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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References
Himms-Hagen, J. Brown adipose tissue thermogenesis: interdisciplinary studies. FASEB J. 4, 2890–2898 (1990).
Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).
Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).
Hany, T. F. et al. Brown adipose tissue: a factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur. J. Nucl. Med. Mol. Imaging 29, 1393–1398 (2002).
Nedergaard, J., Bengtsson, T. & Cannon, B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).
Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. New Engl. J. Med. 360, 1509–1517 (2009).
Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. New Engl. J. Med. 360, 1518–1525 (2009).
Frontini, A. & Cinti, S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 11, 253–256 (2010).
Cousin, B. et al. Occurrence of brown adipocytes in rat white adiposetissue: molecular and morphological characterization. J. Cell Sci. 103, 931–942 (1992).
Guerra, C., Koza, R. A., Yamashita, H., Walsh, K. & Kozak, L. P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412–420 (1998).
Himms-Hagen, J. et al. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am. J. Physiol. Cell Physiol. 279, C670–C681 (2000).
Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).
Walden, T. B., Timmons, J. A., Keller, P., Nedergaard, J. & Cannon, B. Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes. J. Cell. Physiol. 218, 444–449 (2009).
Sun, L. et al. MiR193b-365 is essential for brown fat differentiation. Nat. Cell Biol. 13, 958–965 (2011).
Ivey, K. N. et al. MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell 2, 219–229 (2008).
Chen, J. F. et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat. Genet. 38, 228–233 (2006).
Liu, N. et al. microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 22, 3242–3254 (2008).
van Rooij, E. et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc. Natl Acad. Sci. USA 103, 18255–18260 (2006).
Care, A. et al. MicroRNA-133 controls cardiac hypertrophy. Nature Med. 13, 613–618 (2007).
Klein, J., Fasshauer, M., Klein, H. H., Benito, M. & Kahn, C. R. Novel adipocyte lines from brown fat: a model system for the study of differentiation, energy metabolism, and insulin action. Bioessays 24, 382–388 (2002).
Spandl, J., White, D. J., Peychl, J. & Thiele, C. Live cell multicolor imaging of lipid droplets with a new dye, LD540. Traffic 10, 1579–1584 (2009).
Murano, I., Barbatelli, G., Giordano, A. & Cinti, S. Noradrenergic parenchymal nerve fiber branching after cold acclimatisation correlates with brown adipocyte density in mouse adipose organ. J. Anat. 214, 171–178 (2009).
Liu, N. et al. An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133. Proc. Natl Acad. Sci. USA 104, 20844–20849 (2007).
Hansen, L. H., Madsen, B., Teisner, B., Nielsen, J. H. & Billestrup, N. Characterization of the inhibitory effect of growth hormone on primary preadipocyte differentiation. Mol. Endocrinol. 12, 1140–1149 (1998).
Tozzo, E., Shepherd, P. R., Gnudi, L. & Kahn, B. B. Transgenic GLUT-4 overexpression in fat enhances glucose metabolism: preferential effect on fatty acid synthesis. Am. J. Physiol. 268, E956–E964 (1995).
Trajkovski, M. et al. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474, 649–653 (2011).
Krutzfeldt, J. et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689 (2005).
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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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.
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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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DOI: https://doi.org/10.1038/ncb2612
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