title: IRS-2 Partially Compensates for the Insulin Signal Defects in IRS-1-/-Mice Mediated by miR-33.
abstract: Insulin signaling is coordinated by insulin receptor substrates (IRSs). Many insulin responses, especially for blood glucose metabolism, are mediated primarily throughIrs-1andIrs-2.Irs-1knockout mice show growth retardation and insulin signaling defects, which can be compensated by other IRSsin vivo; however, the underlying mechanism is not clear. Here, we presented anIrs-1truncated mutated mouse (Irs-1-/-) with growth retardation and subcutaneous adipocyte atrophy.Irs-1-/-mice exhibited mild insulin resistance, as demonstrated by the insulin tolerance test. Phosphatidylinositol 3-kinase (PI3K) activity and phosphorylated Protein Kinase B (PKB/AKT) expression were elevated in liver, skeletal muscle, and subcutaneous adipocytes inIrs-1deficiency. In addition, the expression of IRS-2 and its phosphorylated version were clearly elevated in liver and skeletal muscle. With miRNA microarray analysis, we found miR-33 was down-regulated in bone marrow stromal cells (BMSCs) ofIrs-1-/-mice, while its target geneIrs-2was up-regulatedin vitrostudies. In addition, miR-33 was down-regulated in the presence ofIrs-1and which was up-regulated in fasting status. What's more, miR-33 restored its expression in re-feeding status. Meanwhile, miR-33 levels decreased andIrs-2levels increased in liver, skeletal muscle, and subcutaneous adipocytes ofIrs-1-/-mice. In primary cultured liver cells transfected with an miR-33 inhibitor, the expression of IRS-2, PI3K, and phosphorylated-AKT (p-AKT) increased while the opposite results were observed in the presence of an miR-33 mimic. Therefore, decreased miR-33 levels can up-regulate IRS-2 expression, which appears to compensate for the defects of the insulin signaling pathway inIrs-1deficient mice.
authors.affiliation: Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Tang
authors.affiliation: Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Man
authors.affiliation: Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Hao-Neng
authors.initials: HN
authors.lastname: Tang
authors.affiliation: Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Ci-La
authors.initials: CL
authors.lastname: Zhou
authors.affiliation: Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Tan
authors.affiliation: Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Hou-De
authors.initials: HD
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055504:Insulin Receptor Substrate Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D011972:Receptor, Insulin
keywords: IRS-1; IRS-2; insulin signaling pathway; miR-33