THE WARNING SIGNALS OF AN IMPENDING OBESITY CRISIS have been flashing for decades. Now, amongst ever more dire statistics, there is reason to believe that the trajectory may soon begin to shift. The predictions have been truly alarming. By 2030, researchers estimate that nearly half of Americans will have obesity, and by 2035, it will affect nearly a quarter of the world’s population. The health consequences can be ruinous. Obesity is a driver of over 200 serious weight-related diseases, and some researchers believe it may be a contributor to our country’s shrinking life expectancy—the disease can shave as many as 14 years off an individual’s life. But overcoming obesity is no longer a hopeless battle. Scientists are entering a new era of obesity research that recognizes the condition not as a choice, but as a chronic neurometabolic disease with a clear pathophysiology. And for the first time, patients with obesity have novel, highly effective therapeutics that, by targeting the underlying mechanisms of the disease, are transforming treatment. “The field is moving forward rapidly,” says Michelle Van Name, MD, assistant professor of pediatrics (endocrinology). “We are gaining more and more insights as well as treatment options for our patients.” A tripling of worldwide obesity Obesity is a chronic and relapsing neurometabolic disease involving the overproduction of adipose, or fat, tissue that can create problems throughout the body. Clinicians have long defined obesity in adults as a body mass index (BMI) of 30 or above and class 3, or severe, obesity (formerly known as “morbid obesity”) as a BMI of 40 or above. (See “BMI reconsidered.") In a child or teen, clinicians consider those whose weight is in the 95th percentile or higher based on age, height, and sex as having obesity. The list of health complications from obesity is long. It increases the risk of certain cancers, including breast cancer and kidney cancer—particularly a type called renal cell carcinoma. Obesity is also a risk factor for cirrhosis, a chronic disease of the liver that can lead to scarring or liver failure. Other potential risks include joint problems, cardiovascular disease, stroke, sleep apnea, asthma, worsened acid reflux, type 2 diabetes, poor circulation, high blood pressure, and high cholesterol. Beyond physical health, the condition can lead to depression, anxiety, and social phobias. “For almost any bodily system you can think of, being overweight or having obesity can increase the risk of disease in that system,” says Janelle Duah, MD, assistant professor of medicine (general medicine). The societal costs of diabetes alone can be enormous. In 2017, the American Diabetes Association found that diabetes led to $237 billion in direct medical costs and $90 billion in lost productivity. Addressing obesity is essential for mitigating both personal and social impacts. Fortunately, studies show that a reduction of even 5% to 10% in body weight is linked to improved liver function, blood pressure, cholesterol, diabetes, and more. Unfortunately, the trend toward weight gain was recently exacerbated by the pandemic—48% of Americans involved in a 2022 study published in Diabetes & Metabolic Syndrome reported gaining weight as their daily routines were upended by COVID-19. Among those who considered themselves to be slightly overweight before the pandemic, the effects were even starker, with 58% reporting weight gain. The problem is not limited to adults. Sonia Caprio, MD, professor of pediatrics (endocrinology), has been studying type 2 diabetes and childhood obesity for 30 years. In the early days of her career, the prevalence of childhood obesity was relatively low, and youth-onset type 2 diabetes was rare. But now, both of these diseases are on the rise. A 2019 global assessment of child malnutrition by UNICEF reported that, from 2000 to 2016, the proportion of overweight youth increased from 1 in 10 to nearly 1 in 5. Furthermore, a 2021 study in JAMA said that the number of youths in the United States with type 2 diabetes nearly doubled over a recent 16-year period. If these trends continue, scientists warn that there will be dire consequences. In 2022, the Centers for Disease Control and Prevention reported that by 2060, researchers predict that the prevalence of type 2 diabetes in young people will increase by nearly 700%. “Historically, clinicians have ignored the complications facing these kids because they had thought they would get better and lose weight over time,” says Caprio. “We now know this isn’t true, because 80% of kids with obesity become adults with obesity. The problem is not going to melt away and get better.” The perfect storm of an obesogenic environment There is no single culprit driving the rise of obesity, but rather a “perfect storm” of contributing factors, says John Morton, MD, professor of surgery (bariatric, minimally invasive). “One thing for certain is that we can’t say it’s all genetic, because our genes and our gene pool didn’t change overnight,” Morton explains. “So it’s partly genetic, but clearly the environment has also changed.” There are several key elements in play, including physical, social, and cultural factors, that create an obesogenic environment. First, people tend to lead more sedentary lifestyles—a 2014 study led by Stanford University School of Medicine researchers found a significant relationship between a decrease in activity and obesity between 1988 and 2010. Furthermore, various medications can lead to weight gain, including insulin and many antidepressants. Sleep deprivation also plays a role. “If you don’t sleep enough, your body is going to sense that it’s stressed and won’t give up calories because it views calories as necessary preserves,” says Morton. But the biggest change over time, says Morton, is the food supply and portions. “There have been studies showing that dinner plates have increased in size over time,” he says. And now, people tend to include more ultra-processed foods in their diets, which are devoid of many intrinsic nutrients, especially fiber. This has negative consequences for our waistlines. Digesting food burns energy. “That’s partly why you feel sleepy after eating—because the blood supply is going to the stomach and your body is working hard,” says Morton. “If you eat ultra-processed foods, your body doesn’t have to work as hard to digest.” These foods also tend to get converted very quickly into sugar, increasing blood sugar levels. When an individual’s blood sugar rises, their insulin also rises to bring it back down. But insulin is also a growth agent and causes people to gain weight. Finally, Morton adds, there are environmental factors leading to obesity that researchers are still trying to understand. “Clearly, there are some obesogens out there—including chemicals around us that make us gain weight,” he says. For instance, Morton led a 2018 study that found individuals with higher levels of bisphenol-A (BPA)—a chemical widely used in many hard plastics, including many food containers and water bottles—lost less weight after bariatric surgery. “These chemicals tend to mimic estrogen, which is weight-promoting,” says Morton. A new understanding of obesity pathophysiology As a primary care physician with a passion for obesity medicine, Duah traces her interest, in part, to her own experience with the disease. “I struggled with obesity from when I was a kid, but when I went to doctors’ appointments with my parents, we were always told to lose weight. But they never explained how to do this. Or we were told very vaguely to exercise more or eat less,” she says. “A common thought about obesity then was that it was almost like a moral failing—that if you just ate less and exercised more, you wouldn’t have the disease.” Ania Jastreboff, MD, PhD, associate professor of medicine (endocrinology) and of pediatrics (pediatric endocrinology), finds it “incredibly unjust” when patients face such stigma, bias, blame, and shame. “This often makes patients with obesity feel uncomfortable speaking with their provider about having the disease and pursuing obesity treatment,” she adds. To that end, emerging research is finally reshaping medicine’s view of obesity. Obesity specialists now recognize that “calories in, calories out” is a gross oversimplification that fails to consider sleep, stress, medications, and other factors that research has shown contribute to the disease. “Two people could do the same exercise and not burn the same number of calories, even if they have the same weight and build,” says Duah. “There are just so many levels to what affects a person’s body weight other than them eating too much or exercising too little.” Furthermore, researchers now better understand the pathophysiology behind obesity. “Our body has designed a beautiful, sophisticated system whereby hormones signal to our brain about our energy state,” says Jastreboff. “They tell the brain whether we’re hungry, whether we’re full, and specifically how much fuel we’re carrying.” This fuel is stored as fat mass. The body wants to carry enough fat mass so that if there isn’t enough food available, it doesn’t starve. At the same time, it doesn’t want to carry so much fat that it interferes with the activities of daily life. Scientists call that sweet spot the defended fat mass setpoint. Now, this setpoint has been pushed up on a population level due to our obesogenic environment. As a result, even if an individual is overweight or has obesity, their body’s altered physiology makes it difficult to lose weight. “Historically, losing weight has always been bad news for us—it indicated that bad things were happening, like famine,” says Wajahat Mehal, MD, DPhil, professor of medicine (digestive diseases). So, when the body’s internal sensors perceive that it has had less to eat, the body will deploy defense mechanisms even if the individual is still significantly overweight. “I like to think of the physiology in terms of a business model. If a business all of a sudden starts going in the red every month, the CEO isn’t going to say, ‘That’s fine, we have lots of money in the bank.’ The CEO is going to try and figure out what happened.” A transformation in obesity care As part of the paradigm shift in obesity care, the medical community has begun to recognize the condition as a treatable chronic disease, rather than a consequence of insufficient willpower. Patients with obesity now have a range of therapeutic options from lifestyle changes to minimally invasive surgery. The emerging field of culinary medicine empowers people to improve their nutrition in their own kitchens. They may also choose to work on behavioral changes under the guidance of a psychologist. When lifestyle interventions alone aren’t helping, novel, highly effective and well-tolerated anti-obesity medications, such as semaglutide [brand name Wegovy® or Ozempic®], can work to target the underlying pathological mechanisms of the disease. As the prevalence of obesity continues to skyrocket worldwide, these new therapeutics are urgently needed to safely and effectively treat the disease. “The concerning side is that a large percentage of the population is in need of these medications, and the health outcomes when not taking them continue to worsen,” says Mehal, who has seen patients as young as 20 or 30 suffering heart attacks or cirrhosis. But even if young people feel relatively healthy, treating the disease still requires urgency, he adds, because significant health consequences as they enter their 40s and 50s are inevitable. "Not doing anything is a high-risk proposition" Patients may also opt for endoscopic procedures like an intragastric balloon, which is a saline-filled, silicone device placed in the stomach, to help them feel fuller faster. Finally, a range of bariatric surgery procedures are available to alter the digestive process and promote long-term weight loss. “Bariatric surgery has never been more safe or effective,” says Morton. “When I started 22 years ago, we did less than 10,000 cases a year in the United States. Now, we do about 250,000 cases a year." When deciding which interventions are right for an individual, clinicians should consider both the patient’s preference and the stage of disease, Morton says. “The treatment for stage one breast cancer is different from stage four breast cancer. And so we take the same approach in obesity treatment,” he explains. “If your BMI is higher, it makes sense to try surgery first. If it’s lower, it might make more sense to try medications.” At Yale, Morton and his colleagues have been pioneering the use of combination therapy, in which they utilize medications to help patients lose weight before bariatric surgery as well as afterward to help safeguard results. “We have never had a better time for treating obesity,” says Morton. How Yale is advancing obesity medicine Yale School of Medicine (YSM) is home to some of endocrinology’s leading experts who are producing groundbreaking research. Recently, for example, a team led by Mireille Serlie, MD, PhD, professor of medicine (endocrinology), discovered that patients with obesity have a reduced brain response to nutrients in the gut that persists even after weight loss. These findings may explain why patients with obesity struggle with dysregulated eating behavior and keeping off weight “In my clinic, when I see people with obesity, they often tell me, ‘I ate dinner. I know I did. But it doesn’t feel like it,’” Serlie told YaleNews. “And I think that’s part of this defective nutrient-sensing. This may be why people overeat despite the fact that they’ve consumed enough calories." Jastreboff’s team is leading NIH studies investigating obesity pathophysiology by employing anti-obesity medications, such as semaglutide, and clinical trials of potential new anti-obesity medications, including a dual-hormone receptor agonist, tirzepatide, and a triple-hormone receptor agonist, retatrutide. To expand on research in obesity medicine, YSM announced in March the launch of its new Yale Obesity Research Center (Y-Weight), led by Jastreboff. The mission of the center is to improve the lives of people with obesity by leading groundbreaking human, clinical-translational, and outcomes research to investigate novel pharmacological therapies—a focus at the onset of the center. “There is a great need for highly effective and safe obesity treatments,” says Jastreboff. “Through studies conducted in our center, we aim to lead research that will help transform our patients’ lives and health.” Y-Weight’s mission involves three pillars of research, she says. First, human physiology studies, using anti-obesity medications to probe the pathophysiological mechanisms of the disease of obesity. Second, clinical trials that evaluate the efficacy and safety of potential new anti-obesity pharmacotherapeutics. Finally, outcomes research to investigate how anti-obesity medications are utilized and work in the real world, and how they impact long-term health outcomes. In addition to shaping the growing field of obesity medicine through its research, Jastreboff says Y-Weight will also foster the development of physician-scientists and investigators in this specialty, and help educate the next generation of obesity medicine providers and leaders. Finally, the center will work to integrate clinical obesity research into the practice of obesity medicine. “The disease of obesity is a huge problem that we need to look at from multiple different stances and across various specialties and departments,” says Duah. “Our multidisciplinary approach will promote diverse ideas and ways of thinking that help advance research and, in turn, create better programs and protocols for our patients to help with their weight management.” Importantly, as obesity medicine at Yale continues to grow, the goal ultimately is about patient health, not a number on the scale. “My colleagues and I don’t care about a patient’s size or what their body shape is. We’re not picking a random number out of thin air and saying, ‘let’s aim for X many pounds,’” says Mehal. “Our goal is not to achieve an arbitrary body weight, but to have a neutral discussion about what weight loss means to our patients and what holistic health benefits it will have for them.” .