Inconsistency in Circulating Irisin Levels: What is Really Happening?

Abstract

The discovery of irisin as a novel and promising peptidic hormone for the treatment of obesity and diabetes has recently been reported. As a result, great hopes have been raised based on this finding, hypothesizing that irisin might provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions requiring therapeutical and clinical attention. However, controversial results and conclusions on circulating irisin concentrations and correlations with other variables, including its role in metabolism, have recently been reported. Although laboratory assessment of irisin by ELISA is easily available and may provide interesting information for therapeutics and clinical practice, the heterogeneous and often discrepant results published so far, raise serious concerns about its measurement, indicating that it may still not be ready for use or whether irisin really exists. We highlight here some aspects on these discrepancies and contradictions, and put forward their implications.

Key words

myokine - hormone - diabetes - obesity - metabolic syndrome

• References

• 1 Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481: 463-468
• 2 Spiegelman BM. Banting lecture 2012: regulation of adipogenesis: toward new therapeutics for metabolic disease. Diabetes 2013; 62: 1774-1782
• 3 Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012; 8: 457-465
• 4 Bostrom PA, Graham EL, Georgiadi A, Ma X. Impact of exercise on muscle and nonmuscle organs. IUBMB Life 2013; 65: 845-850
• 5 Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM. Exercise Induces Hippocampal BDNF through a PGC-1alpha/FNDC5 Pathway. Cell Metab 2013; 18: 649-659
• 6 Polyzos SA, Kountouras J, Shields K, Mantzoros CS. Irisin: a renaissance in metabolism?. Metabolism 2013; 62: 1037-1044
• 7 Elbelt U, Hofmann T, Stengel A. Irisin: what promise does it hold?. Curr Opin Clin Nutr Metab Care 2013; 16: 541-547
• 8 Villarroya F. Irisin, turning up the heat. Cell Metab 2013; 15: 277-278
• 9 Sanchis-Gomar F, Lippi G, Mayero S, Perez-Quilis C, Garcia-Gimenez JL. Irisin: a new potential hormonal target for the treatment of obesity and type 2 diabetes. J Diabetes 2012; 4: 196
• 10 Sanchis-Gomar F. The skeletal muscle-metabolism axis in prostate-cancer therapy. N Engl J Med 2013; 367: 2257-2258
• 11 Cunha A. Basic research: Irisin – behind the benefits of exercise. Nat Rev Endocrinol 2012; 8: 195
• 12 Enerback S. Adipose tissue metabolism in 2012: Adipose tissue plasticity and new therapeutic targets. Nat Rev Endocrinol 2013; 9: 69-70
• 13 Sanchis-Gomar F, Perez-Quilis C. Irisinemia: A Novel Concept to Coin in Clinical Medicine?. Ann Nutr Metab 2013; 63: 60-61
• 14 Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, Schneider BE, Mantzoros CS. 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 2012; 61: 1725-1738
• 15 Stengel A, Hofmann T, Goebel-Stengel M, Elbelt U, Kobelt P, Klapp BF. Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity – Correlation with body mass index. Peptides 2013; 39: 125-130
• 16 Moreno-Navarrete JM, Ortega F, Serrano M, Guerra E, Pardo G, Tinahones F, Ricart W, Manuel-Fernandez-Real J. 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
• 17 Choi YK, Kim MK, Bae KH, Seo HA, Jeong JY, Lee WK, Kim JG, Lee IK, Park KG. Serum irisin levels in new-onset type 2 diabetes. Diabetes Res Clin Pract 2013; 100: 96-101
• 18 Liu JJ, Wong MD, Toy WC, Tan CS, Liu S, Ng XW, Tavintharan S, Sum CF, Lim SC. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complicat 2013; 27: 365-369
• 19 Park KH, Zaichenko L, Brinkoetter M, Thakkar B, Sahin-Efe A, Joung KE, Tsoukas MA, Geladari EV, Huh JY, Dincer F, Davis CR, Crowell JA, Mantzoros CS. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab 2013; 98: 4899-4907
• 20 Vamvini MT, Aronis KN, Panagiotou G, Huh JY, Chamberland JP, Brinkoetter MT, Petrou M, Christophi CA, Kales SN, Christiani DC, Mantzoros CS. Irisin mRNA and circulating levels in relation to other myokines in healthy and morbidly obese humans. Eur J Endocrinol 2013; 169: 829-834
• 21 Polyzos SA, Kountouras J, Anastasilakis AD, Geladari EV, Mantzoros CS. Irisin in patients with nonalcoholic fatty liver disease. Metabolism 2013; S0026-0495(13)00297-7
• 22 Zhang HJ, Zhang XF, Ma ZM, Pan LL, Chen Z, Han HW, Han CK, Zhuang XJ, Lu Y, Li XJ, Yang SY, Li XY. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. J Hepatol 2013; 59: 557-562
• 23 Pekkala S, Wiklund P, Hulmi JJ, Ahtiainen JP, Horttanainen M, Pollanen E, Makela KA, Kainulainen H, Hakkinen K, Nyman K, Alen M, Herzig KH, Cheng S. Are Skeletal Muscle FNDC5 Gene Expression and Irisin Release Regulated by Exercise and Related to Health?. J Physiol 2013; 591: 5393-5400
• 24 Moraes C, Leal VO, Marinho SM, Barroso SG, Rocha GS, Boaventura GT, Mafra D. Resistance Exercise Training does not Affect Plasma Irisin Levels of Hemodialysis Patients. Horm Metab Res 2013; 45: 900-904
• 25 Norheim F, Langleite TM, Hjorth M, Holen T, Kielland A, Stadheim HK, Gulseth HL, Birkeland KI, Jensen J, Drevon CA. The effects of acute and chronic exercise on PGC-1alpha, irisin and browning of subcutaneous adipose tissue in human. FEBS J 2013;
• 26 Hecksteden A, Wegmann M, Steffen A, Kraushaar J, Morsch A, Ruppenthal S, Kaestner L, Meyer T. Irisin and exercise training in humans – Results from a randomized controlled training trial. BMC Med 2013; 11: 235
• 27 Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, Jung R, Wisloff U, Tjonna AE, Raastad T, Hallen J, Norheim F, Drevon CA, Romacho T, Eckardt K, Eckel J. Evidence against a Beneficial Effect of Irisin in Humans. PLoS One 2013; 8: e73680
• 28 Kraemer RR, Shockett P, Webb ND, Shah U, Castracane VD. A Transient Elevated Irisin Blood Concentration in Response to Prolonged, Moderate Aerobic Exercise in Young Men and Women. Horm Metab Res 2013;
• 29 Aydin S, Kuloglu T, Yilmaz M, Kalayci M, Sahin I, Cicek D. Alterations of irisin concentrations in saliva and serum of obese and normal-weight subjects, before and after 45min of a Turkish bath or running. Peptides 2013; 50C: 13-18
• 30 Hojlund K, Bostrom P. Irisin in obesity and type 2 diabetes. J Diabetes Complications 2013; 27: 303-304
• 31 Timmons JA, Baar K, Davidsen PK, Atherton PJ. Is irisin a human exercise gene?. Nature 2012; 488: E9-E10 discussion E10–E11
• 32 Erickson HP. Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor?. Adipocyte 2013; 2: 289-293
• 33 Schumacher MA, Chinnam N, Ohashi T, Shah RS, Erickson H. Structure of irisin reveals a novel intersubunit beta-sheet fibronectin (FNIII) dimer; implications for receptor activation. J Biol Chem 2013; 288: 33738-33744