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* (Corresponding Author), Nicolas Nunn, Isabella Culotta, Jenna Hunter, Mehdi Boutagouga Boudjadja, Lourdes Valencia-Torres, Gabriella Aviello, David J. Hodson, Brandy M. Snider, Tamer Coskun, Paul J. Emmerson, Simon M. Luckman, Giuseppe D'Agostino

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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 and for the 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 required 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
Pages (from-to)101407
Number of pages10
JournalMolecular Metabolism
Volume55
Early online date16 Dec 2021
DOIs
Publication statusPublished - 1 Jan 2022

Keywords

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

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