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

18 Citations (Scopus)
5 Downloads (Pure)


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
Early online date16 Dec 2021
Publication statusPublished - 1 Jan 2022

Bibliographical note

This work was funded by an MRC Career Development Award (MR/ P009824/1 and MR/P009824/2) to GD’A, as well as an MRC grant to SML/GD’A (MR/T032669/1), a BBSRC grant to SML (BB/M001067/1), and an additional direct contribution from Eli Lilly. D.J.H. was sup- ported by MRC (MR/N00275X/1 and MR/S025618/1), Diabetes UK (17/ 0005681), and the European Research Council (ERC) under the Eu- ropean Union’s Horizon 2020 research and innovation programme (Starting Grant 715884 to D.J.H.). AC was supported for part of this project by a travel grant from the Italian Society of Pharmacology and a fellowship from the Veronesi Foundation (Italy).

Data Availability Statement

Supplementary data to this article can be found online at molmet.2021.101407.


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


Dive into the research topics of 'Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation'. Together they form a unique fingerprint.

Cite this