Irisin: molecular mechanisms, systemic signaling, and translational perspectives of an exercise-induced myokine: a critical and in-depth narrative review
DOI:
https://doi.org/10.69849/b8294w45Keywords:
Irisin, Exercise, Myokine, Signaling, MetabolismAbstract
This critical and in-depth narrative review examines the role of irisin, an exercise-induced myokine, as a central mediator of interorgan communication. Irisin, a peptide derived from the proteolytic cleavage of the FNDC5 protein, is regulated by the transcriptional coactivator PGC-1α and acts systemically by binding to its receptor, integrin αV/β5. This interaction triggers a complex intracellular signaling network involving pathways such as AMPK, MAPKs (p38 and ERK1/2), and PI3K/AKT, thereby modulating fundamental processes like mitochondrial biogenesis, glucose and lipid metabolism, and the inflammatory response. The text provides a detailed analysis of its tissue-specific effects, including the induction of white adipose tissue browning, improvement of glucose uptake and oxidative function in skeletal muscle, neuroprotection and promotion of synaptic plasticity via the BDNF axis in the central nervous system, nitric oxide-dependent vasodilation in the cardiovascular system, and anabolic effects on bone tissue. Despite its promising translational potential for metabolic, neurodegenerative, and cardiovascular diseases, the field is marked by significant controversies, particularly regarding the accuracy of quantification methods (ELISA vs. mass spectrometry), the extrapolation from supraphysiological animal models, and the paucity of robust human clinical trials. The review concludes that methodological standardization and interventional clinical studies are imperative to validate irisin as a reliable biomarker and a viable therapeutic target.
References
ALBRECHT, E. et al. Irisin – a myth rather than an exercise-inducible myokine. Scientific Reports, v. 5, p. 8889, 2015. DOI: https://doi.org/10.1038/srep08889.
ANASTASILAKIS, A. D. et al. Circulating irisin in healthy, young individuals: day-night rhythm, effects of food intake and exercise, and associations with gender, physical activity, diet, and body composition. Journal of Clinical Endocrinology & Metabolism, v. 99, n. 9, p. 3247-3255, 2014. DOI: https://doi.org/10.1210/jc.2014-1367.
BOSTRÖM, P. et al. A PGC1α-dependent myokine that drives browning of white fat and thermogenesis. Nature, v. 481, n. 7382, p. 463-468, 2012. DOI: https://doi.org/10.1038/nature10777.
BRAUN, V.; CLARKE, V. Using thematic analysis in psychology. Qualitative Research in Psychology, London, v. 3, n. 2, p. 77-101, 2006. DOI: https://doi.org/10.1191/1478088706qp063oa.
CANNON, B.; NEDERGAARD, J. Brown adipose tissue: function and physiological significance. Physiological Reviews, v. 84, n. 1, p. 277-359, 2004. DOI: https://doi.org/10.1152/physrev.00015.2003.
CANTÓ, C.; AUWERX, J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Current Opinion in Lipidology, v. 20, n. 2, p. 98-105, 2009. DOI: https://doi.org/10.1097/MOL.0b013e328328d0a4.
CAO, R. Y. et al. FNDC5: A novel player in metabolism and metabolic diseases. Journal of Cellular Physiology, v. 234, n. 6, p. 8389-8402, 2019. DOI: https://doi.org/10.1002/jcp.27709.
CHANG, J. S.; KONG, I. D. Irisin prevents dexamethasone-induced atrophy in C2C12 myotubes. Pflügers Archiv – European Journal of Physiology, v. 472, n. 4, p. 495-509, 2020. DOI: https://doi.org/10.1007/s00424-020-02367-4.
COLAIANNI, G. et al. The myokine irisin increases cortical bone mass. Proceedings of the National Academy of Sciences, v. 112, n. 39, p. 12157-12162, 2015. DOI: https://doi.org/10.1073/pnas.1516622112.
COMMITTEE ON PUBLICATION ETHICS (COPE). Authorship and AI tools: COPE position. [S.l.: s.n.], 2023. Disponível em: https://publicationethics.org/guidance/cope-position/authorship-and-ai-tools. Acesso em: 6 maio 2026.
DONG, J. et al. Irisin inhibits atherosclerosis by promoting M2 macrophage polarization through regulating the αVβ5 integrin/FAK/Akt/STAT6 pathway. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, v. 1866, n. 10, p. 165856, 2020. DOI: https://doi.org/10.1016/j.bbadis.2020.165856.
ERICKSON, H. P. Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor? Adipocyte, v. 2, n. 4, p. 289-293, 2013. DOI: https://doi.org/10.4161/adip.26243.
FERRARI, R. Writing narrative style literature reviews. Medical Writing, v. 24, n. 4, p. 230-235, 2015. DOI: https://doi.org/10.1179/2047480615Z.000000000329.
FOX, J. et al. Effect of an acute exercise bout on immediate post-exercise irisin concentration in adults: A meta-analysis. Scandinavian Journal of Medicine & Science in Sports, v. 28, n. 1, p. 16-28, 2018. DOI: https://doi.org/10.1111/sms.12904.
GENG, Z. et al. FNDC5 attenuates obesity-induced cardiac hypertrophy by inactivating JAK2/STAT3 associated-inflammation and oxidative stress. Journal of Translational Medicine, v. 17, n. 1, p. 107, 2019. DOI: https://doi.org/10.1186/s12967-019-1857-8.
GIANCOTTI, F. G.; RUOSLAHTI, E. Integrin signaling. Science, v. 285, n. 5430, p. 1028-1032, 1999. DOI: https://doi.org/10.1126/science.285.5430.1028.
GOUSPILLOU, G. et al. The relationship between muscle fiber type-specific PGC-1α content and mitochondrial content varies with age. The Journals of Gerontology: Series A, v. 69, n. 7, p. 823-833, 2014. DOI: https://doi.org/10.1093/gerona/glt208.
GREEN, B. N.; JOHNSON, C. D.; ADAMS, A. Writing narrative literature reviews for peer-reviewed journals: secrets of the trade. Journal of Chiropractic Medicine, v. 5, n. 3, p. 101-117, 2006. DOI: https://doi.org/10.1016/S0899-3467(07)60142-6.
HAN, F. et al. Irisin improves endothelial function in obese mice through the AMPK-eNOS pathway. American Journal of Physiology – Heart and Circulatory Physiology, v. 309, n. 9, p. H1501-H1508, 2015. DOI: https://doi.org/10.1152/ajpheart.00443.2015.
HARDIE, D. G. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes & Development, v. 25, n. 18, p. 1895-1908, 2011. DOI: https://doi.org/10.1101/gad.17420111.
HECKSTEDEN, A. et al. Irisin and exercise training in humans – results from a randomized controlled training trial. BMC Medicine, v. 11, p. 235, 2013. DOI: https://doi.org/10.1186/1741-7015-11-235.
HOSSEINI, M.; RESNIK, D. B.; HOLMES, K. The ethics of disclosing the use of artificial intelligence tools in writing scholarly manuscripts. Research Ethics, v. 19, n. 4, p. 449-465, 2023. DOI: https://doi.org/10.1177/17470161231180449.
HOU, N.; HAN, F.; SUN, X. The relationship between circulating irisin levels and endothelial function in lean and obese subjects. Clinical Endocrinology, v. 83, n. 3, p. 339-343, 2015. DOI: https://doi.org/10.1111/cen.12735.
HUH, J. Y. 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. Metabolism, v. 61, n. 12, p. 1725-1738, 2012. DOI: https://doi.org/10.1016/j.metabol.2012.09.002.
HUH, J. Y. et al. Irisin in response to acute and chronic whole-body vibration exercise in humans. Metabolism, v. 63, n. 7, p. 918-921, 2014a. DOI: https://doi.org/10.1016/j.metabol.2014.04.001.
HUH, J. Y. et al. Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans. International Journal of Obesity, v. 38, n. 12, p. 1538-1544, 2014b. DOI: https://doi.org/10.1038/ijo.2014.42.
JEDRYCHOWSKI, M. P. et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metabolism, v. 22, n. 4, p. 734-740, 2015. DOI: https://doi.org/10.1016/j.cmet.2015.08.001.
KIM, H. et al. Irisin mediates effects via integrin αVβ5 receptors. Cell, v. 175, n. 7, p. 1756-1768.e17, 2018. DOI: https://doi.org/10.1016/j.cell.2018.10.025.
KIM, H. et al. Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Cell, v. 178, n. 2, p. 507-508, 2019. DOI: https://doi.org/10.1016/j.cell.2019.06.028.
KURDIOVA, T. et al. Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue. The Journal of Physiology, v. 592, n. 5, p. 1091-1107, 2014. DOI: https://doi.org/10.1113/jphysiol.2013.264655.
KÜSTER, O. C. et al. Novel Blood-Based Biomarkers of Cognitive Function in Healthy Elderly Subjects. Journal of Alzheimer's Disease, v. 58, n. 3, p. 815-826, 2017. DOI: https://doi.org/10.3233/JAD-161170.
LAPLANTE, M.; SABATINI, D. M. mTOR signaling in growth control and disease. Cell, v. 149, n. 2, p. 274-293, 2012. DOI: https://doi.org/10.1016/j.cell.2012.03.017.
LECKER, S. H. et al. Expression of the irisin precursor FNDC5 in skeletal muscle correlates with aerobic exercise performance in heart failure patients. Circulation: Heart Failure, v. 5, n. 6, p. 812-818, 2012. DOI: https://doi.org/10.1161/CIRCHEARTFAILURE.112.969543.
LEE, H. J. et al. Irisin, a novel myokine, regulates glucose uptake in skeletal muscle cells via AMPK. Molecular Endocrinology, v. 29, n. 6, p. 873-882, 2015. DOI: https://doi.org/10.1210/me.2014-1353.
LEE, P. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metabolism, v. 19, n. 2, p. 302-309, 2014. DOI: https://doi.org/10.1016/j.cmet.2013.12.017.
LI, J. et al. Irisin protects against myocardial ischemia/reperfusion injury by activating the Nrf2/HO-1 pathway. Free Radical Biology and Medicine, v. 178, p. 256-267, 2022a. DOI: https://doi.org/10.1016/j.freeradbiomed.2021.12.002.
LI, R. L. et al. Irisin alleviates pressure overload-induced cardiac hypertrophy by inducing protective autophagy via mTOR-independent ULK1 activation. Journal of Molecular and Cellular Cardiology, v. 154, p. 41-53, 2021. DOI: https://doi.org/10.1016/j.yjmcc.2021.02.001.
LOURENCO, M. V. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nature Medicine, v. 25, n. 1, p. 165-175, 2019. DOI: https://doi.org/10.1038/s41591-018-0275-4.
LU, J. et al. Irisin protects against endothelial dysfunction and atherosclerotic progression. American Journal of Physiology – Endocrinology and Metabolism, v. 308, n. 7, p. E507-E517, 2015. DOI: https://doi.org/10.1152/ajpendo.00586.2014.
MAZUR-BIALY, A. I.; POCHEĆ, E. The role of irisin in the regulation of the immune system and inflammation. International Journal of Molecular Sciences, v. 22, n. 6, p. 2947, 2021. DOI: https://doi.org/10.3390/ijms22062947.
MITRA, S. K.; HANSON, D. A.; SCHLAEPFER, D. D. Focal adhesion kinase: in command and control of cell motility. Nature Reviews Molecular Cell Biology, v. 6, n. 1, p. 56-68, 2005. DOI: https://doi.org/10.1038/nrm1549.
MIURA, S. et al. An increase in murine skeletal muscle PGC-1alpha mRNA in response to exercise is mediated by beta-adrenergic receptor activation. Endocrinology, v. 148, n. 7, p. 3441-3448, 2007. DOI: https://doi.org/10.1210/en.2006-1646.
MOON, H. S.; DINCER, F.; MANTZOROS, C. S. Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth. Metabolism, v. 62, n. 8, p. 1131-1136, 2013. DOI: https://doi.org/10.1016/j.metabol.2013.04.007.
MORENO-NAVARRETE, J. M. et al. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. Journal of Clinical Endocrinology & Metabolism, v. 98, n. 4, p. E769-E778, 2013. DOI: https://doi.org/10.1210/jc.2012-2749.
NATALICCHIO, A. et al. The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic β-Cell Survival and Insulin Secretion. Diabetes, v. 66, n. 11, p. 2849-2856, 2017. DOI: https://doi.org/10.2337/db17-0002.
NIE, Y.; LIU, D. N-Glycosylation is required for FNDC5 stability and irisin secretion. Biochemical and Biophysical Research Communications, v. 484, n. 4, p. 976-982, 2017. DOI: https://doi.org/10.1016/j.bbrc.2017.01.145.
NODA, Y. et al. Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid beta generation in Alzheimer's disease. Molecular Brain, v. 11, n. 1, p. 61, 2018. DOI: https://doi.org/10.1186/s13041-018-0401-8.
PARK, H.; POO, M. M. Neurotrophin regulation of neural circuit development and function. Nature Reviews Neuroscience, v. 14, n. 1, p. 7-23, 2013. DOI: https://doi.org/10.1038/nrn3379.
PEDERSEN, B. K. Muscles and their myokines. Journal of Experimental Biology, v. 214, n. 2, p. 337-346, 2011. DOI: https://doi.org/10.1242/jeb.048074.
PEDERSEN, B. K.; SALTIN, B. Exercise as medicine – evidence for prescribing exercise as therapy. Scandinavian Journal of Medicine & Science in Sports, v. 25, n. S3, p. 1-72, 2015. DOI: https://doi.org/10.1111/sms.12581.
PUIGSERVER, P.; SPIEGELMAN, B. M. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocrine Reviews, v. 24, n. 1, p. 78-90, 2003. DOI: https://doi.org/10.1210/er.2002-0012.
QIU, S. et al. Chronic exercise training and circulating irisin in adults: A meta-analysis. Sports Medicine, v. 45, n. 11, p. 1577-1588, 2015. DOI: https://doi.org/10.1007/s40279-015-0373-5.
QIU, S. et al. Acute Exercise-Induced Irisin Release in Healthy Adults: A Systematic Review and Meta-Analysis. Frontiers in Physiology, v. 13, p. 831066, 2022. DOI: https://doi.org/10.3389/fphys.2022.831066.
RANA, K. S. et al. Plasma irisin levels predict telomere length in healthy adults. Age, v. 36, n. 2, p. 995-1001, 2014. DOI: https://doi.org/10.1007/s11357-014-9620-9.
REZA, M. M. et al. Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy. Nature Communications, v. 8, n. 1, p. 1104, 2017. DOI: https://doi.org/10.1038/s41467-017-01131-0.
ROTHER, E. T. Revisão sistemática × revisão narrativa. Acta Paulista de Enfermagem, São Paulo, v. 20, n. 2, p. v-vi, 2007. DOI: https://doi.org/10.1590/S0103-21002007000200001.
SCHUMACHER, M. A. et al. The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer. Journal of Biological Chemistry, v. 288, n. 47, p. 33738-33744, 2013. DOI: https://doi.org/10.1074/jbc.M113.516641.
SONG, H. et al. Irisin promotes human umbilical vein endothelial cell proliferation through the ERK signaling pathway. PLoS ONE, v. 9, n. 10, p. e110273, 2014. DOI: https://doi.org/10.1371/journal.pone.0110273.
TEUFEL, A. et al. Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene, v. 297, n. 1-2, p. 79-83, 2002. DOI: https://doi.org/10.1016/s0378-1119(02)00871-5.
TSUCHIYA, Y. et al. High-intensity exercise causes greater irisin release than low-intensity exercise. Metabolism, v. 63, n. 8, p. 1049-1057, 2014. DOI: https://doi.org/10.1016/j.metabol.2014.05.003.
VARELA-RODRÍGUEZ, B. M. et al. FNDC5 expression and circulating irisin levels are modified by diet and hormonal milieu. Journal of Clinical Medicine, v. 9, n. 4, p. 1114, 2020. DOI: https://doi.org/10.3390/jcm9041114.
VAUGHAN, R. A. et al. Characterization of the metabolic effects of irisin on skeletal muscle in vitro. Diabetes, Obesity and Metabolism, v. 16, n. 8, p. 711-718, 2014. DOI: https://doi.org/10.1111/dom.12268.
WANG, H. et al. Irisin plays a pivotal role to protect the heart against ischemia and reperfusion injury. Journal of Cellular Physiology, v. 232, n. 12, p. 3775-3785, 2017. DOI: https://doi.org/10.1002/jcp.25857.
WRANN, C. D. et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metabolism, v. 18, n. 5, p. 649-659, 2013. DOI: https://doi.org/10.1016/j.cmet.2013.09.008.
WRIGHT, D. C. et al. Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1alpha expression. Journal of Biological Chemistry, v. 282, n. 1, p. 194-199, 2007. DOI: https://doi.org/10.1074/jbc.M606116200.
WU, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell, v. 150, n. 2, p. 366-376, 2012. DOI: https://doi.org/10.1016/j.cell.2012.05.016.
XIN, C. et al. Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway. International Journal of Obesity, v. 40, n. 3, p. 443-451, 2016. DOI: https://doi.org/10.1038/ijo.2015.199.
XIONG, X. Q. et al. FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, v. 1852, n. 9, p. 1867-1875, 2015. DOI: https://doi.org/10.1016/j.bbadis.2015.06.017.
ZHANG, H. J. et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. Journal of Hepatology, v. 59, n. 3, p. 557-562, 2013. DOI: https://doi.org/10.1016/j.jhep.2013.04.030.
ZHANG, Y. et al. Irisin stimulates browning of white adipocytes. Diabetes, v. 63, n. 2, p. 514-525, 2014. DOI: https://doi.org/10.2337/db13-1106.
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