Making Strides Against Obesity

“Obesity is a complex medical condition that is not just a matter of willpower, vanity, eating less, or moving more,” says endocrinologist Jamie Mullally, M.D., associate professor of medicine at NYMC and medical director of obesity medicine at Westchester Medical Center. “As one of today’s most prevalent chronic diseases, obesity increases the risk of numerous adverse health outcomes—diabetes, heart disease, even death.”

Obesity is defined as a Body Mass Index (BMI)—the measure of weight relative to height—above 30. Traditionally, health care providers have focused on treating the consequences of obesity, such as high blood pressure and cholesterol. “Doctors would prescribe medications without regard for side effects—like weight gain,” says Dr. Mullally. Doctors might also ascribe joint pain and other mobility issues to excess weight, without ruling out underlying medical issues like a torn meniscus or herniated disc. Advising those patients to exercise for weight loss creates a vicious cycle. It was only in 2013 that the American Medical Association (AMA) recognized obesity as a chronic disease and should be treated as such.

One Message, Many Pathways

Dr. Mullally trained with Louis J. Aronne, M.D., an obesity medicine pioneer, who realized the benefits of a nuanced approach, such as exploring alternatives to medications that contributed to weight gain. That “tremendous paradigm shift” inspired Dr. Mullally to become certified in obesity medicine. In her endocrinology practice, about half of the patients have obesity. “Each one has a unique treatment path,” she says. “We discuss their weight history, lifestyle, and health; and I make a point of using language that de-stigmatizes: a person with obesity, severe, or Class III instead of morbid.” She also reassures them up front: obesity is not their fault.

“Hearing this can be very impactful,” she says. “Other doctors may have dismissed their medical issues as a consequence of their excess weight. Many health care providers, unfortunately, still hold stereotypes that patients with obesity are lazy and lack willpower, despite scientific evidence that weight is under the complex regulation of biological, neuro-hormonal, genetic, and environmental factors. This stigma can cause irreparable harm.”

Maintaining an active lifestyle is key to all weight loss, says Dr. Mullally. Drastically reducing calories by dieting only works in the short term—then backfires. “Our bodies are designed to defend a higher weight,” she explains. “When you are using willpower to restrict eating, your metabolism slows.” The body, perceiving the threat of scarcity, slips into starvation mode, increasing hunger signals and slowing energy expenditure. “So, the physiology of weight loss is working against you.”

The physiology of weight gain also drives the “hunger-obesity paradox,” which physicians and nutritionists observe in those contending with food insecurity. Diane Lindsay-Adler, M.S., RDN, CDN, clinical assistant professor of pediatrics and adjunct assistant professor of public health, is a registered dietitian at Boston Children’s Health Physicians, where she supports children with obesity– some as young as five. In children, obesity is defined as BMI at or above 95th percentile, though Lindsay-Adler prefers to examine body composition: ratio of fat to muscle to water.

Children with obesity may also be malnourished and food-insecure, she explains, due to their high intake of low-cost, high-calorie food. In addition, “they might have cyclical food restrictions which results in adverse metabolic responses,” prompting the body to hoard calories as it anticipates scarcity. “Food insecurity and obesity are linked in a vicious cycle. Poor dietary intake contributes to obesity and its physiological, physical, and social consequences—from high blood pressure and diabetes to asthma, depression, and social stigma.”

Medications, Movement, and Mindfulness

Recent breakthroughs in medications are also changing the landscape of treatment.

“This is an exciting time for the medical management of obesity,” says Dr. Mullally. “There have been huge advances in the field that are game-changing. In our clinical practice, we are seeing patients on these medications achieve more than 16 to 22 percent weight loss.”

Determining the best medications relies on a thorough understanding of each patient’s obesity. “Is the patient eating in response to cravings or food addiction? Then we might try a drug which adjusts dopamine levels and is also used for smoking cessation. If a patient never feels full, one that mimics the gut hormone which slows digestion and signals fullness to the brain could help.” As the Food and Drug Administration approves more weight-loss drugs, Dr. Mullally hopes that insurance companies will broaden coverage for these medications.

Lindsay-Adler also sees promise in new medications, especially for teenagers. “No matter how hard they try, my patients may be working against a genetic predisposition or struggling with food insecurity,” she says.

Medication is just one piece of the puzzle. The big picture involves mindful eating, frequent movement, and general wellness.

“We promote the idea of starting small, like walking five minutes a day or doing five wall-presses,” Dr. Mullally says. “We discuss the importance of awareness: patients weighing themselves, noticing gains or plateaus, logging their food intake. When people start to snack, especially in the evenings, they are often not aware of the calories they are consuming.” She also taps into the network of WMCHealth, referring patients to cardiologists, gastroenterologists, and orthopedists—and lately, sleep specialists. “Sleeping poorly can dysregulate hormones linked to weight gain,” she explains. “Obstructive sleep apnea is under-diagnosed among patients with obesity and can improve with treatment.”

Rather than a target weight or BMI, Dr. Mullally’s goal is for patients to simply regain control of their health. “We know that even five to 10 percent weight loss can improve diabetes and blood sugar levels, cholesterol levels, fat accumulation in the liver, joint pain, and heart health,” she says. “My patients and I discuss their metabolic health,” which involves advisable ranges of blood sugar, blood pressure, waist circumference, cholesterol, and triglycerides. “But we also look at physical condition and quality of life: their ability to remain active by doing the things they want to do.”

Lindsay-Adler also grounds her counsel in patient education, offering guidance on how to plan, shop, and prepare healthy food on a budget. Among children and teenagers in food insecure households, she says, French fries account for the greatest portion of total vegetable intake. “If I can teach families to carve out time for meal prepping, they can grab healthy food from the fridge or freezer instead of grabbing McDonald’s,” she says. “I show them how to use unit pricing, read nutrition labels, buy frozen fruits and veggies. My goal is to empower individuals.”

What's That Smell?

Lindsay-Adler also works with patients at the Children’s Environmental Health Center of the Hudson Valley, a collaborative enterprise affiliated with NYMC to protect children against toxins, pollutants, and other hazards. As the country’s only center of its kind based out of the Division of Pediatric Pulmonology, it offers Lindsay-Adler access to children with both asthma and obesity, who often have complex medical issues and reduced responses to medications. “Carrying around extra weight makes it harder to breathe.”

Lindsay-Adler’s most recent work, for which she was recognized at the Second Annual Leonard Newman, M.D. ’70, Assistant Professor Research Symposium, assesses the taste and smell sensitivity in children with obesity and asthma. To test existing evidence that children with obesity and children with asthma had decreased perception of taste and smell, she created four groups—including those with asthma, obesity, and both conditions—and gave them smell sticks, taste strips, strips to gauge bitterness sensitivity, and a sino-nasal outcome test to evaluate the condition of the nasal cavity.

Lindsay-Adler then classified patients into three categories: non-tasters, normal tasters, and super-tasters. Although no differences in taste and smell sensitivities were observed among the groups, Lindsay-Adler found that children with obesity—with and without asthma—reported significantly worse nasal blockage, sneezing, and ear pain, as well as higher levels of frustration, restlessness, and irritability than children at healthy weights. Further investigation will explore whether treatment aimed at decreasing sino-nasal symptoms, both physical and emotional, might better address obesity-related conditions.

Lindsay-Adler’s research into the relationship between taste and smell sensitivity in children with obesity and asthma is supported by a grant from the Pediatric Nutrition Practice Group, a dietetic practice group under the umbrella of the Academy of Nutrition and Dietetics. The data she has collected is now under analysis, in preparation for submission to academic journals.

Cracking Genetic Codes

How did NYMC blaze a trail toward a major therapeutic breakthrough for obesity? “It started with scientific curiosity,” says Michal Laniado Schwartzman, Ph.D., professor and chair of pharmacology. Several years ago, her colleague Nader G. Abraham, Ph.D., former professor of medicine and pharmacology, asked Dr. Schwartzman to assist with experiments in mice regarding a signaling molecule—a molecule regulating specific processes or systems in the body—called 20-Hydroxyeicosatetraenoic acid (20- HETE). As a pro-inflammatory lipid (fat) mediator, 20-HETE has been observed to damage vascular function and increase blood pressure. When mice are given testosterone, their 20-HETE levels spike.

“In humans, production of 20-HETE increases in response to injury, stroke, or heart attack, as well as in response to diets enriched in fat,” explains Dr. Schwartzman. “We know that obesity sets in motion this chain reaction toward a higher risk of cardiovascular and metabolic disease such as diabetes, hypertension, cardiac failure, and vascular dysfunction. The biological activity of 20-HETE was somehow driving these complications.” But how?

Dr. Schwartzman’s team obtained mice bred to have increased concentrations of 20-HETE in their tissues and blood. She placed these mice on a high-fat diet—pellets whose nutritional profile were akin to bacon and doughnuts. As hypothesized, those mice developed higher rates of obesity-related disease. “As BMI rises, 20-HETE goes up,” says Dr. Schwartzman.

To dig deeper, Dr. Schwartzman turned to Victor G. Garcia, Ph.D. ’15, assistant professor of pharmacology, who was then among her graduate students. Dr. Garcia accepted her challenge: pinpoint the cellular target or receptor for 20- HETE—that is, the proteins within cells that respond to the signal of 20-HETE and do its bidding. In the summer of 2013, one likely candidate began to emerge: the orphan G protein-coupled receptor GPR75. On October 31, 2013, the research team received independent confirmation that 20-HETE does indeed activate GPR75. “We all gasped: ‘It turns on!’” says Dr. Garcia.

Shortly thereafter, Dr. Schwartzman reached out to Regeneron, the pharmaceutical company in Tarrytown, New York, that frequently collaborates with NYMC. Through their VelociGene technology, Regeneron generated a colony of mice lacking GPR75 globally. The mice arrived at Dr. Schwartzman’s lab and received the same high-fat pellets as their sole source of nutrition. “Typically, a mouse on a high-fat diet will double or even triple in size,” says Dr. Garcia. But with the 20- HETE signals muted from the GPR75 deficiency, these mice gained 44 percent less weight than mice consuming the same diet. The gene deficiency also offered protection from inflammation, insulin resistance, high blood pressure, and diabetes. The link between GPR75 and obesity sharpened into focus.

In 2021, Dr. Schwartzman received an urgent call from the CEO of Regeneron, who had results from a genetic sequencing of 640,000 subjects from the United States Europe and South America, conducted by Regeneron’s Genetics Center LLC. One in 3,000 of them had a “protective loss-of-function” mutation, meaning one inactive copy of the two GPR75 alleles they had received (one from each parent). These individuals had lower rates of diabetes, lower BMI, and better cardiovascular outcome—with strong parallels to the GPR75-deficient mice. All told, they had a 54 percent lower risk of obesity than those without the mutation.

An explosion of scientific interest in this “anti-obesity gene” followed the team’s published findings. In October, Dr. Schwartzman received a $2,268,684 four-year grant from the National Heart, Lung, and Blood Institute, with Dr. Garcia serving as a co-investigator, to more fully grasp the mechanisms linking GPR75 to obesity-driven metabolic and cardiovascular complications.

“For example, inflammation tends to be the villain of obesity— the bad actor who puts every system in the body on alert. We have noted that the activation of GPR75 by 20-HETE creates a major blockage of insulin action, which leads to more glucose (sugar) in the blood. We are also tracking the pathways by which inflammatory cells begin to infiltrate blood vessels,” says Dr. Garcia.

Additional grants awarded to Dr. Garcia including the Sinsheimer Foundation Award and an National Institutes of Health RO3 award provide additional funding to support investigation into the role of GPR75 in the pathogenesis of cardiometabolic diseases.

Guided by their findings, she and Dr. Garcia are dedicating their lab resources, including the students they mentor, to develop a GPR75 blocker known as AAA that might prevent and even reverse obesity. “Working on a drug with so much therapeutic potential is not just exciting,” says Dr. Garcia. “It is life changing.”

Training The Next Generation

Dr. Schwartzman credits student involvement as key to her lab’s success. “Discovery is driven by teamwork. I cannot thank NYMC enough for all its resources and support in terms of clinicians, faculty members, and students.”

In October, Danielle Diegisser, a Ph.D. student in the Graduate School of Biomedical Sciences (GSBMS), presented her contribution to research of the GPR75 blocker, AAA, at an international conference on signaling molecules—receiving two of four awards given to NYMC students. The other two awards went to Alexandra Wolf, a Ph.D. student in the GSBMS, for her work exploring the impact of GPR75 on obesity-driven liver disease and hypertension.

“My professors and mentors at NYMC have greatly expanded my foundational knowledge for research,” Diegisser says. “Working with them has been rewarding and inspiring. I cannot wait to continue this journey with the colleagues I’ve met along the way.”

During the 2023–2024 academic year, Dr. Mullally introduced an overview of obesity medicine while teaching a physiology course, making NYMC among the first medical schools to cover the specialty. She has worked with students in the Culinary Medicine Interest Group, which promotes skills to develop nutrition-integrated care. “I am excited to offer opportunities for NYMCs students as we grow our practice—and work toward creating a state-of-the-art endocrine disease and metabolic center.” In the future, she sees promise in precision medicine based on genetic sequencing, similar to the Regeneron findings.

“With 60 to 70 percent of the population of U.S. overweight or having obesity,” says Dr. Mullally, “we are finally giving the condition its due attention; developing treatment that shows proven, promising results; and training tomorrow’s doctors for this critical specialty.”