Myostatin signals through miR-34a to regulate Fndc5 expression and browning of white adipocytes

Ge, X., Sathiakumar, D., Lua, B.J.G., Kukreti, H., Lee, M., and McFarlane, C. (2017) Myostatin signals through miR-34a to regulate Fndc5 expression and browning of white adipocytes. International Journal of Obesity, 41. pp. 137-148.

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Abstract

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.

Item ID: 52332
Item Type: Article (Research - C1)
ISSN: 1476-5497
Additional Information:

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

Funders: Agency for Science, Technology and Research, Singapore, National Medical Research Council of Singapore (NMRC)
Date Deposited: 06 Feb 2018 03:39
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060104 Cell Metabolism @ 40%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060111 Signal Transduction @ 40%
11 MEDICAL AND HEALTH SCIENCES > 1101 Medical Biochemistry and Metabolomics > 110107 Metabolic Medicine @ 20%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920104 Diabetes @ 20%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 60%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 20%
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