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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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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  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


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bruce M. Spiegelman.

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