A thrifty microRNA in insulin resistance and Type 2 diabetes

项目摘要/摘要 代谢综合征(METS)，一系列疾病和疾病，包括肥胖、胰岛素 抵抗/糖调节异常，非酒精性脂肪性肝病(NAFLD)，循环低密度脂蛋白升高- C/HDLC比率和甘油三酯以及高血压在全球范围内迅速上升，并与 更严重的疾病，如2型糖尿病和心血管疾病。然而，基因和 甲硫氨酸转运蛋白在病因中的分子作用尚不清楚。我们最近发现了microRNAs(miR- 33b/a)作为胆固醇/脂类动态平衡的关键调节因子。我们现在已经采用了全基因组关联 发现miR-128-1 microRNA与胆固醇/血脂异常、肥胖、 2糖尿病和最近的人类阳性选择。我们在小鼠体内和体外的初步研究已经 证实miR-128-1对代谢动态平衡有深远的影响。我们建议在这里测试 假设miR-128-1代表哺乳动物能量代谢的中枢调节因子，而人类 古代对宴请/饥荒周期的进化适应导致miR-128-1活性增强 某些人类群体中的能量储存。虽然在饥荒时期有益，但提高了miR-128-1 发达世界食物丰富的当今时代的活动/水平可能有助于 代谢性疾病，如肥胖和2型糖尿病。小鼠体外细胞培养和体内研究 反义靶向miR-128-1和miR-128-1的代谢性疾病模型(如DIO、ob/ob小鼠) KO小鼠将为miR-128-1在靶向通路引导中的作用提供关键的机械学见解 代谢动态平衡，以及这种microRNA是否适合用于靶向治疗以改善 普遍存在的代谢紊乱，如肥胖和2型糖尿病。

Project Summary/Abstract The metabolic syndrome (MetS), a constellation of conditions and disorders including obesity, insulin resistance/abnormal glucose regulation, nonalcoholic fatty liver disease (NAFLD), elevated circulating LDL- C/HDL-C ratios and triglycerides, and hypertension, is rapidly increasing world-wide and is associated with more severe diseases such as type 2 diabetes and cardiovascular disease. However, the genetic and molecular contributions to the etiology of MetS remain unclear. We recently discovered microRNAs (miR- 33b/a) as key regulators of cholesterol/lipid homeostasis. We have now employed genome-wide association studies (GWAS) to uncover the miR-128-1 microRNA as linked to cholesterol/lipid abnormalities, obesity, type 2 diabetes and recent human positive selection. Our preliminary in vitro and in vivo studies in mice have confirmed that miR-128-1 exerts profound effects on metabolic homeostasis. We propose here to test the hypothesis that miR-128-1 represents a central regulator of mammalian energy metabolism, and that human evolutionary adaptation to feast/famine cycles in ancient times led to increased miR-128-1 activity promoting energy storage in certain human populations. While beneficial in times of famine, elevated miR-128-1 activity/levels in present times with profound food abundance in the developed world could contribute to metabolic diseases such as obesity and type 2 diabetes. Both in vitro cell culture and in vivo studies in mouse metabolic disease models (e.g., DIO, ob/ob mice) with antisense targeting of miR-128-1, as well as miR-128-1 KO mice will provide critical mechanistic insights into the role of miR-128-1 in targeting pathways guiding metabolic homeostasis, and whether this microRNA may be suitable for therapeutic targeting to improve prevalent metabolic disorders such as obesity and type 2 diabetes.