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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

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

  2. 2.

    & The role of exercise and PGC1α in inflammation and chronic disease. Nature 454, 463–469 (2008)

  3. 3.

    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)

  4. 4.

    , , , & Increased muscle PGC-1α expression protects from sarcopenia and metabolic disease during aging. Proc. Natl Acad. Sci. USA 106, 20405–20410 (2009)

  5. 5.

    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)

  6. 6.

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

  7. 7.

    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)

  8. 8.

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

  9. 9.

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

  10. 10.

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

  11. 11.

    , , & Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene 297, 79–83 (2002)

  12. 12.

    , & Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development. Dev. Dyn. 224, 154–167 (2002)

  13. 13.

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

  14. 14.

    & Physical activity and resting metabolic rate. Proc. Nutr. Soc. 62, 621–634 (2003)

  15. 15.

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

  16. 16.

    , , , & Duration of expression and activity of Sleeping Beauty transposase in mouse liver following hydrodynamic DNA delivery. Mol. Ther. 18, 1796–1802 (2010)

  17. 17.

    , , , & Morphologic techniques for the study of brown adipose tissue and white adipose tissue. Methods Mol. Biol. 155, 21–51 (2001)

  18. 18.

    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)

  19. 19.

    , , & Locating proteins in the cell using TargetP, SignalP and related tools. Nature Protocols 2, 953–971 (2007)

  20. 20.

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

  21. 21.

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

  22. 22.

    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)

  23. 23.

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

  24. 24.

    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)

  25. 25.

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

  26. 26.

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

Download references

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.

Author information

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, Massachusetts 02115, USA

    • Mark P. Jedrychowski
    •  & Steven P. Gygi
  3. Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Elisabeth Almer Boström
  4. UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, California 94143, 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. Diabetes Research Center, Department of Endocrinology, Odense University Hospital, DK-5000, Odense, Denmark

    • Birgitte F. Vind
    •  & Kurt Højlund
  7. LakePharma, Inc., 530 Harbor Blvd, Belmont, California 94002, USA

    • Hua Tu

Authors

  1. Search for Pontus Boström in:

  2. Search for Jun Wu in:

  3. Search for Mark P. Jedrychowski in:

  4. Search for Anisha Korde in:

  5. Search for Li Ye in:

  6. Search for James C. Lo in:

  7. Search for Kyle A. Rasbach in:

  8. Search for Elisabeth Almer Boström in:

  9. Search for Jang Hyun Choi in:

  10. Search for Jonathan Z. Long in:

  11. Search for Shingo Kajimura in:

  12. Search for Maria Cristina Zingaretti in:

  13. Search for Birgitte F. Vind in:

  14. Search for Hua Tu in:

  15. Search for Saverio Cinti in:

  16. Search for Kurt Højlund in:

  17. Search for Steven P. Gygi in:

  18. Search for Bruce M. Spiegelman in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bruce M. Spiegelman.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    The file contains Supplementary Figures 1-10 with legends and Supplementary Table 1.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature10777

Further reading

Comments

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.