Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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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)
  • Received : 2016.09.19
  • Accepted : 2017.01.04
  • Published : 2017.02.28
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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

References

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