血管旁脂肪组织miR-34a在引起肥胖相关FGF21抵抗及内皮功能紊乱中的作用机理研究

Obesity-associated cardiovascular diseases (CVDs) account for the high mortality rate of obese individuals. Dysfunction of perivascualr adipose tissues is believed to be one of the major culprits for obesity-associated CVDs. Fibroblast growth factor (FGF) 21 is a multifaceted hormone regulating numerous biological functions including glucose homeostasis, lipolysis, and β-cell functions. Our preliminary data suggest that FGF21 acts directly on endothelial cells to promote endothelium-dependent vasorelaxation. In obesity, the expression of FGF21 in adipose tissue is paradoxically increased while that of its obligatory co-receptor β-klotho is down-modulated, establishing a FGF21 resistance state. Recent investigation revealed that β-klotho expression is under the regulation of microRNA (miR)-34a, a class of small interfering RNA silencing gene expression via post-transcriptonal modification. As our preliminary study observed a markedly increased miR-34a expression in perivascular fat, we hypothesized that miR-34a induction silences β-klotho expression in the blood vessels, resulting in impairment of FGF21 signal. In this proposal, we will examine the significance of miR-34a in controlling β-klotho level under the obese conditions by using ex-vivo as well as animal experiments. The downstream effect of β-klotho loss on endothelial functions will be explored. In addition, we will investigate whether there is any correlation between elevated miR-34a (as well as loss of β-klotho) in adipose tissue and circulating markers of endothelial dysfunction as well as high blood pressure in obese human subjects. This proposal will not only uncover novel mechanistic insight of FGF21 resistance under obesity but also establish a foundation for the future development of microRNA-based therapeutic intervention to combat obesity-associated CVDs.

血管旁脂肪组织通过释放一系列生物活性物质，调节血管的收缩及舒张功能。FGF21 是一个新型的具抗肥胖及抗糖尿病潜能的激素。我们的初步实验显示，以血管旁脂肪产生的FGF21 以旁分泌的方式，促进内皮依赖性血管舒张。但在肥胖时其作用明显降低，提示存在FGF21 抵抗现象。然而，肥胖引起FGF21 抵抗的机理未明。有鉴于最近发现miR-34a能下调FGF21 共受体β-klotho的表达，我们认为miR-34a在肥胖脂肪组织的上升而导致β-klotho的下调是引起FGF21抵抗的机理之一。本研究旨在通过一系列离体、动物和临床相结合的方法验证这一假说，以进一步揭示肥胖相关血管病变的发病机理，为将来开发以FGF21 信号通路为靶点药物打下基础。