Nature Metabolism ( IF 18.9 ) Pub Date : 2023-09-28 , DOI: 10.1038/s42255-023-00899-4
Jia-Le Wang 1 , Xiao-Dong Dou 2 , Jie Cheng 3, 4 , Ming-Xin Gao 4 , Guo-Feng Xu 2 , Wei Ding 5 , Jin-Hui Ding 1 , Yu Li 1 , Si-Han Wang 4 , Zhao-Wei Ji 4 , Xin-Yi Zhao 2 , Tong-Yu Huo 2 , Cai-Fang Zhang 2 , Ya-Meng Liu 2, 6 , Xue-Ying Sha 1 , Jia-Rui Gao 4 , Wen-Hui Zhang 4 , Yong Hao 7 , Cheng Zhang 8 , Jin-Peng Sun 1, 3, 9 , Ning Jiao 2, 6 , Xiao Yu 4
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Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid–transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid–G-protein-coupled receptor 132 (GPR132)–Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N‐palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.
中文翻译:
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靶向 GPR132 治疗糖尿病的化合物的功能筛选和合理设计
胰岛驻留巨噬细胞引起的慢性炎症在 2 型糖尿病的发展中起关键作用。通过系统分析胰岛驻留巨噬细胞中的胰岛内脂质-跨膜受体信号,我们确定了内源性 9(S)-羟基-10,12-十八碳二烯酸-G 蛋白偶联受体 132 (GPR132)-Gi 信号是胰岛巨噬细胞重编程的重要贡献者,并发现巨噬细胞中的 GPR132 缺陷逆转了高脂饮食小鼠的代谢紊乱。GPR132 的冷冻电子显微镜结构与两种内源性激动剂 N-棕榈酰甘氨酸和 9(S)-羟基-10,12-十八碳二烯酸结合,使我们能够通过逐步翻译方法合理设计具有高效力和选择性的 GPR132 激动剂和拮抗剂。我们最终确定了一种选择性 GPR132 拮抗剂 NOX-6-18,它调节胰岛内的巨噬细胞重编程,减少体重增加并增强高脂肪饮食小鼠的葡萄糖代谢。我们的研究不仅表明胰岛内脂质信号传导有助于胰岛巨噬细胞重编程,而且还为识别病理生理过程中重要的 G 蛋白偶联受体靶点提供了广泛适用的策略,然后为糖尿病等难治性疾病的治疗线索的合理设计提供了依据。