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Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism
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DOI：10.1038/s42255-026-01575-z.png)
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Abstract
En 中文
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 (GiprAP-KO and Giprhypo-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. GiprAP-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 GiprAP-KO and control mice, and the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups. Giprhypo-KO mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice. Giprhypo-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 Giprhypo-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. The study employs region-specific knockout of the glucose-dependent insulinotropic polypeptide receptor (GIPR) in either the area postrema or hypothalamus of mice to determine how GIPR agonism and antagonism regulate food intake and body weight via distinct brain regions.
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