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http://dx.doi.org/10.14348/molcells.2017.2228

IRS-2 Partially Compensates for the Insulin Signal Defects in IRS-1-/- Mice Mediated by miR-33  

Tang, Chen-Yi (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
Man, Xiao-Fei (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
Guo, Yue (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
Tang, Hao-Neng (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
Tang, Jun (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
Zhou, Ci-La (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
Tan, Shu-Wen (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
Wang, Min (Department of Endocrinology, Xiangya Hospital, Central South University)
Zhou, Hou-De (Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University)
Publication Information
Molecules and Cells / v.40, no.2, 2017 , pp. 123-132 More about this Journal
Abstract
Insulin signaling is coordinated by insulin receptor substrates (IRSs). Many insulin responses, especially for blood glucose metabolism, are mediated primarily through Irs-1 and Irs-2. Irs-1 knockout mice show growth retardation and insulin signaling defects, which can be compensated by other IRSs in vivo; however, the underlying mechanism is not clear. Here, we presented an Irs-1 truncated 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 in Irs-1 deficiency. 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) of $Irs-1^{-/-}$ mice, while its target gene Irs-2 was up-regulated in vitro studies. In addition, miR-33 was down-regulated in the presence of Irs-1 and which was up-regulated in fasting status. What's more, miR-33 restored its expression in re-feeding status. Meanwhile, miR-33 levels decreased and Irs-2 levels increased in liver, skeletal muscle, and subcutaneous adipocytes of $Irs-1^{-/-}$ 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 in Irs-1 deficient mice.
Keywords
insulin signaling pathway; IRS-1; IRS-2; miR-33;
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