M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 3 ( 2 0 14 ) 17 8–1 80
Available online at www.sciencedirect.com
Metabolism www.metabolismjournal.com
Irisin in humans: recent advances and questions for future research Irisin is a muscle-derived factor, secreted from muscle after shedding of the extracellular portion of the type I membrane protein Fndc5. After its release, Irisin signals to the adipose tissue for the promotion of brown-like adipocytes (“beige cells”). Irisin was characterized two years ago and since its discovery a large number of studies have reported on the biology of Irisin, with the majority being studies of plasma Irisin in human cohorts. Importantly, the key function of Irisin, beige cell formation, has been observed in several studies [1–4]. Moreover, the release of Irisin from Fndc5 to the extracellular space has also been reproduced in a number of studies [2,5–7]. The regulation of Irisin by exercise, however, has been reproduced only in some cohorts [2,5,8–11], whereas a lack of regulation was seen in others [12–14] done under different physiological and/or experimental conditions. Another aspect that remains to be clarified is the timing of Irisin increase after exercise; since the above studies have tested Irisin in different time points before and after exercise the possibility exists that Irisin increases for a finite period of time after exercise but its levels do not stay elevated for a prolonged period of time. An important advance in the understanding of Irisin biology was recently made when Schumacher et al. recently published the structure of Irisin demonstrating dimerization and the authors suggested a model for receptor activation [15]. Two recent studies, Polyzos et al. and Park et al., published in this issue of Metabolism, have addressed the relation between Irisin and two different aspects in the realm of metabolic dysfunction in humans [16] and Park et al. analyzed Irisin levels in subjects with different dietary preferences. For this purpose, the Alternate Healthy Eating Index (AHEI) and Alternate Mediterranean Diet Score (aMED) were used. In a total of 151 subjects, Irisin did not demonstrate any relation to either AHEI or aMED scores suggesting that healthier dietary patterns do not influence circulating Irisin levels. Similarly to previous studies [10,17], however, Irisin displayed a positive relation to BMI and fat mass. These results thus suggest that dietary factors do not impact regulation of Irisin or vice versa. Interestingly though, the authors found that plasma CRP levels negatively correlated with AHEI and aMED.
Polyzos and colleagues focused instead on Irisin levels in subjects with fatty liver disease. 16 subjects with nonalcoholic simple steatosis (NAFLD) and steatohepatitis (NASH) were compared to 24 lean and 28 obese controls [16]. Irisin levels were significantly lower in subjects with NAFL and NASH compared to both the lean controls, but obese controls displayed similar Irisin levels as the diseased cohort. Also, Irisin levels were higher in subjects with portal inflammation. This study partially confirms the previous findings from Zhang et al. [18] where an inverse relation was observed between Irisin and hepatic triglyceride levels. The relation between Irisin and serum AST/ALT levels, however, were different between the two studies. In the discussion of the present paper, Polysos et al. address the fact that Irisin has been negatively associated with BMI in some studies, and positively in others. The authors conclude that consistently Irisin was positively correlated with BMI in healthy subjects [10,19,20] and negatively in subjects with metabolic disease [7,21]. Thus, they propose that differences between the healthy and diseased state might thus explain these previous discrepancies, an important notion that needs to be confirmed or refuted by further studies. Park et al. and Polyzos et al. both analyzed human Irisin levels using a validated ELISA. The measurements of Irisin in humans were recently challenged however [13,22]. Moreover, the expression of Irisin in humans was questioned by Raschke et al. [13] as they highlighted that Fndc5 in humans is utilizing an alternative start codon. Several lines of evidence, however, strongly support the notion that Irisin is expressed, secreted and metabolically regulated in humans: I. Although not mentioned clearly by Raschke et al., the alternative start codon for Fndc5 was already described previously, where an unbiased search found Fndc5 amongst many other expressed non-pseudogenes [23]. II. Studies have compared Fndc5 mRNA levels and plasma Irisin levels and found clear covariation [7] or concordant regulation after intervention [10]. Such covariation would not be expected for a pseudogene, and/or if the ELISA was unspecific. III. We and others have clearly demonstrated the validity of the Aviscera Irisin ELISA kit (now sold by other vendors), which correctly detects spiked Irisin in physiological concentrations [10]. Western blot analysis using
0026-0495/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2013.11.009
M ET ABOL I SM CL IN I CA L A N D EX PE RI ME N TA L 6 3 ( 2 0 14 ) 17 8–1 8 0
antibody from this ELISA, also detects a 25 kDa band in plasma, which is the same size as where fully glycosylated recombinant Irisin migrates [4]. Importantly, this antibody detects native, glycosylated Irisin when spiked to human plasma (PB, data not shown) at physiological concentrations. Thus, this antibody (which is the most predominantly used in the field currently) detects endogenous and exogenous Irisin in human plasma at physiological concentrations. Erickson and Raschke point out that the early studies of Irisin were performed using an older antibody sold by Abcam [2]. The annotation of this antibody suggested that it would be directed primarily against the c-terminus of Fndc5. We and others, however, have observed immunoreactivity using this antibody against recombinant N-terminal Fndc5 (Irisin) and questioned the original annotation. The antibody is now discontinued (possibly for this reason) making it impossible to pinpoint the epitope. Zhang et al. have recently [4] utilized a different irisin antibody provided by Sigma-Aldrich that identified recombinant irisin separated by SDS-PAGE at 25, 22, and 15 kDa. They further confirmed that all bands represent Irisin with different glycosylation. Thus, it is clear that Irisin is present in human plasma and that its concentrations are altered in the metabolically diseased state [6,17,19,21,24–26]. Not all ELISAs and antibodies, however, have been validated. Studies of different commercially available assays give very different baseline values [12]. IV. Lastly, direct measures of Irisin levels in cell culture media from human cells also have resulted in clear signal [6]. In fact, even Raschke et al. found detectable Irisin in the media of human primary myocytes [13]. The comparison to a murine cell line kept under completely other conditions, however, did not allow for any conclusions as to differences between the species [13]. In summary, these converging pieces of evidence, when put together, strongly suggest that Irisin is synthesized from Fndc5 in humans and released to plasma where they are measurable by western or appropriate ELISA methods. In this context, the two clinical papers published in this issue of Metabolism advance significantly our clinical understanding of Irisin in humans. One major challenge for future advances in the understanding of Irisin biology is identification of the cellular receptor. The existence of a specific, high-affinity receptor is supported by the lownanomolar activity of the protein [2,4], and knowledge of its identity would likely unravel new possible target cells/ tissues for Irisin actions. Moreover, the notion of a potential “irisin-resistance” in various disease states, as suggested by various authors, could be directly tested if the receptor system is known. Loss-of-function models will also be important to understand Irisin biology. Genetic mouse models with conditional ablation of the Fndc5 could unravel new, key biological functions for Irisin. Such mice will also reveal potential redundancies in Irisin signaling possibly mediated by the paralog Fndc4. Zhang et al. recently showed that recombinant yeast-produced Irisin could induce UCP-1 25-fold when injected to mice [4], which led to reduced body weight and improved glucose control. These findings are exciting as they suggest that Irisin could be tested therapeutically and raise the hope that Irisin might come of use in obese and diabetic patients in the future.
179
Conflict of interest The authors do not have any conflict of interest related to this manuscript. Pontus A. Boström Department for Cell and Molecular Biology Karolinska Institutet, Sweden José Manuel Fernández-Real Section of Diabetes, Endocrinology, and Nutrition, and IDIBGI Hospital of Girona; and CIBERobn, Spain Christos Mantzoros Division of Endocrinology, Diabetes, and Metabolism Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA Section of Endocrinology, Boston VA Healthcare System Harvard Medical School, Boston, MA 02130, USA E-mail address: [email protected]
REFERENCES
[1] Wu J, Bostrom P, Sparks LM, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012;150(2):366–76. [2] Bostrom P, Wu J, Jedrychowski MP, et al. A PGC1-alphadependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481(7382): 463–8. [3] Shan T, Liang X, Bi P, et al. Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1alpha-Fndc5 pathway in muscle. FASEB J 2013;27(5):1981–9. [4] Zhang Y, Li R, Meng Y, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 2013 [Epub ahead of print]. [5] Wrann CD, White JP, Salogiannnis J, et al. Exercise induces hippocampal bdnf through a PGC-1alpha/Fndc5 pathway. Cell Metab 2013;18(5):649–59 http://dx.doi.org/10.1016/j.cmet. 2013.09.008. [Epub 2013 Oct 10]. [6] Gouni-Berthold I, Berthold HK, Huh JY, et al. Effects of lipidlowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo. PLoS One 2013;8(9): e72858. http://dx.doi.org/10.1371/journal.pone.0072858. [7] Moreno-Navarrete JM, Ortega F, Serrano M, 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(4):E769–78. [8] Aydin S, Aydin S, Kuloglu T, et al. Alterations of irisin concentrations in saliva and serum of obese and normalweight subjects, before and after 45 min of a Turkish bath or running. Peptides 2013;50:13–8 http://dx.doi.org/10.1016/j. peptides.2013.09.011. [Epub 2013 Oct 1]. [9] Kraemer RR, Shockett P, Webb ND, et al. A transient elevated irisin blood concentration in response to prolonged, moderate aerobic exercise in young men and women. Horm Metab Res 2013 [Epub ahead of print]. [10] Huh JY, Panagiotou G, Mougios V, 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 2012;61(12):1725–38.
180
M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 3 ( 2 0 14 ) 17 8–1 80
[11] Lecker SH, Zavin A, Cao P, et al. Expression of the irisin precursor Fndc5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure. Circ Heart Fail 2012;5(6):812–8. [12] Pekkala S, Wiklund P, Hulmi JJ, et al. Are skeletal muscle Fndc5 gene expression and irisin release regulated by exercise and related to health?J Physiol 2013;591(Pt 21): 5393–400 http://dx.doi.org/10.1113/jphysiol.2013.263707. [Epub 2013 Sep 2]. [13] Raschke S, Elsen M, Gassenhuber H, et al. Evidence against a beneficial effect of irisin in humans. PLoS One 2013;8(9): e73680. http://dx.doi.org/10.1371/journal.pone.0073680. [14] Moraes C, Leal VO, Marinho SM, et al. Resistance exercise training does not affect plasma irisin levels of hemodialysis patients. Horm Metab Res 2013;45(12):900–4 http://dx.doi.org/ 10.1055/s-0033-1354402. [Epub 2013 Sep 6]. [15] Schumacher MA, Chinnam N, Ohashi T, et al. Structure of irisin reveals a novel intersubunit beta-sheet fibronectin (FNIII) dimer; implications for receptor activation. J Biol Chem 2013;288(47):33738–44 http://dx.doi.org/10.1074/jbc.M113. 516641. [Epub 2013 Oct 10]. [16] Polyzos SA, Kountouras J, Anastasilakis AD, et al. Irisin in patients with nonalcoholic fatty liver disease. Metabolism 2013;63:178–80. [17] Park KH, Zaichenko L, Brinkoetter M, et al. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab 2013 [Epub ahead of print]. [18] Zhang HJ, Zhang XF, Ma ZM, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults.
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
J Hepatol 2013;59(3):557–62 http://dx.doi.org/10.1016/j.jhep. 2013.04.030. [Epub 2013 May 9]. Stengel A, Hofmann T, Goebel-Stengel M, et al. Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity—correlation with body mass index. Peptides 2013;39:125–30. Liu JJ, Wong MD, Toy WC, et al. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complications 2013;27(4):365–9. Choi YK, Kim MK, Bae KH, et al. Serum irisin levels in newonset type 2 diabetes. Diabetes Res Clin Pract 2013;100(1): 96–101. Erickson HP. Irisin and Fndc5 in retrospect: an exercise hormone or a transmembrane receptor? Adipocyte 2013;2(4): 289–93. Ivanov IP, Firth AE, Michel AM, et al. Identification of evolutionarily conserved non-aug-initiated n-terminal extensions in human coding sequences. Nucleic Acids Res 2011;39(10):4220–34. Zhang HJ, Zhang XF, Ma ZM, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. J Hepatol 2013;59(3):557–62. Wen MS, Wang CY, Lin SL, et al. Decrease in irisin in patients with chronic kidney disease. PLoS One 2013;8(5): e64025 http://dx.doi.org/10.1371/journal.pone.0064025. [Print 2013]. Vamvini MT, Aronis KN, Panagiotou G, et al. Irisin mrna and circulating levels in relation to other myokines in healthy and morbidly obese humans. Eur J Endocrinol 2013;169(6): 829–34.
Available online at www.sciencedirect.com
Metabolism www.metabolismjournal.com
Irisin in humans: recent advances and questions for future research Irisin is a muscle-derived factor, secreted from muscle after shedding of the extracellular portion of the type I membrane protein Fndc5. After its release, Irisin signals to the adipose tissue for the promotion of brown-like adipocytes (“beige cells”). Irisin was characterized two years ago and since its discovery a large number of studies have reported on the biology of Irisin, with the majority being studies of plasma Irisin in human cohorts. Importantly, the key function of Irisin, beige cell formation, has been observed in several studies [1–4]. Moreover, the release of Irisin from Fndc5 to the extracellular space has also been reproduced in a number of studies [2,5–7]. The regulation of Irisin by exercise, however, has been reproduced only in some cohorts [2,5,8–11], whereas a lack of regulation was seen in others [12–14] done under different physiological and/or experimental conditions. Another aspect that remains to be clarified is the timing of Irisin increase after exercise; since the above studies have tested Irisin in different time points before and after exercise the possibility exists that Irisin increases for a finite period of time after exercise but its levels do not stay elevated for a prolonged period of time. An important advance in the understanding of Irisin biology was recently made when Schumacher et al. recently published the structure of Irisin demonstrating dimerization and the authors suggested a model for receptor activation [15]. Two recent studies, Polyzos et al. and Park et al., published in this issue of Metabolism, have addressed the relation between Irisin and two different aspects in the realm of metabolic dysfunction in humans [16] and Park et al. analyzed Irisin levels in subjects with different dietary preferences. For this purpose, the Alternate Healthy Eating Index (AHEI) and Alternate Mediterranean Diet Score (aMED) were used. In a total of 151 subjects, Irisin did not demonstrate any relation to either AHEI or aMED scores suggesting that healthier dietary patterns do not influence circulating Irisin levels. Similarly to previous studies [10,17], however, Irisin displayed a positive relation to BMI and fat mass. These results thus suggest that dietary factors do not impact regulation of Irisin or vice versa. Interestingly though, the authors found that plasma CRP levels negatively correlated with AHEI and aMED.
Polyzos and colleagues focused instead on Irisin levels in subjects with fatty liver disease. 16 subjects with nonalcoholic simple steatosis (NAFLD) and steatohepatitis (NASH) were compared to 24 lean and 28 obese controls [16]. Irisin levels were significantly lower in subjects with NAFL and NASH compared to both the lean controls, but obese controls displayed similar Irisin levels as the diseased cohort. Also, Irisin levels were higher in subjects with portal inflammation. This study partially confirms the previous findings from Zhang et al. [18] where an inverse relation was observed between Irisin and hepatic triglyceride levels. The relation between Irisin and serum AST/ALT levels, however, were different between the two studies. In the discussion of the present paper, Polysos et al. address the fact that Irisin has been negatively associated with BMI in some studies, and positively in others. The authors conclude that consistently Irisin was positively correlated with BMI in healthy subjects [10,19,20] and negatively in subjects with metabolic disease [7,21]. Thus, they propose that differences between the healthy and diseased state might thus explain these previous discrepancies, an important notion that needs to be confirmed or refuted by further studies. Park et al. and Polyzos et al. both analyzed human Irisin levels using a validated ELISA. The measurements of Irisin in humans were recently challenged however [13,22]. Moreover, the expression of Irisin in humans was questioned by Raschke et al. [13] as they highlighted that Fndc5 in humans is utilizing an alternative start codon. Several lines of evidence, however, strongly support the notion that Irisin is expressed, secreted and metabolically regulated in humans: I. Although not mentioned clearly by Raschke et al., the alternative start codon for Fndc5 was already described previously, where an unbiased search found Fndc5 amongst many other expressed non-pseudogenes [23]. II. Studies have compared Fndc5 mRNA levels and plasma Irisin levels and found clear covariation [7] or concordant regulation after intervention [10]. Such covariation would not be expected for a pseudogene, and/or if the ELISA was unspecific. III. We and others have clearly demonstrated the validity of the Aviscera Irisin ELISA kit (now sold by other vendors), which correctly detects spiked Irisin in physiological concentrations [10]. Western blot analysis using
0026-0495/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.metabol.2013.11.009
M ET ABOL I SM CL IN I CA L A N D EX PE RI ME N TA L 6 3 ( 2 0 14 ) 17 8–1 8 0
antibody from this ELISA, also detects a 25 kDa band in plasma, which is the same size as where fully glycosylated recombinant Irisin migrates [4]. Importantly, this antibody detects native, glycosylated Irisin when spiked to human plasma (PB, data not shown) at physiological concentrations. Thus, this antibody (which is the most predominantly used in the field currently) detects endogenous and exogenous Irisin in human plasma at physiological concentrations. Erickson and Raschke point out that the early studies of Irisin were performed using an older antibody sold by Abcam [2]. The annotation of this antibody suggested that it would be directed primarily against the c-terminus of Fndc5. We and others, however, have observed immunoreactivity using this antibody against recombinant N-terminal Fndc5 (Irisin) and questioned the original annotation. The antibody is now discontinued (possibly for this reason) making it impossible to pinpoint the epitope. Zhang et al. have recently [4] utilized a different irisin antibody provided by Sigma-Aldrich that identified recombinant irisin separated by SDS-PAGE at 25, 22, and 15 kDa. They further confirmed that all bands represent Irisin with different glycosylation. Thus, it is clear that Irisin is present in human plasma and that its concentrations are altered in the metabolically diseased state [6,17,19,21,24–26]. Not all ELISAs and antibodies, however, have been validated. Studies of different commercially available assays give very different baseline values [12]. IV. Lastly, direct measures of Irisin levels in cell culture media from human cells also have resulted in clear signal [6]. In fact, even Raschke et al. found detectable Irisin in the media of human primary myocytes [13]. The comparison to a murine cell line kept under completely other conditions, however, did not allow for any conclusions as to differences between the species [13]. In summary, these converging pieces of evidence, when put together, strongly suggest that Irisin is synthesized from Fndc5 in humans and released to plasma where they are measurable by western or appropriate ELISA methods. In this context, the two clinical papers published in this issue of Metabolism advance significantly our clinical understanding of Irisin in humans. One major challenge for future advances in the understanding of Irisin biology is identification of the cellular receptor. The existence of a specific, high-affinity receptor is supported by the lownanomolar activity of the protein [2,4], and knowledge of its identity would likely unravel new possible target cells/ tissues for Irisin actions. Moreover, the notion of a potential “irisin-resistance” in various disease states, as suggested by various authors, could be directly tested if the receptor system is known. Loss-of-function models will also be important to understand Irisin biology. Genetic mouse models with conditional ablation of the Fndc5 could unravel new, key biological functions for Irisin. Such mice will also reveal potential redundancies in Irisin signaling possibly mediated by the paralog Fndc4. Zhang et al. recently showed that recombinant yeast-produced Irisin could induce UCP-1 25-fold when injected to mice [4], which led to reduced body weight and improved glucose control. These findings are exciting as they suggest that Irisin could be tested therapeutically and raise the hope that Irisin might come of use in obese and diabetic patients in the future.
179
Conflict of interest The authors do not have any conflict of interest related to this manuscript. Pontus A. Boström Department for Cell and Molecular Biology Karolinska Institutet, Sweden José Manuel Fernández-Real Section of Diabetes, Endocrinology, and Nutrition, and IDIBGI Hospital of Girona; and CIBERobn, Spain Christos Mantzoros Division of Endocrinology, Diabetes, and Metabolism Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA 02215, USA Section of Endocrinology, Boston VA Healthcare System Harvard Medical School, Boston, MA 02130, USA E-mail address: [email protected]
REFERENCES
[1] Wu J, Bostrom P, Sparks LM, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012;150(2):366–76. [2] Bostrom P, Wu J, Jedrychowski MP, et al. A PGC1-alphadependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481(7382): 463–8. [3] Shan T, Liang X, Bi P, et al. Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1alpha-Fndc5 pathway in muscle. FASEB J 2013;27(5):1981–9. [4] Zhang Y, Li R, Meng Y, et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 2013 [Epub ahead of print]. [5] Wrann CD, White JP, Salogiannnis J, et al. Exercise induces hippocampal bdnf through a PGC-1alpha/Fndc5 pathway. Cell Metab 2013;18(5):649–59 http://dx.doi.org/10.1016/j.cmet. 2013.09.008. [Epub 2013 Oct 10]. [6] Gouni-Berthold I, Berthold HK, Huh JY, et al. Effects of lipidlowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo. PLoS One 2013;8(9): e72858. http://dx.doi.org/10.1371/journal.pone.0072858. [7] Moreno-Navarrete JM, Ortega F, Serrano M, 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(4):E769–78. [8] Aydin S, Aydin S, Kuloglu T, et al. Alterations of irisin concentrations in saliva and serum of obese and normalweight subjects, before and after 45 min of a Turkish bath or running. Peptides 2013;50:13–8 http://dx.doi.org/10.1016/j. peptides.2013.09.011. [Epub 2013 Oct 1]. [9] Kraemer RR, Shockett P, Webb ND, et al. A transient elevated irisin blood concentration in response to prolonged, moderate aerobic exercise in young men and women. Horm Metab Res 2013 [Epub ahead of print]. [10] Huh JY, Panagiotou G, Mougios V, 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 2012;61(12):1725–38.
180
M ET ABOL I SM CL IN I CA L A N D E XP E RI ME N TAL 6 3 ( 2 0 14 ) 17 8–1 80
[11] Lecker SH, Zavin A, Cao P, et al. Expression of the irisin precursor Fndc5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure. Circ Heart Fail 2012;5(6):812–8. [12] Pekkala S, Wiklund P, Hulmi JJ, et al. Are skeletal muscle Fndc5 gene expression and irisin release regulated by exercise and related to health?J Physiol 2013;591(Pt 21): 5393–400 http://dx.doi.org/10.1113/jphysiol.2013.263707. [Epub 2013 Sep 2]. [13] Raschke S, Elsen M, Gassenhuber H, et al. Evidence against a beneficial effect of irisin in humans. PLoS One 2013;8(9): e73680. http://dx.doi.org/10.1371/journal.pone.0073680. [14] Moraes C, Leal VO, Marinho SM, et al. Resistance exercise training does not affect plasma irisin levels of hemodialysis patients. Horm Metab Res 2013;45(12):900–4 http://dx.doi.org/ 10.1055/s-0033-1354402. [Epub 2013 Sep 6]. [15] Schumacher MA, Chinnam N, Ohashi T, et al. Structure of irisin reveals a novel intersubunit beta-sheet fibronectin (FNIII) dimer; implications for receptor activation. J Biol Chem 2013;288(47):33738–44 http://dx.doi.org/10.1074/jbc.M113. 516641. [Epub 2013 Oct 10]. [16] Polyzos SA, Kountouras J, Anastasilakis AD, et al. Irisin in patients with nonalcoholic fatty liver disease. Metabolism 2013;63:178–80. [17] Park KH, Zaichenko L, Brinkoetter M, et al. Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab 2013 [Epub ahead of print]. [18] Zhang HJ, Zhang XF, Ma ZM, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults.
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
J Hepatol 2013;59(3):557–62 http://dx.doi.org/10.1016/j.jhep. 2013.04.030. [Epub 2013 May 9]. Stengel A, Hofmann T, Goebel-Stengel M, et al. Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity—correlation with body mass index. Peptides 2013;39:125–30. Liu JJ, Wong MD, Toy WC, et al. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complications 2013;27(4):365–9. Choi YK, Kim MK, Bae KH, et al. Serum irisin levels in newonset type 2 diabetes. Diabetes Res Clin Pract 2013;100(1): 96–101. Erickson HP. Irisin and Fndc5 in retrospect: an exercise hormone or a transmembrane receptor? Adipocyte 2013;2(4): 289–93. Ivanov IP, Firth AE, Michel AM, et al. Identification of evolutionarily conserved non-aug-initiated n-terminal extensions in human coding sequences. Nucleic Acids Res 2011;39(10):4220–34. Zhang HJ, Zhang XF, Ma ZM, et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. J Hepatol 2013;59(3):557–62. Wen MS, Wang CY, Lin SL, et al. Decrease in irisin in patients with chronic kidney disease. PLoS One 2013;8(5): e64025 http://dx.doi.org/10.1371/journal.pone.0064025. [Print 2013]. Vamvini MT, Aronis KN, Panagiotou G, et al. Irisin mrna and circulating levels in relation to other myokines in healthy and morbidly obese humans. Eur J Endocrinol 2013;169(6): 829–34.
