MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids

• Published in: The Journal of clinical investigation 2015-06, Vol.125 (6), p.2497-2509
• Main Authors: Fu, Xianghui, Dong, Bingning, Tian, Yan, Lefebvre, Philippe, Meng, Zhipeng, Wang, Xichun, Pattou, François, Han, Weidong, Wang, Xiaoqiong, Lou, Fang, Jove, Richard, Staels, Bart, Moore, David D, Huang, Wendong
• Format: Article
• Language: English
• Subjects: Animals; Biomedical research; Comparative analysis; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Dietary Fats - adverse effects; Dietary Fats - pharmacology; Disease Models, Animal; Fatty acid synthesis; Fatty acids; Fatty Acids - genetics; Fatty Acids - metabolism; Female; Genetic aspects; Glucose; Glucose - genetics; Glucose - metabolism; Humans; Insulin; Insulin - genetics; Insulin - metabolism; Insulin Resistance; Lipids; Liver - metabolism; Liver - pathology; Male; Metabolic disorders; Mice; Mice, Transgenic; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Obesity - chemically induced; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Physiological aspects; Risk factors; Rodents; Signal Transduction - drug effects; Signal Transduction - genetics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI75438

Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet-fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.