NIH awards $4M grant to study GLP-1 weight regain

A team of UTHealth Houston researchers has been awarded a five-year, $4 million grant from the National Institutes of Health to identify genetic markers that may contribute to weight gain after stopping GLP-1 medications.

Stopping GLP-1 medications currently triggers unpredictable weight gain, and scientists do not yet know the exact biological pathways behind it.

“We are grateful to receive this grant. The research that follows will help us understand who may be genetically predisposed to gain weight after stopping GLP-1 receptor agonist medications,” said Absalon Gutierrez, MD, the principal investigator and a professor in the Division of Endocrinology, Diabetes, and Metabolism at McGovern Medical School at UTHealth Houston.

GLP-1 receptor agonist medications are not permanent solutions for long-term obesity management, and weight gain after discontinuation is common. According to research, roughly 30% of patients stop taking the medications within six months, and about 50% stop within a year. Most individuals regain more than 60% of their lost weight within a year of stopping the medication, alongside the return of health risks like diabetes or cardiovascular issues. 

Researchers noticed not everyone regains weight or faces health risks at the same rate. This suggests the body may retain a “metabolic memory” or molecular traces of the medication or past weight loss that influence how metabolism behaves long after stopping the medication.

The grant will allow researchers to study genetic markers associated with weight cycling following discontinuation of weight loss medications.

Weight cycling is the repeated loss and regain of body weight associated with stopping and restarting any weight loss strategy. This rebound effect is driven by complex physiological adaptations, including increased appetite, reduced energy expenditure, and hormonal changes that favor weight restoration. It can also lead to muscle loss, metabolic slowdown, and cardiometabolic strain.

The research is being conducted in partnership with Vanderbilt University and the Border Health Research Center at UTHealth Houston School of Public Health in Brownsville. Established in 2003, the center studies risk factors for obesity, diabetes, and related complications among Americans of Mexican descent living in the Lower Rio Grande Valley.

The double-blind study will include 100 participants with obesity from the Border Health Research Cohort. Participants will receive semaglutide for six months. Afterward, half will be randomly selected to discontinue the medication while the other half will remain on GLP-1 therapy. Researchers will analyze genetic markers in both groups, including markers related to insulin metabolism, energy expenditure, appetite hormones, and body composition.

To uncover what happens to the body in every stage of stopping and starting GLP-1 medications, the researchers will take small fat tissue and blood samples to see how gene activity changes after stopping the drug. They will measure circulating molecules, gene expression, and immune signals to see how energy use and metabolism shift, and give participants a test meal to measure real-time blood sugar, insulin response, and appetite. Throughout the trial, participants will also undergo whole-body scans to check body composition, breathing tests to measure resting calorie burn, and surveys to track diet and exercise habits.

“Weight regain after GLP-1 receptor agonist discontinuation is a significant clinical problem,” said Joseph B. McCormick, MD, the co-principal investigator and a professor of epidemiology, who holds the James H. Steele, DVM, Professorship at the School of Public Health. “This randomized, blinded trial will uncover why some people regain weight and others don't, including a possible ‘metabolic memory’ of the initial treatment. Because controlled molecular studies of GLP-1RA exposure and withdrawal haven't been reported, the work could identify new drug targets and predictive biomarkers of therapeutic durability in an understudied population.”

By pinpointing the molecular changes in fat tissue and blood, this trial aims to uncover new biological targets for future treatments, helping doctors prevent weight rebound, long-term weight management, and preserve the long-term health benefits of weight loss even after medication stops.