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A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis

Abstract

Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.

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Figure 1: Muscle-specific PGC1-α transgenic mice have increased brown/beige fat cells in the subcutaneous depot.
Figure 2: FNDC5 is induced with forced PGC1-α expression or exercise, and turns on brown/beige fat gene expression.
Figure 3: FNDC5 is a potent inducer of the brown/beige fat gene program
Figure 4: FNDC5 is proteolytically cleaved and secreted from cells.
Figure 5: Detection of irisin in mouse and human plasma.
Figure 6: Irisin induces browning of white adipose tissues in vivo and protects against diet-induced obesity and diabetes.

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Acknowledgements

This study was supported by National Institutes of Health grants DK54477, DK31405, DK61562 to B.M.S. P.B. and E.A.B. were supported by the Wenner-Gren Foundation, Swedish Heart and Lung Foundation and the ‘Svenska Sällskapet för Medicinsk Forskning’. J.W. was supported by a postdoctoral fellowship from the American Heart Association (Founders Affiliate #09POST2010078). The animal procedures were in accordance with Institutional Animal Use and Care Committee protocols 110-2008 and 056-2009. The authors thank S. Loffredo and M. Kirschner for discussions and suggestions on the manuscript.

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P.B. and B.M.S. planned the majority of experiments and wrote the paper, and P.B. executed most of the experiments. J.W. performed a subset of cultured cell experiments and contributed valuable materials. M.P.J. and S.P.G. performed the peptide fingerprinting identification of irisin cleavage. A.K. contributed with technical assistance and L.Y. and S.K. performed the CLARK electrode experiments. E.A.B. assisted with the hydrodynamic injections. J.C.L. assisted with intravenous injections and K.A.R. with bioinformatics. J.Z.L. and J.H.C. performed in vitro experiments. P.B. and H.T. and LakePharma designed and provided Fc fusion proteins. K.H. and B.F.V. performed the human cohort study, and M.C.Z. and S.C. performed the electron microscopy studies.

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Correspondence to Bruce M. Spiegelman.

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The authors declare no competing financial interests.

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Boström, P., Wu, J., Jedrychowski, M. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012). https://doi.org/10.1038/nature10777

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