Proceedings of the National Academy of Sciences of the United States of AmericaAug 4, 2026

Brain hunger neurons needed for weight loss effects of GLP-1 drugs in female mice

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 5, 2026

Abstract

AgRP neuron activation is required for the full weight-lowering effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in female mice.

Disruption of AgRP neuron circuit integrity reduces the effectiveness of GLP-1RAs for weight loss.
The requirement for AgRP neuron activation varies with factors such as sex, diet, and the method of AgRP disruption.
GLP-1RA treatment is associated with increased neuronal activation, mitochondrial engagement, and synaptic remodeling in AgRP neurons.
A glucocorticoid-to-AgRP signaling pathway is identified as significant for the activation of AgRP neurons.

Simplified

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.

Brain hunger neurons needed for weight loss effects of GLP-1 drugs in female mice

Abstract

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