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Akindehin, S.E. ; Liskiewicz, A. ; Liskiewicz, D. ; Bernecker, M. ; García-Cáceres, C. ; Drucker, D.J.* ; Finan, B.* ; Grandl, G. ; Gutgesell, R.M. ; Hofmann, S.M. ; Khalil, A. ; Liu, X. ; Cota, P. ; Bakhti, M. ; Czarnecki, O. ; Bastidas-Ponce, A. ; Lickert, H. ; Kang, L. ; Maity-Kumar, G. ; Novikoff, A. ; Parlee, S.* ; Pathak, E. ; Schriever, S.C. ; Sterr, M. ; Ussar, S. ; Zhang, Q. ; DiMarchi, R.* ; Tschöp, M.H. ; Pfluger, P.T. ; Douros, J.D.* ; Müller, T.D.

Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice.

Mol. Metab. 83:101915 (2024)

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OBJECTIVE: The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). METHODS: Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. RESULTS: Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance, and acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. CONCLUSIONS: GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.

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