A new hypothesis suggests that GLP-1 drugs activate specific neurons to trigger fat loss. Provided by Getty Images Bank
Popular anti-obesity drugs such as Wegovy, which belong to the glucagon-like peptide-1 (GLP-1) class, have been thought to work by suppressing hunger-inducing neurons. New findings now overturn that hypothesis, suggesting instead that these drugs activate the very neurons that promote hunger.
The research team led by Professor Tamas Horvath at Yale School of Medicine in the United States has proposed a new hypothesis that GLP-1 drugs activate AgRP neurons to induce fat loss, and published their results on August 11 in the international journal Proceedings of the National Academy of Sciences (PNAS).
Before GLP-1 drugs emerged, the weight-loss effects of anti-obesity medications were far from dramatic. Earlier drugs also suppressed appetite to promote weight loss, but they did not achieve the 10–15% or greater reduction in body weight seen with GLP-1 agents such as Ozempic and Wegovy
Assuming that GLP-1 drugs do more than simply curb appetite, the researchers set out to clarify the drugs’ additional roles.
Agouti-related peptide (AgRP) neurons in the brain promote hunger and appetite and have long been identified as a key factor that interferes with weight loss. The prevailing hypothesis had held that GLP-1 drugs would suppress AgRP neuronal activity to produce their weight-loss effect. However, the role of AgRP neurons had not previously been directly tested in in vivo (within a living organism) conditions.
To uncover the biological mechanisms of AgRP neurons, the team conducted animal experiments. They administered GLP-1 drugs to mouse models and monitored body weight, food intake, metabolism, and energy expenditure.
Next, they gave GLP-1 drugs to genetically engineered mice in which AgRP neurons had been selectively removed or inactivated. In these models, once AgRP neurons were absent, the weight-loss effect no longer persisted as it had before their removal.
Additional experiments using electron microscopy, molecular biology techniques, and physiological electrophysiology showed that GLP-1 drugs do not suppress AgRP neurons; instead, they actually activate them.
The researchers stated, “When GLP-1 drugs create a calorie-deficient state, the brain appears to increase the activity of AgRP neurons so that fat is lost or regulated,” adding, “This implies that GLP-1 drugs operate through mechanisms that had not been recognized until now.”
This study is significant because it presents a new principle: GLP-1 drugs may go beyond simple appetite suppression to drive sustained fat reduction through brain neural networks. The findings are expected to provide fresh biological insights for designing next-generation obesity treatments with improved efficacy.
<Reference>doi.org/10.1073/pnas.2614476123
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