肥胖状态下FFA/Fetuin-A/TLR4介导胰腺异位脂肪RAS激活的效应：对胰岛微循环损伤的新机理

胰岛微循环是维持胰岛结构和功能的基础。胰岛微循环障碍是胰岛功能衰竭的关键原因。我们前期研究发现肥胖大鼠血糖正常时胰岛微血管即已出现病理及功能改变，提示其存在高血糖之外的损害因素。肥胖可通过游离脂肪酸（FFA）引起胰腺异位脂肪沉积，且在肥胖状态下脂肪局部肾素-血管紧张素系统（RAS）被激活，是血管病变的早期原因。据此我们推测肥胖状态下FFA激活胰腺脂肪局部RAS，进而介导胰岛微血管损伤。课题拟通过建立大鼠肥胖模型，体外FFA刺激培养脂肪细胞，体外AngII刺激胰岛及胰岛微血管内皮细胞，观测胰岛微血管表型、结构和功能的改变，检测胰腺脂肪组织中脂肪含量、RAS组分以及Fetuin-A/TLR4信号通路的表达情况，探讨胰腺异位脂肪沉积引起局部RAS激活的机理及效应，探讨其对胰岛微血管内皮细胞损伤新机制，旨在早期保护胰岛，也为防治肥胖状态下其他脏器微血管病变提供更多证据。

Islet microcirculation is the basis of structure and function of the islet and also the key reason for failure of islet function. Our previous study found that pathophysiology and function of the islets microvessel had changed in rats although blood glucose was normal, which suggested that other damage factors besides high blood sugar also had an effect on the islet.It's reported that obesity can result in ectopic fat accumulation in pancreatic by free fatty acid and renin - angiotensin system (RAS) is involved in fat cells. RAS, which can be activated in the state of obesity, is the early reason of vascular lesions. So we hypothesize that islet microvascular injury caused by obesity may be associated with activation of RAS by free fatty acid in pancreatic ectopic fat . To explore the mechanism of it, obese rats would be modeled, fat cells stimulated by free fatty acids (FFA) and islet microvascular endothelial cells (IMECs) stimulated by Angiotensin II would be cultured. Then the structure of islet microvessel would be observed. And fat content in pancreatic adipose tissue, RAS component and specific signaling pathway such as Feurin, TLR4 would be tested. The confirmation of the above issues would demonstrate a new mechanism of IMECs injure, and provide a new path for early protection of islet and more evidence of microangiopathy prevention under obesity.