The latest treatments in obesity medicine focus on hormones, placing endocrinologists—physicians who deal with the body’s endocrine system that controls hormones—at the center of the expanding field of obesity medicine, including the development of a new class of drugs that target the brain’s system for regulating body fat.
Highly effective biologic drugs that are effective for treating people with obesity are nutrient-stimulated hormone therapies. These include medications such as semaglutide, which is a GLP-1 receptor agonist, and tirzepatide, which is a GIP/GLP-1 receptor agonist. Both medications mimic the action of hormones (glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP-1) that are secreted in response to food intake. Both medications target receptors in the brain -- and have resulted in sustained weight reduction in individuals with obesity.
Physician-scientist Ania Jastreboff, MD, PhD, associate professor of endocrinology & metabolism, and of pediatric endocrinology at Yale School of Medicine, is finding through her clinical work and research studies that developing sophisticated medications that mimic the ways the body functions is a very effective way to treat obesity.
Jastreboff, an internationally recognized researcher and educator in obesity medicine, was the site principal investigator at Yale and lead author for SURMOUNT-1, a study that demonstrated that people with obesity treated with the novel GIP/GLP-1 receptor agonist, tirzepatide, lost on average 52 pounds with the highest dose of the medication. The results of the study, “Tirzepatide Once Weekly for the Treatment of Obesity,” were published in the New England Journal of Medicine in June 2022. Jastreboff presented findings from the study at the 2022 American Diabetes Association Scientific Sessions. Additionally, Jastreboff leads an R01 looking at the impact of the GLP-1 receptor agonist, semaglutide, on the desire to eat highly palatable foods.
Understanding the Body’s Defended Fat Mass
It's estimated that nearly half of adults in the United States will have a body mass index greater than 30 by 2030. A BMI of 30 or more indicates obesity in adults. For children or adolescents, 20%, or one in five adolescents, have obesity. For adults, currently, it's about 42%.
The body releases hormones that inform the brain about how much fat individuals are carrying, which Jastreboff calls the defended fat mass. This is why developing medications that target physiology makes sense, she said.
“Targeting physiology not only enables creation of highly effective medications, but also medications that are safe and well-tolerated,” Jastreboff explained.
Jastreboff has been at Yale for over a decade and a half, having completed two fellowships at Yale School of Medicine, in endocrinology and pediatric endocrinology, as well as a PhD. Her training prepared her to treat obesity across the lifespan, and to lead clinical research studies of obesity including participants from childhood through adulthood.
She treats obesity in many different patient populations at the Yale Diabetes Center. Some of her patients have obesity without diabetes, while some have obesity and either type 1 or type 2 diabetes.
Jastreboff, whose parents both have PhDs—her father is a neuroscientist, and her mother is a molecular biochemist—became interested in obesity and diabetes when she was a medical student at the University of Maryland. Her interest was in trying to understand why it's so difficult not only to lose weight, but to maintain weight reduction.
“I don't think I ever had the belief that obesity was not a disease,” Jastreboff said. “I always thought that we were approaching obesity the wrong way, that we were putting the onus on the patient -- as if it was their disease to fix -- and of course it's not.”
As a Yale endocrinology fellow, Jastreboff’s attending physician in endocrinology also was interested in obesity medicine early in his career. Robert Sherwin, MD, C.N.H. Long Professor Emeritus of Internal Medicine (endocrinology), encouraged Jastreboff to apply for the investigative medicine program and served as one of her PhD mentors.
Sherwin introduced her to another of her PhD mentors, Rajita Sinha, PhD, Foundations Fund Professor of Psychiatry and professor in the Child Study Center, and of neuroscience. Sinha encouraged Jastreboff to study the neurobiology of obesity. Jastreboff’s overarching message is that: “We need to treat obesity as we treat any other complex, chronic disease. We need to target disease pathophysiology."
How the Body Fights Back
Jastreboff’s research focuses on novel anti-obesity medications, specifically nutrient stimulated hormone therapeutics. She believes that a critical need in the field is to better understand obesity pathophysiology, especially how the body signals to the brain how much fat an individual should carry to store sufficient energy to function optimally; this is called the defended fat mass. “We need to create treatments that re-regulate the defended fat mass, so that it is lowered to a place where we're carrying a more healthy amount of adipose tissue,” she said.
“With a better understanding of what leads to the disease of obesity, we can create treatments that target that pathophysiology, not putting the onus incorrectly on our patients, and certainly not saying, ‘Well, in order to treat your obesity, you should eat less and move more,’ We need to give our patients treatments which work, treatments like these medications," she said.
Jastreboff cites the environment as a cause of obesity, specifically what she and other scientists call the obesogenic environment. “It's not just the food, it's not just the fact that we lead fairly sedentary lives,” Jastreboff explained. “It's the stress, it's the lack of sleep, it's the circadian rhythm disruption, it's things in our obesogenic environment that have led to this elevated defended fat mass on a population level.”
Brian Wojeck, MD, MPH, assistant professor of clinical medicine (endocrinology) is interested in multiple factors that can affect a person’s ability to maintain a healthy weight. His practice pursues several medical interests related to obesity. Wojeck recently finished a Yale fellowship in endocrinology mentored by Silvio Inzucchi, MD, professor of medicine (endocrinology) and Klar Yaggi MD, professor of medicine (pulmonary, critical care & sleep medicine). He treats patients in Stamford and Westport for weight management. He also treats patients in North Haven for sleep disorders.
Wojeck’s interests are in diabetes, obesity medicine, and sleep medicine, and in how treatments for sleep disorders, diabetes, and obesity overlap. He also is interested in how new drugs might help treat sleep apnea as well as obesity. “My goal is to combine these different fields,” he said.
In about the past five years, the medical treatment of obesity as a complex and chronic health condition has gained traction due to the availability of new FDA-approved drugs. “We can do really significant things with weight management and improving long-term health outcomes safely with medicines that we couldn't before, and there's a whole scope of other obesity interventions that we can use as well,” Wojeck said.
When Yale’s Center for Weight Management, a multi-disciplinary center in North Haven opens, he plans to see patients there, and will bring a sleep component. “Any obesity center should be multi-disciplinary to truly treat this kind of really complicated problem,” he said.
The Center for Weight Management is a joint effort between Yale New Haven Health and Yale School of Medicine. Jastreboff is one of the center’s three co-directors. The others are Wajahat Mehal, PhD, MD, professor of medicine (digestive diseases), director of the Yale Weight Loss Program and of the Yale Fatty Liver Disease Program, and John Morton, MD, MPH, MHA, professor of surgery and medical director of bariatric surgery at Yale New Haven Health. The center also will have an exercise physiologist and a psychologist in the same space.
Obesity in Children and Adolescents, and Inequality
If you have obesity when you're a child or an adolescent, you're much more likely to have obesity when you’re an adult, Jastreboff said. “If we intervene earlier, during childhood or adolescence, are we potentially going to be able to treat obesity more effectively to prevent the onset of type 2 diabetes, and hopefully decrease risk for cardiovascular disease.” She asked, “Is there also a potential for impacting the disease mechanisms before they are ingrained -- before you develop that metabolic memory?”
Jastreboff and colleagues, Rajita Sinha, PhD, and Wendy Silverman, PhD, were awarded an R01 grant for a study that looks at parents who have obesity and have young children ages 2 to 5 years to see whether interventions for the parents can potentially help the children who have not yet developed obesity. “It's a mindful parenting intervention that also includes a nutrition component. It’s an example of one of the studies where we're looking at obesity prevention, before obesity develops.”
Equal access to therapies is also an issue she is focused on, noting that Medicaid in Connecticut does not cover anti-obesity medications. “If these medicines aren't accessible to our patients, then how can we help them?” she said. “Any treatment, in order for it to work, has to be affordable and accessible.”
Listen to Jastreboff discuss obesity medicine on the Health & Veritas podcast with Yale physician-professors Howard Forman and Harlan Krumholz. She also discusses “The Road Ahead: The Future of Obesity Medicine,” on the Weight Matters podcast.
Yale’s Section of Endocrinology & Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge; applying new information to patient care; and training the next generation of physicians and scientists to become leaders in the field. To learn more about their work, visit Endocrinology & Metabolism.