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International journal of obesity : journal of the International Association for the Study of Obesity v.41 no.1, 2017년, pp.137 - 148   SCI SCIE
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Myostatin signals through miR-34a to regulate Fndc5 expression and browning of white adipocytes

Ge, X (Cell & Molecular Biology Group, Singapore Institute for Clinical Sciences (A*STAR), Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore ) ; Sathiakumar, D (Cell & Molecular Biology Group, Singapore Institute for Clinical Sciences (A*STAR), Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore ) ; Lua, B J G (School of Biological Sciences, Nanyang Technological University, Singapore ) ; Kukreti, H (School of Biological Sciences, Nanyang Technological University, Singapore ) ; Lee, M (Cell & Molecular Biology Group, Singapore Institute for Clinical Sciences (A*STAR), Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore ) ; McFarlane, C (Cell & Molecular Biology Group, Singapore Institute for Clinical Sciences (A*STAR), Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore ) ;
  • 초록  

    Background/Objectives:Myostatin (Mstn) has a pivotal role in glucose and lipid metabolism. Mstn deficiency leads to the increased browning of white adipose tissue (WAT), which results in the increased energy expenditure and protection against diet-induced obesity and insulin resistance. In this study, we investigated the molecular mechanism(s) through which Mstn regulates browning of white adipocytes.Methods:Quantitative molecular analyses were performed to assess Mstn regulation of miR-34a and Fndc5 expression. miR-34a was overexpressed and repressed to investigate miR-34a regulation of Fndc5. Luciferase reporter analysis verified direct binding between miR-34a and the Fndc5 3′-untranslated region (UTR). The browning phenotype of Mstn −/− adipocytes was assessed through the analysis of brown fat marker gene expression, mitochondrial function and infrared thermography. The role of miR-34a and Fndc5 in this browning phenotype was verified through antibody-mediated neutralization of FNDC5, knockdown of Fndc5 by small interfering RNA and through miR-34a gain-of-function and loss-of-function experiments.Results:Mstn treatment of myoblasts inhibited Fndc5 expression, whereas the loss of Mstn increased Fndc5 levels in muscles and in circulation. Mstn inhibition of Fndc5 is miR-34a dependent. Mstn treatment of C2C12 myoblasts upregulated miR-34a expression, whereas reduced miR-34a expression was noted in Mstn −/− muscle and WAT. Subsequent overexpression of miR-34a inhibited Fndc5 expression, whereas blockade of miR-34a increased Fndc5 expression in myoblasts. Reporter analysis revealed that miR-34a directly suppresses Fndc5 expression through a miR-34a-specific binding site within the Fndc5 3′UTR. Importantly, Mstn-mediated inhibition of Fndc5 was blocked upon miR-34a inhibition. Mstn −/− adipocytes showed reduced miR-34a, enhanced Fndc5 expression and increased thermogenic gene expression, which was reversed upon either neutralization of Fndc5 or Fndc5 knockdown. In agreement, Mstn −/− adipocytes have increased mitochondria, improved mitochondrial function and increased heat production.Conclusions:Mstn regulates Fndc5/Irisin expression and secretion through a novel miR-34a-dependent post-transcriptional mechanism. Loss of Mstn in mice leads to the increased Fndc5/Irisin expression, which contributes to the browning of white adipocytes.


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