Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Helmholtz Diabetes School, Helmholtz Diabetes Center, Munich, Germany.
Institute for Diabetes and Obesity, Helmholtz Munich, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department of Physiology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Poland.
Mol Metab. 2024 May;83:101915. doi: 10.1016/j.molmet.2024.101915. Epub 2024 Mar 14.
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).
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.
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. 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.
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.
葡萄糖依赖性胰岛素释放多肽（GIP）通过中枢 GIP 受体（GIPR）信号降低体重，但潜在机制在很大程度上仍不清楚。在这里，我们评估了 GIP 是否通过表达瘦素受体（Lepr）的细胞中的 GIPR 信号来调节体重和葡萄糖控制。
使用单细胞 RNAseq 分析评估下丘脑、后脑和胰腺中 Gipr 和 Lepr 的共表达。生成了 Lepr 细胞中 Gipr 缺失的小鼠，并对其进行了代谢特征分析，以评估其在饮食诱导肥胖（DIO）、葡萄糖控制和瘦素敏感性方面的变化。进一步使用长效单激动剂和 GIPR 和 GLP-1R 的双重激动剂来评估这些药物对 DIO 野生型（WT）和 Lepr-Gipr 敲除（KO）小鼠能量和葡萄糖代谢的影响。
Gipr 和 Lepr 在胰腺中表现出强烈的共表达，但在下丘脑和后脑中则没有。与 WT 对照相比，DIO Lepr-Gipr KO 小鼠在体重、食物摄入和饮食诱导的瘦素抵抗方面没有差异。酰基 GIP 和 GIPR：GLP-1R 双重激动剂 MAR709 仍然完全有效，可降低 DIO Lepr-Gipr KO 小鼠的体重和食物摄入量。与 Gipr 和 Lepr 高度共定位在包括β细胞在内的内分泌胰腺中的证明一致，我们发现 GIPR：GLP-1R 双重激动剂相对于单一 GLP-1R 激动剂对血糖的优越作用在 Lepr-Gipr KO 小鼠中消失。
表达瘦素受体的细胞/神经元中的 GIPR 信号不参与体重或食物摄入的控制，但对于 GIPR：GLP-1R 双重激动剂相对于单一 GLP-1R 激动剂对血糖的优越作用至关重要。
