver cell, a fat cell, even a skin cell, you put it in a Petri dish, it will cycle with a 24-hour rhythm. And so, the whole model changed, where we now have a master pacemaker in the brain, but that is like a conductor of an orchestra, that synchronizes all the rhythm, all the clocks throughout our body. So then the question was, well how on Earth can a single cell generate a 24-hour rhythm if there is no neural network? And so,

the quest for this molecular machinery actually resulted just last year in a Nobel Prize In physiology and medicine by Jeffrey Hall, Mike Rosbash, and Mike Young, who discovered using the fruit fly, the underlying molecular machinery, which was a transcription translation feedback loop, so circadian clock genes, of which the protein products inhibit their own production. And the Nobel Prize committee recognized this contribution as a fundamental discovery in biology. But, in addition, they also recognized the implications for health and disease. And so, for example, this is a quote from the Nobel Prize committee that, "Our wellbeing is

affected By the temporal mismatch between this internal timing system and our environment." And, the most famous example is, of course, jet lag if you travel to Europe or to Asia, or for listeners there, to the United States. You will experience what the powers of the circadian system. But a more dramatic example is shift work, where people are chronically exposed to the back and forth of the behavioral cycle that is working against their internal body clock. It has been associated with a variety of diseases. And so, examples of circadian disruption Include genetic mutations that can disturb

the clock, anatomical, as I mentioned to you, lesion studies. Behavioral, if you miss time, either the environment or behavior, such as the sleep-wake cycle, feeding, or the light-dark cycle. And shift workers, as I've mentioned, and also under highly-controlled laboratory studies that we've been focusing on primarily. And all of these point to increases in the risk of obesity, diabetes, cardiovascular disease, and World Health Organization Has recognized shift work as a probable carcinogenic. So this is work by Christopher Morris, a very talented post-doc in my lab, who has shown that circadian misalignment has adverse effects for glucose

control, so blood sugar control, as a risk factor for Type 2 diabetes, for increases in inflammatory markers, and increases in blood pressure, both risk markers for cardiovascular disease. And these studies were done in healthy controls, raising the question among critics, well, maybe this is not true in real shift workers because maybe they're adapted, or maybe they're selected, And they are not affected. Also here, unfortunately, we found that chronic shift workers are not immune against the adverse health effects of circadian misalignment. We also found that it's not just the impaired sleep during the day that contributes

to this adverse effect. So circadian alignment, I think, is a second behavioral component we should consider, and the forefront of new discoveries to help with diet and exercise to improve cardiometabolic health. And then finally, I want to talk about meal timing, which, of course, meal timing is one of these elements, one of these behaviors that may be aligned or misaligned relative to your circadian system. And so, in 2009, work by Deanna Arble and colleagues show that eating during the time window where the animals would normally be sleeping, but the animals then become obese. And so,

then the question was, what about humans? And so, this led to a very fruitful collaboration with Marta Garaulet, whom I met about six years ago, who-- with whom I was discussing this common interest in food timing And obesity, where she had this beautiful population of patients who are either obese, or were overweight, who she then had undergo a 20-week-long weight loss intervention where the question was, does the timing of their main meal, in this case, lunch in Spain, whether this was predictive of the success of their weight loss. And, to our surprise, we found that

the effect was actually quite large, and that the early eaters lost about 25% more than the late eaters. We didn't find differences in energy intake or physical activity, and we're now Studying whether energy expenditure, that the previous speaker also commented on, might be a key mechanism that links meal timing to differences in weight regulation. But, there are many other pieces of evidence that have now-- are now showing to you-- starting to show that meal timing, either lunch timing, both with behavioral interventions, or bariatric surgery, or-- and even timing relative to the circadian cycle, that actually

is important for adiposity, that the distribution between big dinner and small breakfast, or vice versa, Is a key player, that glucose control that is known in normal glycemic individuals to decrease from morning to evening is an important circadian control, and that late dinner eating, when your melatonin levels are already elevated, that this leads to impairment of glucose tolerance. And this is especially true if you are one of the about half of the population who is a carrier of this melatonin receptor snip. So, yes. Mealtime, I think, is a potential third behavioral component that we may

add-- want to add To those promising new approaches, and the battle against obesity. And so, the take-home messages are that, in addition to physical activity and what we eat, we may want to start considering the quantity and quality of sleep, and also, when we eat, and also circadian disturbances including shift work, social jet lag, that I can talk about if there is interest, night eating and lights at night. And, in more general terms, circadian time, so far, has received very little attention in the prevention, treatment and diagnosis of disease. And so, if any of you

are interested in helping us uncover these new mechanisms and possible uses for future treatment, then we have a number of studies that are ongoing that are listed on clinical trials of partners.org. And, with that, I would like to thank all my colleagues, and I would like to thank you for your attention. Thanks. [APPLAUSE] And so, with this, I would like to invite Christos Mantzoros to speak, and Chris just told me that this year was a good year for him. This year he received no less than four national and international awards, including on obesity, endocrinology, nutrition,

et cetera. So, over to you, Chris. [APPLAUSE] Thank you. Thank you, Frank. Good evening, good morning, good afternoon, depending on where in the world you are. I have only limited time to talk about a really big problem, obesity, and put everything together. So what I'm planning to do in the next 20 minutes is try to address three questions. How does our genetic makeup interact with the environment, nutrition and exercise to regulate our body weight? For some of us, keeping it normal, for others, failing and creating obesity, or extreme leanness, like anorexia nervosa or hypothalamic amenorrhea.

Number two, what can we do? What is our current understanding of the mechanisms? And, what can we do to prevent this from happening? And, number three, how are we learning from these mechanisms, And we can treat the problem? So these are my conflicts of interest, and this is the problem. The problem is that over the past 40 years, here in the United States, the rates of obesity are going up. One third of the population is overweight. One third of the population is obese, and only one third is lean. And if these trends continue for another

10 years, most of us are going to be obese and it will be the exception to be lean. Well, there's also the problem. The problem is that each and every nation in the world follows the United States, in part a little, and there is only a lag phase of a few years, which corresponds to the degree of Westernization of their societies. So everybody's following us, maybe not good in this case, right? And why do we care? Do we care whether we have a few extra pounds or not? Some of us who are really lucky, they

don't really Care from the health aspect point of view, and let me explain, but most of us do, because it causes health problems. So if we are one of those people, about 20% of the population who are born with a genetically-endowed large storage space for fat, where they can store all their fat, there is no health problems with obesity. And this is CAT scans of one of these people. So the fact remains in the subcutaneous tissue. This is the abdomen. These are the extremities. But what happens to most of us? To most of us, especially

those who are Orientals, they don't have a lot of storage space, or, in the Western population, when we exceed the storage space for fat, the fat we eat, the energy, has to be stored somewhere. And if it cannot be stored in the adipose tissue, it will go in the liver and cause fatty liver disease, or will go to the muscle, and cause ectopic deposition in muscle, or will go intra-abdominal. And this is what our bodies do not like. So they send macrophages, immune cells, To try to clean the fat from areas that it's not supposed

to be, from muscle, or the liver. And this creates inflammation, and the intra-abdominal fat creates low levels of a hormone called Adiponectin, which is a protective insulin sensitizer. And this leads to metabolic syndrome, inflammation, and if this continues for years, will lead to disease states like diabetes, disease, and cancers. So also, the obesity becomes more and more frequent in the United States. The rate of diabetes goes up, the rate of cancers, non-alcoholic fatty liver disease, which Is the more frequent cause of liver failure, cirrhosis, and transplants than hepatitis C, B, and alcohol together today. We

did not know of this 30 years ago. Many cancers are caused by this problem. So, if an angel would come to our world to make obesity disappear, about 2/3 of endometrial cancer would disappear, 1/3 of breast cancer, gastric, esophageal cancer, liver cancers, would go away. So why is that, and what can we do to prevent this from happening, and what can we do to save billions, hundreds of billions Of dollars we all pay for our insurance premiums every year for this problem? What is our current understanding? When I started studying this as a young trainee

20 years ago, two decades ago, the classical textbooks of physiology, here guidance on the left, had only a brief two paragraphs about the adipose tissue, that fat is a depot storage organ where we dump all the calories we're not going to use. We knew nothing about it. But since the problem was going, it was becoming more and more frequent and significant, We started studying this. And we know now, that there is a complex mechanism in our brains, hypothalamus, the reward system, and the cortex. In bisons, only the hypothalamus. But in our brains, are much more

complicated. It's the reward system that plays a role, and the cortex. That coordinates, gets information from genes, hormones in the periphery, the environment, and integrates this information. And in people who keep their body weight normal, it normalizes food intake and energy expenditure. In others, it fails. Let's see this in detail. So how important are our genes? The previous speaker said that our genetic makeup has not changed once. We had the opportunity over the past five, six years to check the entire genome of thousands, of hundreds of thousands of human beings. And we found that genes

play a role, like one gene leading to obesity in a very, very distinct minority of people. So very few people, one in hundreds of thousands, would have a mutation in the molecule that Is secreted from adipose tissue called leptin, or molecules that are downstream of leptin, melanocortins, for example. And because of this single gene mutation, or gene variance, they develop obesity, very, very small minority. But, these are the lucky ones. Because, if we find it through genetic testing, and we use a medication that attacks downstream of this mutation, we can treat this obesity very easily.

So this is a child, you know, animals and humans, a child with leptin deficiency. We gave him leptin and he's normal. Melanocortin deficiency, give melanocortins, normal. This is beautiful, emphasizes the biology of the mechanisms underlying the pathophysiology of obesity, but does not apply to most of us. Most of us, there are many, many genes that play a minor role, and they interact with the environment. They interact with the environment even before we are born. Why? As I'm going to show you later, how our mothers and fathers live causes epigenetic changes in our genome. Also, it's

very important what happens early in life. Most of us don't remember that from the very first cell that creates us to the neonate, there are 45 divisions, and there is only 55 up to the adult life. So a lot of changes during our in utero life. So, as I told you, it's very important how the mother sleeps, whether she has sufficient quantity, a good-quality diet, and whether where she lives, there is pollution or not. That's what our studies have shown. It's very important. It's also very important, what happens during pregnancy. So if the mother smokes

or drinks alcohol, if she does not sleep well, if she does not follow a healthy diet, this has an impact on the baby. Change is the epigenetic modifications in the brain. Immediately after pregnancy, it's very important the duration of lactation, and also, whether the babies sleep well and whether they have the right Mediterranean diet. And I'll come back to this in a few minutes to tell you what we think the right diet is today. And this is also important as we grow older, to sleep we'll, avoid smoking and too much alcohol, And have the right

diet and exercise. We'll put this together. So, studies have shown that if one follows a low-calorie, low-fat diet, and exercise is about 30 minutes every day, this is better than medications in terms of preventing diabetes, in terms of avoiding diabetes late in life. And if someone has a heart problem, following the right Mediterranean type of diet here in these studies delays significantly years the next heart attack. This is also important, not only for secondary prevention, but also primary prevention. So if someone is healthy and wants to remain healthy, what are the most things that we

need to do? Just a few simple things. No smoking, alcohol in moderation, this means for women up to one drink a day, and, for men, up to two drinks a day, exercising at least 30 minutes per day, replacing red meat with fish or white meat, and replacing saturated animal fat with olive oil or nuts, very simple things, difficult to follow. Animal fat? With olive oil. so cardiologists have stents to open the arteries. You know, this could be a bare metal stent in your kitchen, which would have exactly the same magnitude of an effect. Right? To

prevent cardiovascular disease, cancers, arrythmias. And if my cardiology colleagues tell you that they have drug-diluting metal stents, you also have a drug-diluting metal stent in your kitchen, right? You load your mental stent with fish and vegetables and olive oil and nuts. So, how do we put everything together, trying to associate this with numbers? So if you are a middle-aged man or a woman, say 50 years old, what is important to make you live a longer, healthier life? These are five things it was just published in circulation from our community, nurses and health professionals helps them.

Five factors. One, following the diet I told you about. Number two, not smoking. Number three, physical activity. Number four, alcohol. Number five, keeping s normal body weight. If someone has all five, a woman who is now 50 is going to live up to 93 years old. If none of the five, 73. So it is a big difference in terms of years lost or years gained if we follow this advice. But most of us say, "Well, I'm trying to lose weight, And my body goes back to the set point" that the first speaker told you about.

So I tried to lose weight, and then I exercise less, and something else happens also, that earlier in life, we have a lean set point. We try to lose weight. This brings us back. But as we grow older, our set point moves up, and we gain weight as we grow older. So, we did not know what this meant, and what caused this a few years ago. But, since the discovery of leptin a couple of decades ago, We started learning more about it. And this is an active area of research. We cannot-- we don't know everything,

but we know a lot at this point. So we know that in normal people, as we limit our energy intake, and this is our claim to fame, leptin levels go down. This is leptin, is an adipose site, secreted hormone, which is a thermostat. It tells the brain how much fat we have in our body. So as we try to decrease our body weight, this thermostat goes down, tells the brain, "Do something else. Eat more, exercise less." Why? Because our brain has the same mechanisms that we had thousands or millions of years ago when we were

starving. Not in societies of affluence, but in societies of starvation. And we need it to survive. So, the low leptin levels make us survive by regulating all these hormones here. If someone tries hard, one can train the system and remain in low body weight, or something goes wrong in these hormones, and it will remain in low body weight. This is anorexia nervosa, or female triad in exercise, right? Strenuously exercising athletes. Just the opposite happens, and we can utilize this medication now, to treat these women who have exercise-induced amenorrhea. or anorexia nervosa. We can normalize all

their neuroendocrine abnormalities. So we leverage this knowledge. So what happens if we overeat? Thanksgiving, Christmas, we overeat. For most of us, there are other hormones That are going to be activated, like DLP1s and incretins. And, for most of us, without even understanding it, a few days later, our body weight will come back to normal. And if we exceed this for a long period of time and we also have diabetes, there is another set of molecules called glucose receptors, and they help us excrete calories in the urine. And we leverage this now to create medications. If

our own bodies cannot bring us back to normal, we can use these medications to help our bodies lose weight. And these medications, most of them, act in the brain. So you will hear from a lot of speakers talking about the hypothalamus. This is what we had learned a few years ago from mouse studies. The hypothalamus is responsible for our survival. So in mice, and lower like animals, it is important to regulate food intake. But, in humans, we have a much bigger brain, and much more complex brain. So it's the reward system, which is also activated,

or inactivated, by these hormones. A lot of people will tell you, "I eat because I want to be rewarded, or because I feel sad." And it-- also, our cortex, which is responsible for our executive functions. For some of us, we will just eat when we go out, outside from this conference, just because there is food. And we'll be talking to people. We'll be distracted. Our cortex will not regulate what we eat. These medications make us more aware of what we eat. This is just the beginning, but we Are learning how to control now, appetite in

humans. So as I told you, we are also leveraging this to treat women or men who have either extreme leanness, in this case, anorexia nervosa, hypothalamic amenorrhea, strenuously exercising women athletes. 5% of our college-age young girls, or 5% of our medical students where women who exercise a lot have the female triad, hypothalamic amenhorrea. And they suffer from stress fractures. They don't realize why. You know, they say we exercise a lot. But their hormones are abnormal. If we give them back leptin, which is the hormone that is missing, as I told you earlier, we fully normalize

all their hormones, and we can treat their bone density and avoid fractures. So we've shown this a few years ago. We also leverage now, GLP-1. We create medications. I don't want to give names, which decrease body weight by 10%, new medications 15%, when combined with the right diet. They are not as good as surgery, which decreases body weight by about 30%, but we are getting there. We are also learning from surgery, and this is one of our studies where we study why people who undergo surgery, they keep their body weight down. So we study the

hormones that are secreted, and these are some of the hormones, the pre-Progluamune-derived hormones like GLP-1, oxyntomodulin, glicentin that go up. And these will be medications in the next few years. So the goal will be not to have surgeries, but to have 30%, 40% weight loss by giving back to people the hormones that change after surgery. Now why are we doing this? Are we so smart to think about it? Not really. You know, this is exactly the same way that people who treated hypertension 50 years ago were moving in science. So 60, 70 years ago, people

would measure blood pressure and would say it's a normal variant, even for very famous and beloved people. One of them, whom I always keep in mind, is President Roosevelt. President Roosevelt Had high blood pressure. No one was treating it. He suffered strokes and he died from it. And then people started realizing there is a problem we need to treat. So obesity, people were not paying attention to it, right, a few years ago. Now, then what did the people do? What did people-- how did people treat high blood pressure? Crude [INAUDIBLE] surgeries. Now the most effective

way today is surgeries. And through these surgeries, people Learn how to create hormones and medications to treat. And that's what we are doing now. So if we treat people with these medications, or surgery, we can improve their diabetes with surgery about 80% of people, with medications most of them. And now, I told you about cancers when I started. If you do surgeries for obesity, you decrease cancers by about 35% over a period of 20 years. And we just submitted a paper, that with a toolbox approach for treating obesity, medical treatment, we decreased cancers by about

25%. So one in four people would not have cancers If we treat their risk. So what if we cannot treat obesity, or if cannot remove it? So people are learning now what are the molecules downstream of the obese cells, the adipocytes? What are the hormones that are going down, and why these are causing diseases. So this is from our work. Adiponectin is an endogenous insulin sensitizer, the levels of which go down if we Have intra-abdominal obesity. And when we have low levels of this protective hormone, we develop diabetes, pro-inflammatory state, you know, adipokine changes, and

this leads to non-alcoholic fatty liver disease, diabetes, or cancers. So can we make adiponectin and give it to people? Adiponectin is a complex molecule, but we are learning about the receptors. So people now are developing either medications that bind to the adiponectin receptor to treat these conditions, or medications That can stimulate fat. And when the fight is decreasing, the production of this hormone, this goes up. And, we have that these medications, and we are testing these medications. This is for diabetes, and works better than medications that we know of today. And now this molecule is

being tried for other disease states like non-alcoholic fatty liver disease or other disease states we have no treatment for. Great. So, I gave you a lot of information today. But going back to the essentials, what I would like you to remember is that there are some people who are lucky, and they have a lot of storage space in their fat. They can eat more than others, be overweight, and have no problems. Others, if they exceed the storage space in their fat, adipose fat will go to ectopic positions: liver, muscle, intra-abdominally, and create medical problems. We

are learning how to leverage biology to create new medications, but for all of us, I think prevention is better than treatment. So how do we prevent obesity? By exercising, alcohol in moderation, nuts and olive oil, fish instead of meat, fruits and vegetables. So, in essence, a Mediterranean-type diet. Exercise, so walking up these hills to go home. Or cultivating the fields, or, even moving, right, to a Mediterranean nation to adopt the lifestyle, if we can not bring it here. In fact, that's my secret, and that's where I spend a couple of months every year. This is

an Nafplio, in Greece, a small town on the water, And I recharge my batteries there. I follow the Mediterranean diet, and I get inspired before I come back, because on this hill here overlooking the port, was working the very first scientist in the human history, the written history, Palamedis, as he was mentioned in Iliad and Odyssey. So having said that, I would like to thank you for your attention. I hope you get some information in your mind. [APPLAUSE] Right, right on time. One word only. So everyone, I know that a lot of people have to

leave the actual audience. We're going to answer questions, both from the audience and from the live stream. So if you have to leave, you can feel free to leave. We will stay and devote at least 15 minutes to questions. I'm going to pose the question. If I can answer, then I'll try to answer, but there are several questions that are specific to Dr. Scheer or Dr. Mantzoros. So one of the key things that we didn't do, and I apologize. I guess none of us really did it, really, give just a slide of this, was one

of the questions was, define the word obesity. So when I talked earlier about obesity, we use body mass index to define obesity, and a patient has obesity if they have a BMI that's greater than or equal to 30, if they're an adult patient. I won't specifically talk about pediatric patients because their BMI criteria is somewhat different. A person has mild obesity if their BMI is between 30 and 34.9. They have moderate obesity if they have a BMI of 35 to 39.9, and they have severe obesity if their BMI is greater than or equal to 40.

Now, the BMI in and of itself is just a measure that looks at height and weight, and there are calculators online. One of the ones that people use most frequently here in the US is the NHLBI, which is the National Heart, Lung, and Blood Institute calculator from the NIH where you put in your height and your weight and it calculates a BMI to determine where you fall. So that is the terminology that we're using. We did not focus on pediatric obesity. That is done by growth chart measurements. Persons that have a percentile and that's physically

from the age of two and 20 years of age, if your BMI percentile is less than the 84th percentile, that's considered of normal weight status. If it's between 85th and the 95th, that's considered to have overweight, and then obesity defined by someone that has a BMI of greater than the 95th percentile. And then, we can get into mild, moderate, and severe beyond the 95th percentile For pediatric patients. So it's important to recognize that BMI by itself, because pediatric patients are growing, it's not utilized in the same way we look at it for adults. Can I

take it to the next level, if I may? Because I see that-- He wants to take it to the next level. I'd love that. Our audience is sophisticated. Yes, I like that. So a few weeks ago, a body builder came into my clinic. A bodybuilder, OK. And his BMI was 27, and he said, am I now obese or overweight? He wanted the challenge. Well, BMI is convenient from the population point of view. But in essence, obesity is excess adipose fat. So BMI applies to most people, but not all. And if we want to take it

one step further, what is significant obesity is too much fat that causes health issues, metabolic syndrome, or insulin resistance. So, if we could, and we had an inexpensive, a convenient measurement like the BMI in the clinic, like if we could measure fat mass in a cheaper And faster way, we could be using different criteria. But for convenience, we use BMI. Absolutely. In addition to that, for every single patient that comes in to see me at MGH, I do measure waist circumference, which does give us a bit more information. For females, having a circumference of less

than or equal to 35 inches is our target. For men, having a circumference less than or equal to 40 inches is our target. We can utilize that in conjunction with height and weight to view very quick measures. But as he's stated, using more physiologic measures really gets us down to the personalized or precision medicine that is becoming commonplace. Now, the next question was, are there mental health issues tied to obesity, and do those issues get treated along with the disease? I'm going to take a stab at this. Every single person that I see, we do

screen for issues that are related to their mental health. As you saw in my slides, there is a correlation with persons that have obesity and have mental health issues, such as anxiety, depression, bipolar disorder. Approximately a third of our patients at the weight center at MGH do have concurrent issues with these, I guess, psychological issues that are being concurrently treated. And what I also mentioned to you earlier is that many of the medications that we utilize to treat these conditions then cause weight gain. So we have to figure out ways to medicate the weight gain

associated with the use of these agents. And we are able to mitigate that with the use of pharmacotherapy such as metformin, which is in front that usually used To treat diabetes, or for persons that have PCOS or polycystic ovarian syndrome. So that's interesting. Does anyone want to weigh in on that question? There's a lot of specific questions to you guys. So this is a question, I think, that was answered, but the question was, do people who are obese, and we're changing that, people that have obesity, have a greater risk for pancreatic cancer and how does

this differ by gender? Do you want to take this? I know that-- do you want to talk to this? Yeah, it is a complex relationship. And this is more complex and difficult to study because pancreatic cancer evolves so fast. But, obesity does have an effect on pancreatic cancer [INAUDIBLE]. When people develop pancreatic cancer, they start losing weight, and they get emaciated. But for each and every GI cancer, esophageal cancer, pancreatic, stomach, liver, colon cancer, obesity is contributing to a great percentage of people. We cannot say for everyone. Absolutely. This is specifically for Dr. Scheer. It

says, "How does less sleep cause people to decrease tolerance of glucose, if the body relies on it for cellular respiration?" Right, so the interesting thing about reduced sleep, and it's linked to glucose control, is that, in essence, we are still in a very early stage in understanding the molecular machinery of what overlies that. So hypotheses exist to look at autonomic nervous system. So since the vagal balance changes, that may make tissues less sensitive to insulin, Or may even reduce the release of insulin. Other hypotheses are that increases in cortisol might be involved that would decrease

the sensitivity to insulin. But really, the whole field is still looking for, kind of the explanation. One interesting point is that the phenotype, however, is even located in the fat tissue itself, so very nice work by Joseph Broussard's is showing that if you sleep deprive people, you do a biopsy of their subcutaneous adipose tissue, and you look at the sensitivity to insulin Of the adipose tissue, that is affected. So it's really, even so that suggests that at least acutely, even without the autonomic nervous system or hormonal systems, it is a property in the fat issue

itself, which may, of course, be an after effect of those factors. That's excellent. Hopefully you guys got some great information there. One of the questions, and the next question, is what about surgical procedures to correct obesity? Are those usually effective? I'll take a stab at this. So there are several surgical procedures, what we call bariatric surgery, that are utilized both here in the US and throughout the world to treat persons that have moderate to severe obesity. They are effective. They're the most effective tool that we have for treatment for those patients, and what was mentioned

earlier is that we see significant reduction in those co-morbid conditions associated with obesity including cancers, including things like sleep apnea, hypertension, and things of this sort. Now, I think it's important for us to recognize, When we look at the two primary procedures done throughout the world, the number one procedure now has become the vertical sleeve gastrectomy, and the second most common procedure now is the Roux-en-Y gastric bypass. That was kind of the leader for many years. Overall, it leads to significant weight loss. So, on average, if we have excess body weight, let's say, 100 pounds

in excess, a sleeve, on average, will lead to 50% to 60% of that excess body weight being lost, so an average 50 to 60 pounds at the low point. And then, a Roux-en-Y gastric bypass, About 60 to 70 pounds, which means that these patients will still likely have obesity, right? Just the degree of the obesity has improved, and it requires quite a bit of work on the part of the patient, and we see significant changes in hormones, as was mentioned earlier, that vary from patient to patient that determines their degree of relative success with these

procedures. Would you like to also comment, or is-- Yeah, no. Bariatric surgery is by far the most effective way Of reducing body weight today. These are the two mostly used surgeries. There are less effective treatments that are also better to tolerate. Most people are, if they're going to go through surgery, they don't prefer to have a lap band, or they don't prefer to have balloons in their stomach, which is another way to limit food intake. But I think the most exciting aspect of it is that we are understanding now why surgeries work. Now, this is

the glass is half full or half empty. We understand the hormones that are responsible for 50% of the weight loss and maintaining, there is another 50% that we haven't discovered. So we are half way at this point. Now this is a question for each of us, and the question is, how do we pick this as a specialty? How do we choose to specialize and focus our life on these, and this complex issue of obesity? And I'll talk first, and then I guess we'll go down the-- get down the pathway here. So as an African-American woman,

I became particularly intrigued of the racial and ethnic Disparities in obesity. We did not focus on that today, but what I do know about here in the United States is that 60% of all African-American women here in the US have obesity. Another 20% have, or are as overweight, which means that 80% of all African-American women here in the United States have overweight or obesity. I found this to be particularly disturbing as someone that comes from that background to understand why this is and what are the nuances that really explain that. And that really is what

led me to this work, Back about 15 plus years ago. So that's my story. But I'm going to let Frank tell his story. Yeah, so, that's interesting, because I was, for a long time, interested in the regulation of leptin from a circadian point of view, because colleagues were already in Amsterdam who had been looking at this, and colleagues in Boston. And then, actually, by serendipitous luck, really, we stumbled upon the effects of circadian misalignments, or what happens when people who are actually changing their sleep/wake cycle, their feeding/fasting Cycle by 12 hours. And so, initially, we

were struggling with understanding the regulation of leptin as a hormone until we realized that it wasn't just the circadian system influencing it. It wasn't just the sleep-wake cycle influencing it. It was the interaction when these two didn't line up correctly that we saw some of the leptin levels were dropping. And so, that really was the initiation of this interest, and it's important in obesity. For me, I think, I think that this Was because of two influential people in my life. If I look back. As a student in training here, I had-- I attended the lecture

by the late Judah Folkman, who was a very great scientist of Children's Hospital, who was teaching medical students and young doctors about research. And he said, you have to decide in life, so he started like your question. He says, you know, there are 33,000 diseases in medicine today. Only for 6,000 of those we have effective treatments. If you want to be an effective doctor, you need to decide. Focus on one, do good work, and it's up to you whether you are going to focus on a rare disease and try to create a big difference, or

a very common disease, and have a small difference. I said, I would like to have a common disease, maybe make some difference. And then I started talking to people, and I went to talk to Jeffrey Flier, who he was our former dean. And at that time, Jeff was about to discover, and closing, narrowing down, to the gene which was responsible For obesity in an animal model. And he said, this is a risky project. So he talked to me about projects, and he wrote on the blackboard like 10 projects, from the easiest to the most difficult

one. And the 10th and most difficult and most risky one would be, well, we may have a gene for obesity. And if this works, this may be the beginning of trying to make a difference in a big disease problem. I said, OK. This is my lab. This is my career. I'll take number one, which is the easiest, and number 10, because this was the riskiest. So two, to split the difference. And split difference, hedge my bets, right. So number one, the easiest, never worked out. But number 10, the most difficult, was leptin, and this defined

my career. That's amazing. So obviously, different things that brought us to this fill. This question is not quite clear, but I'll try to make it cohesive. I think what the question is, is it says, Sometimes even with good diet, exercise, Weight Watchers' group, you can still have obesity. What can really being done to help those people that are motivated to treat this serious condition when they've really tried everything, and, I think, this is kind of why I have devoted my life to obesity medicine, so I only care for patients that have a history of obesity,

both pediatric and adult patients. You come to me when you've tried the things that we've talked about. We've tried modifying our diet, looking At lean proteins, whole grains, fruits, and vegetables. We've tried physical activity. We try modifying our sleep and things of that sort. And when you've done all of these things and you're still struggling, you need to go to someone that specializes in what we can do to treat your obesity. And maybe just modify your behavior further. Maybe we use pharmacotherapy agents, which are medications used to treat obesity. Maybe we utilize surgery, or maybe

we come across the next frontier of things That we just have yet to discover because I think that's what excites us about this work is that there's so much that is yet to be discovered. Our ability to collaborate across disciplines, really, is when we uncover the best possible strategies of approaching this multi-factorial, multi-disciplinary disease. So that's my response to that. And I'm going to shift over a bit, because this question is more specific to Frank, here. And this is, as we age, do we require more or less sleep, especially as it's related to weight management?

Actually, let me-- there's a Facebook current question that I tried to organize these. Then, the question is from Facebook, what is the ideal duration of sleep? So duration, and then more or less as we age, and how that relates to weight. Right. So the question whether we need less sleep as we age is a very challenging question. Of course we see that as people in general, when they age, the amount of sleep obtained teens becomes less. Then the question is, well, if you give people Maximum amount of sleep opportunity in a lab, let's say you

them 16 hours of sleep, 24 hours a day, for a week or so. And people asymptote at a particular level of sleep. And so, older people, in general, will asymptote to a shorter amount of sleep. Now the question is, is that because they don't need it, or because they can't achieve it? And there's really two camps in the field, two-- yeah, in the field of sleep medicine. However, there is clear evidence that with aging, especially animal experimental and data, but also human data, that Are changes in the hypothalamic structures, such as the ventral, lateral, pre-optic

area involved in sleep regulation, where the number of neurons decreases, such that the ability to obtain a particular amount of sleep is decreasing. So even though people get less sleep doesn't mean they need less sleep. The key question then becomes, OK, how can you then achieve a higher amount of sleep with the change biology? So I think that's a challenging question that people are, of course, working on. How much sleep do we need? So, also, there-- the field, well I think the field has settled on kind of an ideal sleep duration. So I think for

adults, the common duration of sleep that is recommended is at least seven hours of sleep. Now, recognizing that there are individual differences in sleep amount that we need, the simplest question you can ask-- well, there's two questions you can ask to see if you have obtained enough sleep. One, is, do you feel sleepy? Sounds too simple to be true, but that's A very strong indicator. The second question you can ask, is, do you need an alarm clock in the morning to wake up? If the answer is yes, you're not getting enough sleep. And then, I

was just reminded of-- so I'm organizing of the National Sleep Meeting this year, a very exciting lunch debate between Shawn Youngstedt and Charles Czeisler who will be discussing whether sleeping too long can be bad for you. And I think this is another really interesting point of view, that a small group of sleep investigators Think that, well, if you sleep longer than a particular amount, whether this can carry adverse health. I think, personally, that there is no evidence for that. The idea comes from epidemiological work where people have found a new shaped curve with people who

have increased risk for Type 2 diabetes or cardiovascular disease. You can also see this association with very long sleep, which I think is probably primarily reverse causality, where disease leads to lengthy periods of time in bed. All right, so this would be for Christos. This is coming from Nigeria. It says, "The middle age spread type of obesity would be an interesting group to focus on. Are there currently any studies targeting individuals between the ages of 40 and 60?" I am not certain what is happening in Africa, but I would say-- I think they're asking, they're

just from Nigeria. Right. I think they're asking-- But I would say that here in the United States of America, or in Europe, or from the scientific point of view, we should not be focusing on specific age ranges because this is a spectrum, starts very early in our lives, and does not end. You remember in my slide, the effect of nutrition and the years gained by following the right nutrition and exercise persist up to the age of 90, and maybe after we are 95 or 100. The effect is like very small. But, yes, we should focus

on everybody who has a problem. Absolutely. Now this is also from Facebook. It doesn't tell me the country. But this is more of a policy-based question. It says, "Could policies aimed at reducing the growing wealth and wage disparity have any effect on rising rates of obesity and mental health disorders?" So I'm a policy person also, and I think it's hard to just pinpoint one policy and say that that leads to significant change. I think that we need multi-sector, multifactorial approaches to this issue, but I would Love to hear from our additional speakers to see if

they would like to weigh in on this question. Do you want to? You may not want to. No. I mean, there is a lot that has been proposed in terms of making one small change. I think it's so multi-factorial, and people don't realize that if we change one thing in our nutrition, for example, or the way we, you know, we live and behave, people will eat something else. And these experiments have happened In the past with very limited success, very limited success. So it's a multi-factorial approach starting from how we live our lives as individuals,

but also how we live our lives as members of our society. And we forget this in Western societies who are more individualistic. It depends on how we build our cities, whether we walk, whether we exercise, how we commute to work, how we build our systems, or for feeding the population, what we tax in terms of nutrients and food items, how we train our students and our children, and so on and so forth. OK, so I would have to tie up our questions here, so I'm going to ask one last question which I think it's a

two-parter. And the question is as follows: "Is there legitimate science behind this, and this is what this is. Every person has a fixed number of fat cells, you can't lose them. They just shrink when you lose weight, and grow when you gain weight. And if this is indeed true, how does someone use that to maintain a healthy weight?" So they're talking about adipocytes or fat tissue, Fat cells, and whether or not there's this fixed number of cells that you're born with, and it adjusts based upon weight loss. So does anyone want to take this? Yes

and no. Yes, in the past, we thought that there is a fixed number of adipocytes. Now we think that there are certain periods in our life that the number of adipocytes may change. But it is true that obesity, to a large extent, does not depend of the number of adipocytes. It depends on how full these adipocytes are or not. So given this, we don't know all the signals in endocrinology. We think about hormones as signals. The adipocyte communicates to the other organs, information, constantly, to our brain, to the other organs, and this is what happens.

If, say, hormone is low or high, right? The message goes to the pancreas to create diabetes, or another organ to create cancers. This is the idea of one. Or to of the brain, leptin, right, to change our appetite. Now we need to find all these signals, hormones, and I hope I'm not oversimplifying. If a signal is low, missing, like adiponectin, or leptin, we give it back. If a signal is high, we try to block the communication by decreasing the levels. That's what we're going to do in the future. Absolutely. So I want to thank everyone

here in the live audience and from around the world for tuning in to Weighing the Facts of Obesity. We will stay around and answer some additional questions here live, but thank you so much for your time. [APPLAUSE] Very nice. Thank you.