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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
- Source :
- Costa, A, Ai, M, Nunn, N, Culotta, I, Hunter, J, Boudjadja, M B, Valencia-Torres, L, Aviello, G, Hodson, D J, Snider, B M, Coskun, T, Emmerson, P J, Luckman, S M & D'Agostino, G 2021, ' Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation ', Molecular Metabolism, vol. 55, 101407 . https://doi.org/10.1016/j.molmet.2021.101407, Molecular Metabolism, Molecular Metabolism, Vol 55, Iss, Pp 101407-(2022)
- Publication Year :
- 2021
-
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.<br />Highlights • CCKAP/NTS neurons are required for the full anorectic and body weight-lowering effect of GLP-1 receptor agonists. • GLP-1 receptor agonists promote the formation of conditioned taste avoidance by activating CCKAP/NTS neurons. • CCKAP/NTS neurons are not activated in response to GIP receptor agonists. • GIP receptor agonists reduce GLP-1 receptor agonist-induced neuronal responses in the caudal brainstem. • GIP receptor agonists reduce GLP-1 receptor agonist-induced conditioned taste avoidance.
- Subjects :
- Blood Glucose
Male
Glucagon-like peptide-1
endocrine system
Glucose-dependent insulinotropic polypeptide
media_common.quotation_subject
Appetite
Gastric Inhibitory Polypeptide
Brief Communication
Glucagon-Like Peptide-1 Receptor
Receptors, Gastrointestinal Hormone
Mice
Nucleus of the solitary tract
Glucagon-Like Peptide 1
Appetite Depressants
Medicine
Animals
Hypoglycemic Agents
Insulin
Receptor
Internal medicine
Molecular Biology
Glucagon-like peptide 1 receptor
media_common
Cholecystokinin
Neurons
business.industry
Area postrema
digestive, oral, and skin physiology
Brain
Nausea
Cell Biology
Liraglutide
Glucagon
RC31-1245
Mice, Inbred C57BL
Anorectic
Exenatide
Female
Brainstem
business
Neuroscience
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Costa, A, Ai, M, Nunn, N, Culotta, I, Hunter, J, Boudjadja, M B, Valencia-Torres, L, Aviello, G, Hodson, D J, Snider, B M, Coskun, T, Emmerson, P J, Luckman, S M & D'Agostino, G 2021, ' Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation ', Molecular Metabolism, vol. 55, 101407 . https://doi.org/10.1016/j.molmet.2021.101407, Molecular Metabolism, Molecular Metabolism, Vol 55, Iss, Pp 101407-(2022)
- Accession number :
- edsair.doi.dedup.....f3c8f4b8195f8ad7f7f17bc35a2d9541