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Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Simon M. Lu, 2024. "Brainstem BDNF neurons are downstream of GFRAL/GLP1R signalling," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54367-y
    DOI: 10.1038/s41467-024-54367-y
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