MiR-155 Enhances Insulin Sensitivity by Coordinated Regulation of Multiple Genes in Mice

• Published in: PLoS genetics 2016-10, Vol.12 (10), p.e1006308-e1006308
• Main Authors: Lin, Xiaolin, Qin, Yujuan, Jia, Junshuang, Lin, Taoyan, Lin, Xia, Chen, Li, Zeng, Hui, Han, Yanjiang, Wu, Lihong, Huang, Shun, Wang, Meng, Huang, Shenhao, Xie, Raoying, Liang, Liqi, Liu, Yu, Liu, Ruiyu, Zhang, Tingting, Li, Jing, Wang, Shengchun, Sun, Penghui, Huang, Wenhua, Yao, Kaitai, Xu, Kang, Du, Tao, Xiao, Dong
• Format: Article
• Language: English
• Subjects: Adipose Tissue - metabolism; Adipose Tissue - pathology; Animals; Binding sites; Biology and Life Sciences; Cancer; Cell Proliferation - genetics; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes therapy; Endocrinology; Experiments; Gene Expression Regulation; Genes; Glucose; Glucose - metabolism; Homeostasis; Hospitals; Humans; Hyperglycemia - blood; Hyperglycemia - genetics; Hyperglycemia - pathology; Immunology; Immunotherapy; Insulin; Insulin - genetics; Insulin - metabolism; Insulin Receptor Substrate Proteins - genetics; Insulin resistance; Insulin Resistance - genetics; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Laboratory animals; Medical research; Medicine and Health Sciences; Metabolism; Methods; Mice; Mice, Transgenic; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Musculoskeletal system; Phosphorylation; Physiological aspects; Proto-Oncogene Proteins c-akt - genetics; Research and Analysis Methods; Rodents
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006308

miR-155 plays critical roles in numerous physiological and pathological processes, however, its function in the regulation of blood glucose homeostasis and insulin sensitivity and underlying mechanisms remain unknown. Here, we reveal that miR-155 levels are downregulated in serum from type 2 diabetes (T2D) patients, suggesting that miR-155 might be involved in blood glucose control and diabetes. Gain-of-function and loss-of-function studies in mice demonstrate that miR-155 has no effects on the pancreatic β-cell proliferation and function. Global transgenic overexpression of miR-155 in mice leads to hypoglycaemia, improved glucose tolerance and insulin sensitivity. Conversely, miR-155 deficiency in mice causes hyperglycemia, impaired glucose tolerance and insulin resistance. In addition, consistent with a positive regulatory role of miR-155 in glucose metabolism, miR-155 positively modulates glucose uptake in all cell types examined, while mice overexpressing miR-155 transgene show enhanced glycolysis, and insulin-stimulated AKT and IRS-1 phosphorylation in liver, adipose tissue or skeletal muscle. Furthermore, we reveal these aforementioned phenomena occur, at least partially, through miR-155-mediated repression of important negative regulators (i.e. C/EBPβ, HDAC4 and SOCS1) of insulin signaling. Taken together, these findings demonstrate, for the first time, that miR-155 is a positive regulator of insulin sensitivity with potential applications for diabetes treatment.