Authors
Mateus d'Ávila, João Cavalcanti-de-Albuquerque, Roberto Collado-Pérez, Zhong-Wu Liu, Jenna Hunter, Anne White, Joseph Schlessinger, Giuseppe D'Agostino, Tamas L Horvath
Published in
Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 32. Pages e2614476123. Aug 11, 2026. Epub Aug 04, 2026.
Abstract
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.
PMID:
42550908
Bibliographic data and abstract were imported from PubMed on 05 Aug 2026.
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