Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation

Alessia Costa, Minrong Ai, Nicolas Nunn, Isabella Culotta, Jenna Hunter, Mehdi Boutagouga Boudjadja, Lourdes Valencia-Torres, Gabriella Aviello, David Hodson, Brandy Snider, Tamer Coskun, Paul Emmerson, Simon Luckman, Giuseppe D'Agostino

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective medications to reduce appetite and body weight. These actions are centrally mediated, however the neuronal substrates involved are poorly understood.

Methods: We employed a combination of neuroanatomical, genetic and behavioral approaches in the mouse to investigate the involvement of caudal brainstem cholecystokinin-expressing neurons in the effect of the GLP-1RA exendin-4. We further confirmed key neuroanatomical findings in the non-human primate brain.

Results: We found that cholecystokinin-expressing neurons in the caudal brainstem are required for the anorectic and body weight-lowering effects of GLP-1RAs, as well as for induction of GLP-1RA-induced conditioned taste avoidance. We further show that, while cholecystokinin-expressing neurons are not a direct target for glucose-dependent insulinotropic peptide (GIP), GIP receptor activation results in a reduced recruitment of these GLP-1RA-responsive neurons and a selective reduction of conditioned taste avoidance.

Conclusions: In addition to disclosing a neuronal population that is necessary for the full appetite- and body weight-lowering effect of GLP-1RAs, our data also provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea – a major factor for withdrawal from treatment.
Original languageEnglish
Article number101407
JournalMolecular metabolism
Early online date26 Nov 2021
DOIs
Publication statusE-pub ahead of print - 26 Nov 2021

Keywords

  • Brain
  • Appetite
  • Nausea
  • Glucagon-like peptide-1
  • Glucose-dependent insulinotropic polypeptide
  • Cholecystokinin
  • Area Postrema
  • Nucleus of the solitary tract

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