[HTML][HTML] Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation
A Costa, M Ai, N Nunn, I Culotta, J Hunter… - Molecular …, 2022 - Elsevier
A Costa, M Ai, N Nunn, I Culotta, J Hunter, MB Boudjadja, L Valencia-Torres, G Aviello…
Molecular metabolism, 2022•ElsevierObjective 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 …
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 …
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.
Elsevier