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bioRxiv · 10.64898/2025.11.29.691273

Brainstem GLP-1 neurons modulate physiological satiation and drive sustained weight loss in obese mice

Jiang, W.·Skoug, C.·Rodrigues, I.·Ciabatti, E.·Gribble, F. M.·Reimann, F.·Brierley, D. I.·Holt, M. K.·Trapp, S.
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Abstract

Glucagon-like peptide-1 receptor (GLP-1R) activation in the brain strongly reduces appetite, but most brain GLP-1Rs are not accessible for systemically administered GLP-1R agonists. Acute activation of nucleus tractus solitarius (NTS) GLP-1 neurons, targeting brain GLP-1Rs, strongly suppresses food intake separate from GLP-1R agonists. However, it is unknown if their chronic stimulation is a viable strategy for appetite suppression, or if obesity disrupts their function. Here we demonstrate that GLP-1 neurons, distributed through NTS and IRT, determine meal size and their number is inversely correlated with bodyweight gain. GLP-1 neurons in IRT and NTS differ in their inputs but generate outputs in largely overlapping areas. Higher body weight and fat mass predicts a higher percentage of active GLP-1 neurons. Their chemogenetic activation is an efficient means of reducing food intake, and in obese mice chronic activation elicits sustained weight loss. In conclusion, GLP-1 neurons are a feasible target for obesity treatment.

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Jiang, W., Skoug, C., Rodrigues, I., Ciabatti, E., Gribble, F. M., Reimann, F., Brierley, D. I., Holt, M. K., Trapp, S.. 2025-12-02. Brainstem GLP-1 neurons modulate physiological satiation and drive sustained weight loss in obese mice. https://doi.org/10.64898/2025.11.29.691273

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