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

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 beh...

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Main Authors: Alessia Costa (Author), Minrong Ai (Author), Nicolas Nunn (Author), Isabella Culotta (Author), Jenna Hunter (Author), Mehdi Boutagouga Boudjadja (Author), Lourdes Valencia-Torres (Author), Gabriella Aviello (Author), David J. Hodson (Author), Brandy M. Snider (Author), Tamer Coskun (Author), Paul J. Emmerson (Author), Simon M. Luckman (Author), Giuseppe D'Agostino (Author)
Format: Book
Published: Elsevier, 2022-01-01T00:00:00Z.
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Summary: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.
Item Description:2212-8778
10.1016/j.molmet.2021.101407

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