ISLR参与肥胖小鼠胰岛素抵抗的机制研究

中国正在面临由肥胖引发的代谢综合征的严重威胁，但我们对由肥胖引发的胰岛素抵抗这一核心机制的理解却十分有限。本研究将重点解析一种由肥胖引发胰岛素抵抗形成的机制。.前期在肌肉和脂肪的发育与代谢研究中，我们发现一个在肥胖和正常个体中差异表达的重要基因ISLR，当时功能未知。经研究，我们最近在Nature Communication报道了肌肉中ISLR可以通过自噬调控发育的机制；而在脂肪组织中我们发现了更加值得关注的信息，高脂诱导小鼠肥胖的过程中，伴随胰岛素抵抗的形成，ISLR异常高表达。因此，我们希望回答ISLR是否参与了肥胖过程中胰岛素抵抗的形成，以及ISLR调节肥胖引发胰岛素抵抗的分子机制。初步结果表明，ISLR敲除小鼠在高脂诱导下能够阻止胰岛素抵抗的发生。项目将利用敲除鼠及体外细胞系模型，通过蛋白互作的挖掘和验证，系统阐述ISLR对胰岛素信号的调控作用，揭示肥胖诱导的胰岛素抵抗新机制。

China has become the fattest nation in the world. The increased prevalence of metabolic syndrome (MetS) and type 2 diabetes (T2D) has become a worldwide problem threatening human health seriously and the pathogenesis has become a research hotspot in recent years. Obesity is associated with an increased risk of MetS and T2D in most areas around the world. Insulin signaling dysregulation is core to the pathogenesis of obesity-induced metabolic syndrome and type 2 diabetes. Adipose tissue is an endocrine organ within the essential nature of the adipocytes used for the storage of excess triglycerides (TGs), which is a targeting of insulin to maintain whole-body energy and metabolic homeostasis. How the deteriorative functions and abnormal metabolism levels in adipose tissues in obese individuals affect systemic homeostasis is still unclear. . In this study, immunoglobulin superfamily containing leucine-rich repeat (ISLR) is abnormal high expressed in adipocytes of white adipose tissue in obese mice fed high-fat diet. To investigate the roles of ISLR in adipocytes on HFD, we established a line of ad- ISLRko mice, in which ISLR was specifical deletion in adipocytes, by crossing mice with floxed ISLR alleles with mice carrying transgene containing cre-recombinase driven by the Adipoq promoter. Our data indicate that ISLR knockout inhibits HFD-induced obesity and increases insulin sensitivity in mice. Based on cell biology research platform in vitro and in vivo, this project elaborates the regulated function of ISLR in adipose tissue and reveals a new molecular mechanism of obesity-induced insulin resistance. This project is aimed at finding a new therapeutic target for metabolic diseases. Under the support, 3 graduated students will be trained, more than 2 SCI paper (IF>5) should be published and 1 patent should be applied.