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.

Adipocyte and Cell Biology

Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans



Irisin is a recently identified exercise-induced myokine suggested to induce browning of white adipocytes. Deficiency of myostatin, and thus stimulation of muscle growth, has also been reported to induce irisin and its precursor FNDC5 expression in muscle and drive the browning of white adipocytes in mice, implying that irisin may be related to muscle growth in addition to its beneficial effects in adipocytes. In humans, the effect of irisin in muscle hypertrophy as well as adipocyte metabolism has not been fully investigated.


Primary cultured human myocytes/adipocytes and 3T3-L1 cells were used to examine irisin-regulated gene/protein expression. Lipid accumulation, ATP content, glycolysis, lipolysis and metabolite profile were measured in control and irisin-treated (10 and 50 nM) adipocytes.


In human myocytes, FNDC5 mRNA and irisin secretion were increased during myogenic differentiation, along with PGC1α and myogenin expression. Irisin treatment significantly increased insulin-like growth factor 1 and decreased myostatin gene expression through ERK pathway. PGC1α4, a newly discovered PGC1α isoform specifically related to muscle hypertrophy, was also upregulated. In human adipocytes, irisin induced uncoupling protein 1 and consequently increased adipocyte energy expenditure, expression of metabolic enzymes and metabolite intermediates, resulting in inhibition of lipid accumulation. Irisin and FNDC5 treatment also reduced preadipocyte differentiation, suggesting an additional mechanism in suppressing fat mass.


These results suggest that irisin/FNDC5 has a pleiotropic role in muscle and improvement of adipocyte metabolism in humans.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6


  1. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne-Parikka P et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–1350.

    Article  CAS  Google Scholar 

  2. Nocon M, Hiemann T, Muller-Riemenschneider F, Thalau F, Roll S, Willich SN et al. Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis. Eur J Cardiovasc Prev Rehabil 2008; 15: 239–246.

    Article  Google Scholar 

  3. Colberg SR, Sigal RJ, Fernhall B, Regensteiner JG, Blissmer BJ, Rubin RR et al. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care 2010; 33: e147–e167.

    Article  Google Scholar 

  4. Bird SR, Hawley JA . Exercise and type 2 diabetes: new prescription for an old problem. Maturitas 2012; 72: 311–316.

    Article  Google Scholar 

  5. Egan B, Zierath JR . Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab 2013; 17: 162–184.

    Article  CAS  Google Scholar 

  6. Pedersen BK, Febbraio MA . Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012; 8: 457–465.

    Article  CAS  Google Scholar 

  7. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481: 463–468.

    Article  Google Scholar 

  8. Kelly DP . Medicine. Irisin, light my fire. Science 2012; 336: 42–43.

    Article  Google Scholar 

  9. Cunha A . Basic research: Irisin—behind the benefits of exercise. Nat Rev Endocrinol 2012; 8: 195.

    PubMed  Google Scholar 

  10. Polyzos SA, Kountouras J, Shields K, Mantzoros CS . Irisin: a renaissance in metabolism? Metabolism: clinical and experimental 2013; 62: 1037–1044.

    Article  CAS  Google Scholar 

  11. Bostrom PA, Fernandez-Real JM, Mantzoros C . Irisin in humans: recent advances and questions for future research. Metab Clin Exp 2014; 63: 178–180.

    Article  CAS  Google Scholar 

  12. Park KH, Zaichenko L, Brinkoetter M, Thakkar B, Sahin-Efe A, Joung KE et al. Circulating Irisin in Relation to Insulin Resistance and the Metabolic Syndrome. J Clin Endocrino Metab 2013; 98: 4899–4907.

    Article  CAS  Google Scholar 

  13. Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y et al. Irisin Stimulates Browning of White Adipocytes through Mitogen-Activated Protein Kinase p38 MAP Kinase and ERK MAP Kinase Signaling. Diabetes 2013; 63: 514–525.

    Article  Google Scholar 

  14. Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, Schneider BE et al. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metab Clin Exp 2012; 61: 1725–1738.

    Article  CAS  Google Scholar 

  15. Raschke S, Eckel J . Adipo-myokines: two sides of the same coin—mediators of inflammation and mediators of exercise. Mediators Inflamm 2013; 2013: 320724.

    Article  Google Scholar 

  16. Shan T, Liang X, Bi P, Kuang S . Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1alpha-Fndc5 pathway in muscle. FASEB J 2013; 27: 1981–1989.

    Article  CAS  Google Scholar 

  17. Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M . Mechanisms regulating skeletal muscle growth and atrophy. FEBS J 2013; 280: 4294–4314.

    Article  CAS  Google Scholar 

  18. Gouni-Berthold I, Berthold HK, Huh JY, Berman R, Spenrath N, Krone W et al. Effects of lipid-lowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo. PloS One 2013; 8: e72858.

    Article  CAS  Google Scholar 

  19. Smih F, Rouet P, Lucas S, Mairal A, Sengenes C, Lafontan M et al. Transcriptional regulation of adipocyte hormone-sensitive lipase by glucose. Diabetes 2002; 51: 293–300.

    Article  CAS  Google Scholar 

  20. Huh JY, Kim Y, Jeong J, Park J, Kim I, Huh KH et al. Peroxiredoxin 3 is a key molecule regulating adipocyte oxidative stress, mitochondrial biogenesis, and adipokine expression. Antioxid Redox Signaling 2012; 16: 229–243.

    Article  CAS  Google Scholar 

  21. Yuan M, Breitkopf SB, Yang X, Asara JM . A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat Protoc 2012; 7: 872–881.

    Article  CAS  Google Scholar 

  22. Xia J, Psychogios N, Young N, Wishart DS . MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Res 2009; 37: W652–W660.

    Article  CAS  Google Scholar 

  23. Goeman JJ, van de Geer SA, de Kort F, van Houwelingen HC . A global test for groups of genes: testing association with a clinical outcome. Bioinformatics 2004; 20: 93–99.

    Article  CAS  Google Scholar 

  24. Bonet ML, Oliver P, Palou A . Pharmacological and nutritional agents promoting browning of white adipose tissue. Biochim Biophys Acta 2013; 1831: 969–985.

    Article  CAS  Google Scholar 

  25. Moreno-Navarrete JM, Ortega F, Serrano M, Guerra E, Pardo G, Tinahones F et al. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab 2013; 98: E769–E778.

    Article  CAS  Google Scholar 

  26. Roca-Rivada A, Castelao C, Senin LL, Landrove MO, Baltar J, Belen Crujeiras A et al. FNDC5/irisin is not only a myokine but also an adipokine. PloS One 2013; 8: e60563.

    Article  CAS  Google Scholar 

  27. Aydin S, Kuloglu T, Eren MN, Celik A, Yilmaz M, Kalayci M et al. Cardiac, skeletal muscle and serum irisin responses to with or without water exercise in young and old male rats: Cardiac muscle produces more irisin than skeletal muscle. Peptides 2013; 52C: 68–73.

    Google Scholar 

  28. Dun SL, Lyu RM, Chen YH, Chang JK, Luo JJ, Dun NJ et al. Irisin-immunoreactivity in neural and non-neural cells of the rodent. Neuroscience 2013; 240: 155–162.

    Article  CAS  Google Scholar 

  29. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D et al. Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway. Cell Metab 2013; 18: 649–659.

    Article  CAS  Google Scholar 

  30. Raschke S, Eckardt K, Bjorklund Holven K, Jensen J, Eckel J . Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells. PloS One 2013; 8: e62008.

    Article  CAS  Google Scholar 

  31. Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Harrison BC et al. A PGC-1alpha isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 2012; 151: 1319–1331.

    Article  CAS  Google Scholar 

  32. Moraes C, Leal VO, Marinho SM, Barroso SG, Rocha GS, Boaventura GT et al. Resistance Exercise Training does not Affect Plasma Irisin Levels of Hemodialysis Patients. Horm Metab Res 2013; 45: 900–904.

    Article  CAS  Google Scholar 

  33. Hecksteden A, Wegmann M, Steffen A, Kraushaar J, Morsch A, Ruppenthal S et al. Irisin and exercise training in humans—Results from a randomized controlled training trial. BMC Med 2013; 11: 235.

    Article  Google Scholar 

Download references


JYH researched data and wrote the manuscript. FD and EM researched data and reviewed the manuscript. CM designed the studies, supervised laboratory measurements and reviewed/edited the manuscript.

JYH is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

This study was supported by Award Number 1I01CX000422-01A1 from the Clinical Science Research and Development Service of the VA Office of Research and Development.

Author information

Authors and Affiliations


Corresponding author

Correspondence to C S Mantzoros.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Huh, J., Dincer, F., Mesfum, E. et al. Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans. Int J Obes 38, 1538–1544 (2014).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • irisin
  • myokine
  • muscle hypertrophy
  • adipocyte browning

This article is cited by


Quick links