Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism
Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism
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嗅觉 G 蛋白偶联受体自主感知胰岛素肽可调节葡萄糖代谢
DOI：
10.1016/j.cmet.2021.12.022
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发表时间：
2022-02-01
期刊：
影响因子：
29
通讯作者：
Yu，Xiao
中科院分区：
文献类型：
--
作者：
Cheng，Jie;Yang，Zhao;Yu，Xiao
与功能完整的胰岛素一起，糖尿病相关的胰岛素肽由β细胞分泌。通过筛选胰岛嗅觉受体（ORs）的表达和功能特征，我们确定Olfr109是检测胰岛素肽的受体。胰岛素肽insB:9-23与Olfr109结合可通过Gi-cAMP信号通路减少胰岛素分泌，并通过β细胞-巨噬细胞回路和β-arrestin-1介导的CCL2途径促进胰岛巨噬细胞增殖，β-arrestin-1−/−小鼠模型证实了这一点。在秋田和高脂饮食（HFD）喂养的小鼠中，全体性Olfr109缺乏或缺乏诱导的bypx1 - cre +/−Olfr109fl/ fl特异性地减轻了胰岛内炎症反应并改善了葡萄糖稳态。我们进一步确定了insB:9-23与Olfr109之间的结合模式。一种基于胃肽素的Olfr109拮抗剂改善了糖尿病和肥胖小鼠模型的葡萄糖稳态。总的来说，我们发现胰岛β细胞利用Olfr109自主检测自我分泌的胰岛素肽，这种检测阻止胰岛素分泌并与巨噬细胞相互作用，增加胰岛内炎症。
Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by β cells. By screening the expression and functional characterization of olfactory receptors (ORs) in pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a β cell-macrophage circuit and a β-arrestin-1-mediated CCL2 pathway, as evidenced by β-arrestin-1−/−mouse models. Systemic Olfr109 deficiency or deficiency induced byPdx1-Cre+/−Olfr109fl/flspecifically alleviated intra-islet inflammatory responses and improved glucose homeostasis inAkita- and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic β cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.