期刊
MOLECULAR METABOLISM
卷 55, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.molmet.2021.101407
关键词
Brain; Appetite; Nausea; Glucagon-like peptide-1; Glucose-dependent insulinotropic polypeptide; Cholecystokinin; Area postrema; Nucleus of the solitary tract
资金
- MRC Career Development Award [MR/P009824/1, MR/P009824/2]
- MRC [MR/N00275X/1, MR/S025618/1, MR/T032669/1]
- BBSRC [BB/M001067/1]
- Diabetes UK [17/0005681]
- European Research Council (ERC) under the European Union [715884]
- Italian Society of Pharmacology
- Veronesi Foundation (Italy)
- BBSRC [BB/M001067/1] Funding Source: UKRI
- MRC [MR/S025618/1, MR/T032669/1, MR/P009824/2, MR/P009824/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/M001067/1, BB/S008098/1] Funding Source: researchfish
- Medical Research Council [MR/T032669/1] Funding Source: researchfish
The study identified that cholecystokinin-expressing neurons in the caudal brainstem are crucial for the effects of GLP-1RAs and provide a novel framework for understanding and ameliorating GLP-1RA-induced nausea.
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 d a major factor for withdrawal from treatment. (c) 2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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