GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model.
GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model.
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DOI：
10.1172/jci160097
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发表时间：
2022-11-01
影响因子：
15.9
通讯作者：
Oh, Da Young
中科院分区：
文献类型：
--
作者：
de Souza, Camila O.;Paschoal, Vivian A.;Sun, Xuenan;Vishvanath, Lavanya;Zhang, Qianbin;Shao, Mengle;Onodera, Toshiharu;Chen, Shiuhwei;Joffin, Nolwenn;Bueno, Lorena M. A.;Gupta, Rana K.;Oh, Da Young
肥胖诱导的β细胞质量增加及其导致的β细胞功能障碍的分子机制需要进一步阐明。我们的研究表明，GPR 92，在胰岛巨噬细胞中表达，通过饮食干预代谢组织的调制。因此，我们旨在通过使用高脂饮食诱导的（HFD诱导的）肥胖小鼠模型来确定GPR 92在胰岛炎症中的作用。与WT小鼠相比，GPR 92-KO小鼠表现出葡萄糖耐受不良和胰岛素水平降低-尽管胰岛增大-以及胰岛巨噬细胞含量和炎症水平增加。这些结果表明，胰岛巨噬细胞中GPR 92的缺乏可引起β细胞功能障碍，导致葡萄糖稳态破坏。或者，用GPR 92激动剂焦磷酸法呢酯刺激导致WT小鼠中HFD诱导的胰岛炎症的抑制和胰岛素分泌的增加，但在GPR 92-KO小鼠中则不然。因此，我们的研究表明，GPR 92可能是通过抑制与糖尿病进展相关的胰岛炎症来缓解β细胞功能障碍的潜在靶点。
The molecular mechanisms underlying obesity-induced increases in β cell mass and the resulting β cell dysfunction need to be elucidated further. Our study revealed that GPR92, expressed in islet macrophages, is modulated by dietary interventions in metabolic tissues. Therefore, we aimed to define the role of GPR92 in islet inflammation by using a high-fat diet–induced (HFD-induced) obese mouse model. GPR92-KO mice exhibited glucose intolerance and reduced insulin levels — despite the enlarged pancreatic islets — as well as increased islet macrophage content and inflammation level compared with WT mice. These results indicate that the lack of GPR92 in islet macrophages can cause β cell dysfunction, leading to disrupted glucose homeostasis. Alternatively, stimulation with the GPR92 agonist farnesyl pyrophosphate results in the inhibition of HFD-induced islet inflammation and increased insulin secretion in WT mice, but not in GPR92-KO mice. Thus, our study suggests that GPR92 can be a potential target to alleviate β cell dysfunction via the inhibition of islet inflammation associated with the progression of diabetes.