Yale Study Finds Ozempic May Work Through Hunger-Linked Brain Cells

A new Yale study suggests that semaglutide, the active ingredient in the weight-loss drug Ozempic, may owe some of its effect to a group of brain cells long thought to work against weight loss. Semaglutide belongs to a class of medicines that mimic glucagon-like peptide 1 (GLP-1), a hormone that helps regulate blood sugar, digestion and appetite, and is now widely prescribed for type 2 diabetes and obesity. The findings appear in the Proceedings of the National Academy of Sciences (PNAS).

The cells in question are agouti-related peptide (AgRP) neurons, found in the hypothalamus, the brain region that helps regulate hunger, metabolism and energy balance. AgRP neurons normally become more active when the body is short on energy, driving eating and resisting further weight loss, so they have generally been seen as an obstacle to slimming. Instead, the Yale team found that sustained semaglutide treatment activated these hunger neurons in mice rather than suppressing them, using electrophysiology, molecular analysis and electron microscopy to track the change.

When the researchers removed the AgRP neurons or blocked their function, semaglutide produced less sustained weight loss in female mice on a standard diet. The effect depended on diet, though: under high-fat-diet conditions the neurons were not required for the same weight-loss response, suggesting semaglutide may recruit different brain circuits depending on an animal's nutritional state. The calorie deficit created during treatment appears to raise AgRP neuron activity, and the same neurons seem to contribute to the physiological changes that support fat loss.

"This completely changes how we think about the mechanism involved in these medications and provides new insight into the biology underlying their long-term effects, opening an avenue for the development of more efficient drugs," said Mateus d'Ávila, a Ph.D. candidate in Tamas Horvath's lab at Yale School of Medicine and the study's first author. The experiments were conducted in mice, and whether the same mechanism operates in humans remains unknown.