Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21075-80. doi: 10.1073/pnas.1118922109. Epub 2011 Dec 12.
Diabetes mellitus is the most common metabolic disorder worldwide and a major risk factor for cardiovascular disease. MicroRNAs are negative regulators of gene expression that have been implicated in many biological processes, including metabolism. Here we show that the Let-7 family of microRNAs regulates glucose metabolism in multiple organs. Global and pancreas-specific overexpression of Let-7 in mice resulted in impaired glucose tolerance and reduced glucose-induced pancreatic insulin secretion. Mice overexpressing Let-7 also had decreased fat mass and body weight, as well as reduced body size. Global knockdown of the Let-7 family with an antimiR was sufficient to prevent and treat impaired glucose tolerance in mice with diet-induced obesity, at least in part by improving insulin sensitivity in liver and muscle. AntimiR treatment of mice on a high-fat diet also resulted in increased lean and muscle mass, but not increased fat mass, and prevented ectopic fat deposition in the liver. These findings demonstrate that Let-7 regulates multiple aspects of glucose metabolism and suggest antimiR-induced Let-7 knockdown as a potential treatment for type 2 diabetes mellitus. Furthermore, our Cre-inducible Let-7-transgenic mice provide a unique model for studying tissue-specific aspects of body growth and type 2 diabetes.
糖尿病是全球最常见的代谢紊乱疾病，也是心血管疾病的主要危险因素。微小 RNA 是基因表达的负调控因子，参与许多生物学过程，包括代谢。在这里，我们表明 Let-7 家族的微小 RNA 调节多个器官中的葡萄糖代谢。在小鼠中，Let-7 的全局和胰腺特异性过表达导致葡萄糖耐量受损和葡萄糖诱导的胰腺胰岛素分泌减少。Let-7 过表达的小鼠还表现出脂肪量和体重减少，以及体型缩小。用 antimiR 对 Let-7 家族进行全局敲低足以预防和治疗饮食诱导肥胖小鼠的葡萄糖耐量受损，至少部分是通过改善肝脏和肌肉中的胰岛素敏感性。高脂饮食小鼠的 antimiR 治疗也导致瘦体重和肌肉量增加，但脂肪量不增加，并防止肝脏异位脂肪沉积。这些发现表明 Let-7 调节葡萄糖代谢的多个方面，并表明 antimiR 诱导的 Let-7 敲低可能是治疗 2 型糖尿病的一种潜在方法。此外，我们的 Cre 诱导型 Let-7 转基因小鼠为研究组织特异性的身体生长和 2 型糖尿病的方面提供了独特的模型。
