短链脂肪酸通过调节固有免疫、内皮细胞和胰岛素靶组织介导肠道产丁酸菌改善胰岛素抵抗的分子机制

肥胖是2型糖尿病的独立危险因素，表现为胰岛素抵抗（IR），炎症是其重要诱因。文献和我们的工作发现胰岛素靶组织以及固有免疫和内皮细胞这两个新因素与炎症和IR有关，近来报道肠道菌群也参与其中。肥胖个体肠道产丁酸菌减少，改善IR的不同干预方式大多能增加产丁酸菌及其产物短链脂肪酸（SCFAs）的量，肠道SCFAs可进入血循环，通过其G蛋白偶联受体（GPCR）作用于上述组织细胞等，介导肠道菌群与肠外的联系。我们推测，补充产丁酸菌可通过产生SCFAs缓解IR。但SCFAs如何通过GPCR信号通路与炎症及胰岛素信号通路cross-talk，相关的分子机制不明。本研究拟给予肥胖小鼠不同产丁酸菌或SCFA，借助焦磷酸测序、气相色谱、流式细胞术等分别检测肠道菌群结构、SCFAs浓度以及上述组织细胞的不同信号通路，明确SCFAs介导产丁酸菌改善IR的分子机制，寻求预防和治疗IR的新策略，为临床干预研究奠定基础。

Obesity is an independent risk factor of Type 2 Diabetes. Obesity is characterized by inflammation of metabolic tissues (adipose, liver and skeletal muscle) that leads to insulin resistance (IR). It is now well recognized in the literature and from our previous work that innate immune cells and endothelial cells within these tissues and the circulation are involved in the presentation of inflammation and IR during obesity. Recently, the gut microbiota has been recognized to play a major role in the inflammation of metabolic tissues. It has been reported that a major change in the gut of obese rodents and humans is a reduction in butyrate-producing bacteria. Several strategies designed to improve IR, also increase the amount of butyrate-producing bacteria and their products, short-chain fatty acids (SCFAs). Gut-derived SCFAs enter the circulation to mediate the effect of gut microbiota on innate immune cells, endothelial cells and insulin target cells via G-protein coupled receptors (GPCRs). Therefore, we hypothesize that supplementation of butyrate-producing bacteria could relieve IR through their production of SCFAs. However, how the GPCR signaling pathways activated by SCFAs cross-talk with inflammation and insulin signaling pathways is not clear yet. In order to illustrate the molecular mechanisms of the relief of insulin resistance by SCFAs from butyrate-producing bacteria, we will administer different butyrate-producing bacteria or SCFAs to obese mice. The changes of gut microbiota, concentration of SCFAs and different signal pathways in the above tissues and cells will be studied by pyrosequencing, gas chromatopraphy and FACS analyses, respectively. Our study may provide new strategy for prevention and treatment of IR and could lay the foundation for clinical intervention study in the future.