Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  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 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-10 with legends and Supplementary Table 1. (PDF 1062 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing