AgRP neurons are required for the weight-lowering effects of GLP-1 receptor agonists in female mice.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, produce robust and sustained weight loss, yet the central mechanisms supporting their long-term efficacy remain incompletely understood. Agouti-related peptide (AgRP) neurons of the arcuate nucleus are classically activated by negative energy balance and promote feeding and energy conservation. Based on this framework, GLP-1RAs have generally been expected to suppress or bypass AgRP neuron activity. Here, we report that AgRP neuron activation is required for the full weight-lowering effects of GLP-1RAs in female mice. Across complementary AgRP loss-of-function models, disruption of AgRP circuit integrity reduced the full weight-lowering effects of GLP-1RAs. This requirement varies with sex, diet, and mode of AgRP disruption. We found that GLP-1RA treatment is associated with increased markers of neuronal activation, mitochondrial engagement, and synaptic remodeling in AgRP neurons. We further identify a glucocorticoid-to-AgRP signaling axis as an important pathway mediating this functional recruitment of AgRP neurons. Together, these findings reveal that contrary to prevailing assumptions, GLP-1RA engages AgRP neurons to sustain weight loss, highlighting an unexpected role for these neurons in coordinating adaptive metabolic responses to pharmacologically induced negative energy balance.