Dissociable hindbrain GLP1R circuits for satiety and aversion.

Autor: Huang KP; Monell Chemical Senses Center, Philadelphia, PA, USA., Acosta AA; Monell Chemical Senses Center, Philadelphia, PA, USA., Ghidewon MY; Monell Chemical Senses Center, Philadelphia, PA, USA.; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, USA., McKnight AD; Monell Chemical Senses Center, Philadelphia, PA, USA.; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, USA., Almeida MS; Monell Chemical Senses Center, Philadelphia, PA, USA., Nyema NT; Monell Chemical Senses Center, Philadelphia, PA, USA., Hanchak ND; Monell Chemical Senses Center, Philadelphia, PA, USA., Patel N; Monell Chemical Senses Center, Philadelphia, PA, USA., Gbenou YSK; Monell Chemical Senses Center, Philadelphia, PA, USA., Adriaenssens AE; Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK., Bolding KA; Monell Chemical Senses Center, Philadelphia, PA, USA.; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, USA., Alhadeff AL; Monell Chemical Senses Center, Philadelphia, PA, USA. aalhadeff@monell.org.; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, USA. aalhadeff@monell.org.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Aug; Vol. 632 (8025), pp. 585-593. Date of Electronic Publication: 2024 Jul 10.
DOI: 10.1038/s41586-024-07685-6
Abstrakt: The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting 1,2 , effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTS GLP1R neurons triggers satiety in the absence of aversion, whereas activation of AP GLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTS GLP1R and AP GLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTS GLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: