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

Nature volume 481, pages 463–468 (2012)Cite this article

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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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References

  1. Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998)

    Article  CAS  Google Scholar 

  2. Handschin, C. & Spiegelman, B. M. The role of exercise and PGC1α in inflammation and chronic disease. Nature 454, 463–469 (2008)

    Article  ADS  CAS  Google Scholar 

  3. Sandri, M. et al. PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl Acad. Sci. USA 103, 16260–16265 (2006)

    Article  ADS  CAS  Google Scholar 

  4. Wenz, T., Rossi, S. G., Rotundo, R. L., Spiegelman, B. M. & Moraes, C. T. Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging. Proc. Natl Acad. Sci. USA 106, 20405–20410 (2009)

    Article  ADS  CAS  Google Scholar 

  5. Xu, X. et al. Exercise ameliorates high-fat diet-induced metabolic and vascular dysfunction, and increases adipocyte progenitor cell population in brown adipose tissue. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300, R1115–R1125 (2011)

    Article  CAS  Google Scholar 

  6. Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011)

    Article  CAS  Google Scholar 

  7. Vind, B. F. et al. Impaired insulin-induced site-specific phosphorylation of TBC1 domain family, member 4 (TBC1D4) in skeletal muscle of type 2 diabetes patients is restored by endurance exercise-training. Diabetologia 54, 157–167 (2011)

    Article  CAS  Google Scholar 

  8. Nielsen, A. R. & Pedersen, B. K. The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15. Appl. Physiol. Nutr. Metab. 32, 833–839 (2007)

    Article  CAS  Google Scholar 

  9. Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008)

    Article  ADS  CAS  Google Scholar 

  10. Komatsu, M. et al. Multiple roles of PPARα in brown adipose tissue under constitutive and cold conditions. Genes Cells 15, 91–100 (2010)

    Article  CAS  Google Scholar 

  11. Teufel, A., Malik, N., Mukhopadhyay, M. & Westphal, H. Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene 297, 79–83 (2002)

    Article  CAS  Google Scholar 

  12. Ferrer-Martínez, A., Ruiz-Lozano, P. & Chien, K. R. Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development. Dev. Dyn. 224, 154–167 (2002)

    Article  Google Scholar 

  13. Cederberg, A. et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106, 563–573 (2001)

    Article  CAS  Google Scholar 

  14. Speakman, J. R. & Selman, C. Physical activity and resting metabolic rate. Proc. Nutr. Soc. 62, 621–634 (2003)

    Article  Google Scholar 

  15. Enerbäck, S. Human brown adipose tissue. Cell Metab. 11, 248–252 (2010)

    Article  Google Scholar 

  16. Bell, J. B., Aronovich, E. L., Schreifels, J. M., Beadnell, T. C. & Hackett, P. B. Duration of expression and activity of Sleeping Beauty transposase in mouse liver following hydrodynamic DNA delivery. Mol. Ther. 18, 1796–1802 (2010)

    Article  CAS  Google Scholar 

  17. Cinti, S., Zingaretti, M. C., Cancello, R., Ceresi, E. & Ferrara, P. Morphologic techniques for the study of brown adipose tissue and white adipose tissue. Methods Mol. Biol. 155, 21–51 (2001)

    CAS  PubMed  Google Scholar 

  18. Wu, J. et al. The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex. Cell Metab. 13, 160–169 (2011)

    Article  CAS  Google Scholar 

  19. Emanuelsson, O., Brunak, S., von Heijne, G. & Nielsen, H. Locating proteins in the cell using TargetP, SignalP and related tools. Nature Protocols 2, 953–971 (2007)

    Article  CAS  Google Scholar 

  20. Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 460, 1154–1158 (2009)

    Article  ADS  CAS  Google Scholar 

  21. Rasbach, K. A. et al. PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types. Proc. Natl Acad. Sci. USA 107, 21866–21871 (2010)

    Article  ADS  CAS  Google Scholar 

  22. Bostrom, P. et al. The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes. Diabetes 59, 1870–1878 (2010)

    Article  Google Scholar 

  23. Villén, J. & Gygi, S. P. The SCX/IMAC enrichment approach for global phosphorylation analysis by mass spectrometry. Nature Protocols 3, 1630–1638 (2008)

    Article  Google Scholar 

  24. Handschin, C. et al. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1α muscle-specific knock-out animals. J. Biol. Chem. 282, 30014–30021 (2007)

    Article  CAS  Google Scholar 

  25. Boström, P. et al. C/EBPβ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143, 1072–1083 (2010)

    Article  Google Scholar 

  26. Chinsomboon, J. et al. The transcriptional coactivator PGC-1α mediates exercise-induced angiogenesis in skeletal muscle. Proc. Natl Acad. Sci. USA 106, 21401–21406 (2009)

    Article  ADS  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Dana-Farber Cancer Institute and Harvard Medical School, 3 Blackfan Circle, CLS Building, Floor 11, Boston, Massachusetts 02115, USA ,

    Pontus Boström, Jun Wu, Anisha Korde, Li Ye, James C. Lo, Kyle A. Rasbach, Jang Hyun Choi, Jonathan Z. Long & Bruce M. Spiegelman

  2. Department of Cell Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mark P. Jedrychowski & Steven P. Gygi

  3. Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Elisabeth Almer Boström

  4. UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 94143, California, USA

    Shingo Kajimura

  5. Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Electron Microscopy Unit-Azienda Ospedali Riuniti, Ancona 60020, Italy,

    Maria Cristina Zingaretti & Saverio Cinti

  6. Department of Endocrinology, Diabetes Research Center, Odense University Hospital, DK-5000, Odense, Denmark,

    Birgitte F. Vind & Kurt Højlund

  7. LakePharma, Inc., 530 Harbor Blvd, Belmont, California 94002, USA ,

    Hua Tu

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  1. Pontus Boström
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Contributions

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.

Corresponding author

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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