A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis
Pontus Boström, Jun Wu, Mark P Jedrychowski, Anisha Korde, Li Ye, James C Lo, Kyle A Rasbach, Elisabeth Almer Boström, Jang Hyun Choi, Jonathan Z Long, Shingo Kajimura, Maria Cristina Zingaretti, Birgitte F Vind, Hua Tu, Saverio Cinti, Kurt Højlund, Steven P Gygi, Bruce M Spiegelman, Pontus Boström, Jun Wu, Mark P Jedrychowski, Anisha Korde, Li Ye, James C Lo, Kyle A Rasbach, Elisabeth Almer Boström, Jang Hyun Choi, Jonathan Z Long, Shingo Kajimura, Maria Cristina Zingaretti, Birgitte F Vind, Hua Tu, Saverio Cinti, Kurt Højlund, Steven P Gygi, Bruce M Spiegelman
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.
Conflict of interest statement
The authors have no financial interest to disclose.
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References
- Puigserver P, et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–839.
- Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature. 2008;454:463–469.
- Sandri M, et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A. 2006;103:16260–16265.
- Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci U S A. 2009;106:20405–20410.
- 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. 2011;300:R1115–1125.
- Seale P, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121:96–105.
- Vind BF, 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. 2011;54:157–167.
- Nielsen AR, Pedersen BK. The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15. Appl Physiol Nutr Metab. 2007;32:833–839.
- Tseng YH, et al. Newrole of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454:1000–1004.
- Komatsu M, et al. Multiple roles of PPARalpha in brown adipose tissue under constitutive and cold conditions. Genes Cells. 2010;15:91–100.
- Teufel A, Malik N, Mukhopadhyay M, Westphal H. Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene. 2002;297:79–83.
- Ferrer-Martinez A, Ruiz-Lozano P, Chien KR. Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development. Dev Dyn. 2002;224:154–167.
- Cederberg A, et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell. 2001;106:563–573.
- Speakman JR, Selman C. Physical activity and resting metabolic rate. Proc Nutr Soc. 2003;62:621–634.
- Enerback S. Human brown adipose tissue. Cell Metab. 2010;11:248–252.
- Bell JB, Aronovich EL, Schreifels JM, Beadnell TC, Hackett PB. Duration of expression and activity of Sleeping Beauty transposase in mouse liver following hydrodynamic DNA delivery. Mol Ther. 2010;18:1796–1802.
- Cinti S, Zingaretti MC, Cancello R, Ceresi E, Ferrara P. Morphologic techniques for the study of brown adipose tissue and white adipose tissue. Methods Mol Biol. 2001;155:21–51.
- Wu J, et al. The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1alpha/ATF6alpha complex. Cell Metab. 2011;13:160–169.
- Emanuelsson O, Brunak S, von Heijne G, Nielsen H. Locating proteins in the cell using TargetP, SignalP and related tools. Nat Protoc. 2007;2:953–971.
- Kajimura S, et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009;460:1154–1158.
- Rasbach KA, et al. PGC-1alpha regulates a HIF2alpha-dependent switch in skeletal muscle fiber types. Proc Natl Acad Sci U S A. 2010;107:21866–21871.
- 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. 2010
- Villen J, Gygi SP. The SCX/IMAC enrichment approach for global phosphorylation analysis by mass spectrometry. Nat Protoc. 2008;3:1630–1638.
- Handschin C, et al. Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem. 2007;282:30014–30021.
- Bostrom P, et al. C/EBPbeta controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell. 2010;143:1072–1083.
- Chinsomboon J, et al. The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle. Proc Natl Acad Sci U S A. 2009;106:21401–21406.
Source: PubMed