Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism.

Authors

Jo Edward Lewis, Mireia Montaner, Danae Nuzzaci, Paula-Peace James-Okoro, Norio Harada, Nobuya Inagaki, W Scott Dodson, Patrick J Knerr, Jonathan D Douros, Fiona Mary Gribble, Frank Reimann

Published in

Nature metabolism. Jul 24, 2026. Epub Jul 24, 2026.

Abstract

The development of dual agonists for the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has been a landmark moment in the treatment of type 2 diabetes and obesity. However, for reasons that are incompletely understood, in preclinical and clinical studies, adding either a GIPR agonist or GIPR antagonist to GLP-1R agonism causes additional weight loss¹. Here we show that distinct brain regions mediate the appetite-suppressing effects of GIPR agonists and the synergistic weight loss effects conferred by GIPR antagonists. We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (Gipr^AP-KO and Gipr^hypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide. Gipr^AP-KO mice exhibit partial protection against diet-induced obesity, reduced responsiveness to the appetite-suppressing effects of acyl-GIP and a reduced ability of acyl-GIP to prevent avoidance triggered by peptide YY. Weight loss effects of liraglutide are comparable in Gipr^AP-KO and control mice, and the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups. Gipr^hypo-KO mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice. Gipr^hypo-KO also abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide-an effect that is not mediated by nucleus tractus solitarius preproglucagon neurons. GIPR antagonism and Gipr^hypo-KO also sensitise to cagrilintide-induced weight loss. Overall, our results suggest that the AP is responsible for the appetite-suppressing effects of GIPR agonism but that GIP receptors in the hypothalamus underlie the ability of GIPR antagonism to enhance the weight loss effects of GLP-1R and amylin receptor agonists.

PMID:
42498824
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.

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