Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling

Claire H. Feetham, Valeria Collabolletta, Amy A. Worth, Rosemary Shoop, Sam Groom, Court Harding, Mehdi Boutagouga Boudjadja, Tamer Coskun, Paul J. Emmerson, Giuseppe D’Agostino and Simon M. Luckman ()
Additional contact information
Claire H. Feetham: University of Manchester
Valeria Collabolletta: University of Manchester
Amy A. Worth: University of Manchester
Rosemary Shoop: University of Manchester
Sam Groom: University of Manchester
Court Harding: University of Manchester
Mehdi Boutagouga Boudjadja: University of Manchester
Tamer Coskun: Eli Lilly & Company
Paul J. Emmerson: Eli Lilly & Company
Giuseppe D’Agostino: University of Manchester
Simon M. Luckman: University of Manchester

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Growth differentiation factor 15, GDF15, and glucagon-like peptide-1 (GLP-1) analogues act through brainstem neurons that co-localise their receptors, GDNF-family receptor α-like (GFRAL) and GLP1R, to reduce food intake and body weight. However, their use as clinical treatments is partially hampered since both can also induce sickness-like behaviours, including aversion, that are mediated through a well-characterised pathway via the exterolateral parabrachial nucleus. Here, in mice, we describe a separate pathway downstream of GFRAL/GLP1R neurons that involves a distinct population of brain-derived neurotrophic factor (BDNF) cells in the medial nucleus of the tractus solitarius. Thus, BDNFmNTS neurons are required for the weight-reducing actions of both GDF15 and the GLP1RA, Exendin-4. Moreover, acute activation of BDNFmNTS neurons is sufficient to reduce food intake and drive fatty acid oxidation and might provide a route for longer-term weight loss.

Date: 2024
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DOI: 10.1038/s41467-024-54367-y

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