Ozempic Recruits the Brain's Hunger Neurons to Help Sustain Weight Loss, Yale Study Finds

Scientists have long thought that agouti-related peptide (AgRP) neurons — brain cells well known for driving hunger — worked against weight loss. A new Yale study, published in the Proceedings of the National Academy of Sciences (PNAS), finds the opposite: during treatment with GLP-1 drugs such as Ozempic, these neurons appear to be recruited to help sustain fat loss.

GLP-1 medications, whose active ingredient is semaglutide, can produce sustained weight loss of 10 to 15% or more, far surpassing earlier obesity drugs that reduced appetite about as effectively but did not produce the same lasting results. Researchers in Tamas Horvath's lab at Yale School of Medicine set out to test directly whether AgRP neurons were required for semaglutide's lasting effects, something no study had done before in a living animal during chronic treatment.

Using a mouse model, the team tracked body weight, food intake, metabolism and energy expenditure during semaglutide treatment, and used genetic techniques to eliminate or silence AgRP neurons. In mice engineered to lack these neurons, GLP-1 drugs could no longer sustain weight loss. Further experiments using electron microscopy, molecular biology and electrophysiology showed that, rather than being suppressed by semaglutide, the AgRP neurons were activated.

"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 PhD candidate in neuroscience in Horvath's lab and first author of the study.

The experiments were conducted in mice, and the researchers say further research is needed to determine whether the same mechanism operates in humans.