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MyomiR-133 regulates brown fat differentiation through Prdm16

Nature Cell Biology volume 14, pages 1330–1335 (2012)Cite this article

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Abstract

Brown adipose tissue (BAT) uses the chemical energy of lipids and glucose to produce heat, a function that can be induced by cold exposure or diet1. A key regulator of BAT is the gene encoding PR domain containing 16 (Prdm16), whose expression can drive differentiation of myogenic and white fat precursors to brown adipocytes2,3. Here we show that after cold exposure, the muscle-enriched miRNA-133 is markedly downregulated in BAT and subcutaneous white adipose tissue (SAT) as a result of decreased expression of its transcriptional regulator Mef2. miR-133 directly targets and negatively regulates PRDM16, and inhibition of miR-133 or Mef2 promotes differentiation of precursors from BAT and SAT to mature brown adipocytes, thereby leading to increased mitochondrial activity. Forced expression of miR-133 in brown adipogenic conditions prevents the differentiation to brown adipocytes in both BAT and SAT precursors. Our results point to Mef2 and miR-133 as central upstream regulators of Prdm16 and hence of brown adipogenesis in response to cold exposure in BAT and SAT.

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Figure 1: miR-133 is downregulated after cold exposure.
Figure 2: miR-133 is an inhibitor of BAT differentiation.
Figure 3: miR-133 decreases the level of brown adipocyte differentiation of the SVF from SAT.
Figure 4: miR-133 directly targets PRDM16.
Figure 5: Regulation of brown adipocyte differentiation and function by miR-133, and its upstream control by Mef2.

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Acknowledgements

We thank F. von Meyenn, M. Gustafsson Trajkovska, J. Kruetzfeldt and C. Wolfrum for technical help and discussions. This work was in part supported by the ERC grant Metabolomirs (MS), the Leducq Foundation and a Prodoc grant from the Swiss National Science Foundation (SNSF).

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  1. Mirko Trajkovski

    Present address: Present address: Institute of Structural and Molecular Biology, University College London (UCL), Darwin Building, Gower Street, London WC1E 6BT, UK,

Authors and Affiliations

  1. Institute of Molecular Health Sciences, ETH Zurich, Schafmattstrasse 22, HPL H36, 8093 Zurich, Switzerland

    Mirko Trajkovski, Kashan Ahmed & Markus Stoffel

  2. Competence Center of Systems Physiology and Metabolic Disease, ETH Zurich, Schafmattstrasse 22, 8093 Zurich, Switzerland

    Mirko Trajkovski, Kashan Ahmed & Markus Stoffel

  3. Regulus Therapeutics, Inc., 3545 John Hopkins Court, San Diego, California 92121-1121, USA

    Christine C. Esau

  4. Faculty of Medicine, University of Zurich, Zurich, Switzerland

    Markus Stoffel

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  1. Mirko Trajkovski
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  3. Christine C. Esau
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  4. Markus Stoffel
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Contributions

M.T. developed the hypothesis, performed experimental work, analysed the data and wrote the manuscript. K.A. performed and analysed Figs 1c,d, 2l,m and 4h,j. C.C.E. provided the anti-miR compounds and contributed to the design of the miR-inhibition experiments. M.S. initiated the project, developed the hypothesis, analysed the data and coordinated the project and wrote the paper.

Corresponding authors

Correspondence to Mirko Trajkovski or Markus Stoffel.

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Competing interests

M.S. is a member of the scientific advisory board of Regulus Therapeutics. C.C.E. is an employee of Regulus Therapeutics, which develops miRNA targeted therapies.

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Trajkovski, M., Ahmed, K., Esau, C. et al. MyomiR-133 regulates brown fat differentiation through Prdm16. Nat Cell Biol 14, 1330–1335 (2012). https://doi.org/10.1038/ncb2612

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