Commentary 591

Authors

F. Sanchis-Gomar1, R. Alis2, H. Pareja-Galeano1, M. Romagnoli2, 3, C. Perez-Quilis1

Affiliations

1

Department of Physiology, Faculty of Medicine, University of Valencia, Fundación Investigación Hospital Clínico Universitario/INCLIVA, Valencia, Spain 2 University Research Institute “Dr. Viña Giner”, Molecular and Mitochondrial Medicine, Catholic University of Valencia “San Vicente Mártir”, Valencia, Spain 3 Department of Physical Education and Sports, Catholic University of Valencia “San Vicente Mártir”, Valencia, Spain

Key words ▶ myokine ● ▶ hormone ● ▶ diabetes ● ▶ obesity ● ▶ metabolic syndrome ●

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

Introduction



received 23.10.2013 accepted 28.11.2013 Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1363283 Published online: January 23, 2014 Horm Metab Res 2014; 46: 591–596 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence F. Sanchis-Gomar, MD Department of Physiology Faculty of Medicine University of Valencia Av. Blasco Ibañez 15 46010 Valencia Spain Tel.: + 34/96/386 46 50 Fax: + 34/96/386 46 42 [email protected]

The fairly recent discovery of a novel and promising peptidic hormone for the treatment of obesity and/or diabetes, called irisin, was reported by Boström et al. [1]. These authors stated that irisin acts on the cells of white adipose tissue and its concentrations increase after endurance exercise training in both mice and humans [1, 2]. Increased circulating irisin concentrations therefore contextually raise total energy expenditure and prolong life expectancy, reduce bodyweight, and mitigate diet-induced insulin resistance in certain animal models [3]. According to Boström and co-workers, circulating irisin levels are upregulated after exercise in mice and humans, resulting in a modest increase in irisin plasma concentrations [4]. Moreover, these authors report that the regulation of irisin following exercise seems to be greater in elderly subjects and after acute exercise [4]. Irisin is thought to be a proteolytic derivative of muscle integral membrane protein fibronectin type III domain containing 5 (FNDC5), which is released into the bloodstream in response to some types of exercise, but not all. Furthermore, peripheral delivery of FNDC5 to the liver via adenoviral vectors resulted in elevated blood irisin and induced

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.

expression of Bdnf and other neuroprotective genes in the hippocampus [5]. Consequently, great expectations were rapidly raised based on this finding [6–8]. It was hypothesized that irisin might provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions [9, 10], thus raising expectations for implementing this hormone in therapeutics [11–13].

Circulating Irisin Levels in Obesity, Diabetes, and Exercise: Results from Published Studies



Several studies that assess circulating irisin concentrations in healthy, obese and/or diabetic sub▶ Table 1) jects have recently been published (● [14–22]. In all of them, plasma or serum irisin levels were measured by ELISA kits and controversial results and conclusions were reported. In fact, a normal range of circulating irisin levels has not yet been established. In these studies, 3 different ELISA kits were used: a) ELISA, Aviscera Biosciences, Santa Clara, CA (USA), which gave 8–10 % inaccurate intra- and inter-assay results; b) ELISA, USCN Life Science, Wuhan (China), which provided less than 10 % inaccurate intra-

Sanchis-Gomar F et al. Irisin Measurement … Horm Metab Res 2014; 46: 591–596

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Inconsistency in Circulating Irisin Levels: What is Really Happening?

and inter-assay results; and c) ELISA, Phoenix Pharmaceuticals, Burlingame, CA (USA), which was characterized by an intraassay inaccuracy of 7 %. Choi et al. reported that a negative correlation may exist between the hemoglobin A1c (HbA1c) and circulating levels of irisin [17]. Stengel et al. showed that irisin correlates positively with both insulin concentration and body mass index (BMI) [15]. At variance with this finding, MorenoNavarrete et al. showed that irisin correlates negatively with BMI [16]. In accordance with these results, Polyzos et al. reported lower irisin concentrations in obese controls when compared with lean controls [21], whereas Zhang et al. reported that serum irisin levels were reduced in obese adults with nonalcoholic fatty liver disease (NAFLD) [22]. However, irisin levels in these studies differed strikingly (from 24 pg/ml to 2 μg/ml) ▶ Table 1 and ● ▶ Fig. 1). Age also seems to associate negatively (● with irisin levels [14]. Interestingly, Stengel et al. also observed that women with anorexia nervosa and low BMI (12.6 ± 0.7 kg/m2) have lower plasmatic irisin levels than obese patients. Nevertheless, it was concluded that type 2 diabetes (T2D) patients have lower concentrations of this hormone [16, 17], which coincides with the findings of Liu et al. (204 ± 72 ng/ml in T2D vs. 257 ± 24 ng/ml in nondiabetic controls). On the other hand, Vamvini and colleagues have observed that circulating irisin may be positively associated with circulating follistatin levels, although irisin concentrations are not shown in their paper [20]. Follistatin promotes muscle hypertrophy and therefore a link between them could exist. Surprisingly, Choi et al. reported very low concentrations of serum irisin levels in normal glucose tolerance and in T2D patients of 38.86 ± 2.48 pg/ml (i. e., 0.03886 ± 0.00248 ng/ml) and 24.53 ± 3.53 pg/ml (i. e., 0.02453 ± 0.00353 ng/ml), respectively [17]. Thus, we conclude that one cannot rely on reports of plasma or serum levels that range from 24 pg/ml (probably not within the range of most ELISA ▶ Table 1). kits) to 2 μg/ml (much too high for a hormone) (● More intriguingly and illogically based on the article by Boström et al., several authors have recently reported that exercise training does not affect circulating irisin in humans [23–25]. Hecksteden et al. also failed to observe increases in irisin concentrations in healthy subjects after aerobic endurance training [26]. These facts are evidence of a nonbeneficial effect of irisin induced by exercise [27], although Kraemer et al. have reported a transient elevated circulating irisin (only during the first hour) in response to moderate aerobic exercise in young men and women [28]. Aydin et al. measured irisin concentrations in saliva and serum of obese and normal weight subjects, before and after 45 min in a Turkish bath or running, using the commercial ELISA kits from Phoenix Pharmaceuticals, Burlingame, CA (USA) [29]. These authors found that saliva and serum irisin concentrations in obese subjects were lower than those in their normal weight counterparts after exercise or a Turkish bath, whereas saliva and serum irisin concentrations in both groups were higher. In the obese group, the increase in serum irisin after exercise was not significant when compared with the controls whereas the increase in saliva irisin after exercise was significant in both the obese and control groups. The serum irisin level also increased significantly after using the Turkish bath in the obese group while this group experienced no significant increase in serum irisin level after exercise [29]. Although these authors did not show the precise values of saliva and/or irisin concentrations, the value range in serum and saliva was approximately 70–110 ng/ml and 250–550 ng/ml, respectively [29]. Due to the concentration differences described above, some authors have concluded that vendor to vendor differences (i. e., Sanchis-Gomar F et al. Irisin Measurement … Horm Metab Res 2014; 46: 591–596

Aviscera Bioscience vs. Phoenix Pharmaceuticals) may play a key role in these discrepancies [15]. In addition, many other explanations have been put forward to explain these discrepancies and, perhaps unexpected, results. For instance, it has been stated that muscle mass is the main predictor for circulating irisin, and that a decrease in irisin levels after weight loss is explained by reduced muscle mass, suggesting that the positive association of irisin with BMI is explained, at least in part, by muscle mass [14]. However, Liu et al. have reported exactly the opposite, that is, circulating irisin negatively correlates with BMI [18]. On the other hand, Liu and co-workers have correlated age positively with irisin [18], whereas Huh et al. reported an inverse relationship between irisin and age [14]. More recently, Park and colleagues assessed the associations between baseline serum irisin levels and metabolic syndrome (MetS) in 151 subjects [19]. These authors reported that baseline irisin levels were significantly higher in subjects with MetS compared to subjects without MetS. In addition, irisin was associated negatively with adiponectin but positively with BMI, systolic and diastolic blood pressure, fasting glucose, triglycerides, and HOMA-IR. They concluded that irisin is associated with an increased risk of MetS, cardiometabolic variables, and cardiovascular disease in humans [19]. In addition, they evaluated 3 different commercially available irisin ELISA kits: one (Cat. # EK-067–52) manufactured by Aviscera (Santa Clara, CA., USA), another (Cat. # EK-067–29) from Phoenix Pharmaceuticals (Burlingame, CA.), and a third from Adipogen (Cat. # AG-45A-0046EK-KI01, San Diego, CA, USA). The results of the evaluation showed that the detectable range of each kit was 0.066–1 024 ng/ml for #EK-067–52, 0.1–1 000 ng/ml for #EK-067–29, and 0.001–5 ng/ml for the Adipogen kit [19]. In addition, values measured in the same subjects using the Adipogen kit were higher than those that have previously been suggested as physiological concentrations of irisin [1], and approximately one order of magnitude higher than levels measured in the same subjects by the other 2 kits mentioned above. Finally, it has also been argued that, for instance, the measurement discrepancies could reflect gender differences, but could also suggest a disassociation between FNDC5 expression and circulating irisin under some conditions, among a plethora of other weak arguments [30].

Discussion and Conclusions



When analyzing all the above-mentioned results, our main concern at this point was not only the diverse levels of irisin, but also the different directions of correlations or associations. Overall, in our opinion, validating studies in this field are mandatory and validating these ELISA kits is also necessary. Several authors have already expressed their concerns about the relationship reported between exercise, irisin expression, and its beneficial metabolic effects [23, 27, 31]. Our concerns, along with those of Timmons et al. [31], have been recently confirmed by an article published by Erickson [32]. The author underlines 3 important aspects of circulating irisin determination and its assumed physiological effects. First, the currently available antibodies against irisin used in the ELISA commercial kits have not been validated. In fact, the latest recommendation made by Erikson is that all published assays of irisin protein levels should be questioned. Second, he questions the results reported by Boström et al. [1] since these authors used a truncated recombinant irisin/

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592 Commentary

Control Type 2 diabetes Lean Overweight Obese Normal weight Anorexia nervosa Obesity (BMI 30–40) Obesity (BMI 40–50) Obesity (BMI > 50) Nondiabetic control Type 2 diabetes

[16]

Obese adults with IHTG contents of 5.7 ± 2.0 Obese adults with IHTG contents of 11.0 ± 1.6 Obese adults with IHTG contents of 18.0 ± 2.8 Obese adults with IHTG contents of 31.7 ± 7.5

[22]

74 74 74 74

54.7 ± 7.0 55.0 ± 6.6 53.1 ± 7.3

14 150 44 48

44

107

69 7 18 34 17 8 8 8 8 8 60 96

104 104

117 17 14

n

53.1 ± 7.0

Between 43.0 and 48.0 Between 44.3 and 47.0 53.14 ± 8.92 18.48 ± 0.16 54.2 ± 1.6 52.6 ± 1.6

50.9 ± 10.93 53.57 ± 10.32 47.28 ± 10.15 51.62 ± 10.64 54 ± 11.83 48.5 ± 4.3 26.1 ± 2.9 48.3 ± 4.1 47.3 ± 4.0 45.9 ± 5.0 40.6 ± 12.7 58.7 ± 9.3

65.07 ± 9.55 64.34 ± 40

49.32 ± 8.63 20.5 ± 1.5 53.1 ± 8.9

Age (years)

17/0 –

29/45

24/50

19/55

25/49

8/6 150/0 24/20 28/20

23/21

48/59

– – – – – 4/4 0/8 4/4 4/4 4/4 25/60 58/96

38/66 35/69



Sex (M/F)

28.6 ± 2.8

28.1 ± 2.7

27.5 ± 2.4

27.1 ± 2.7

50.18 ± 10.62 23.18 ± 3.75 25.3 ± 0.3 30.9 ± 0.6

32.9 (29.1–38.2)

27.0 (23.5–31.6)

27.61 ± 3.8 29.58 ± 3.4 23.33 ± 1.2 27.23 ± 1.58 32.47 ± 2.6 22.6 ± 0.9 12.6 ± 0.7 36.9 ± 1.2 44.9 ± 1.1 70.1 ± 2.7 25.0 ± 4.8 27.6 ± 4.6

24.53 ± 1.12 24.53 ± 1.16

30.23 ± 5.28 21.9 ± 1.6 50.2 ± 10.6

BMI (kg/m2)

Serum

Serum

Serum

Serum

Serum Serum Serum Serum

Plasma

Plasma

Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma Plasma

Serum Serum

Plasma Plasma Serum

Sample

A

A

A

A

A A C C

A

A

A A A A A C C C C C B B

B B

A A A

Method

5.31 (0.98–11.84) ng/ml

6.48 (1.43–13.04) ng/ml

8.62 (3.05–18.01) ng/ml

9.01 (3.57–18.88) ng/ml

not reported not reported 49.7 ± 2.0 ng/ml 33.7 ± 2.7 ng/ml

214.4 (174.4–254.2) ng/ml

162.2 (133.5–206.9) ng/ml

1 848.9 ± 507.5 ng/ml 1 507.7 ± 222.1 ng/ml 2 157.9 ± 600.7 ng/ml 1 783.7 ± 426.9 ng/ml 1 652.2 ± 421.8 ng/ml 774.5 ± 46.2 ng/ml 667.0 ± 45.1 ng/ml 794.9 ± 64.8 ng/ml 900.6 ± 43.4 ng/ml 917.2 ± 67.4 ng/ml 257 ± 24 ng/ml 204 ± 72 ng/ml

38.86 ± 2.48 pg/ml 24.53 ± 3.53 pg/ml

113.12 ± 20.62 ng/ml 420.3 ± 32.7 ng/ml 112.7 ± 32.2 ng/ml

Mean irisin concentration

Serum irisin levels were statistically different in obese controls compared with lean controls Serum irisin levels were reduced in obese adults with NAFLD

Irisin may be positively associated with follistatin circulating levels

Circulating irisin was significantly lower in individuals with Type 2 diabetes compared with nondiabetic controls Baseline irisin levels were significantly higher in subjects with metabolic syndrome compared to subjects without metabolic syndrome

Circulating irisin is affected under conditions of altered BMI with highest levels in severely obese patients

Circulating irisin levels were positively correlated with biceps circumference, BMI, glucose, ghrelin, and IGF-1. Irisin levels were negatively correlated with age, insulin, cholesterol, and adiponectin levels Serum irisin levels were significantly decreased in the new-onset type 2 diabetes patients compared with the normal glucose tolerance subjects Circulating irisin levels were negatively associated with obesity and insulin resistance

Main results

Sanchis-Gomar F et al. Irisin Measurement … Horm Metab Res 2014; 46: 591–596

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NAFLD: Nonalcoholic fatty liver disease; Post-Ex: Post exercise; SD: Standard deviation

A: ELISA, Aviscera Biosciences, Santa Clara, CA, USA; B: ELISA, USCN Life Science, Wuhan, China; C: ELISA, Phoenix Pharmaceuticals, Burlingame, CA, USA; BMI: Body mass index; IGF-1: Insulin-like growth factor 1; IHTG: Intrahepatic triglyceride contents;

[21]

Morbidly obese subjects Healthy young subjects Baseline levels in lean controls Baseline levels in obese controls

Metabolic syndrome

[20]

[19]

[18]

No metabolic syndrome

Normal glucose tolerance Type 2 diabetes

[17]

[15]

Healthy women Moderately trained young healthy Obese patients

Subjects

[14]

(Ref)

Study

Table 1 Characteristics of the studies in which circulating levels of irisin are determined.

Commentary 593

Control Aerobic endurance training Strength endurance training

[26]

Sanchis-Gomar F et al. Irisin Measurement … Horm Metab Res 2014; 46: 591–596

50 ± 7 49 ± 7 48 ± 7

40–65

(13/26) (8/15) (17/23)

not reported

26

39 23 40

not reported

7/11

not reported not reported not reported not reported 13/13

Sex (M/F)

26

18

26

21

14

14

21

n

24.5 ± 3.1 23.5 ± 3.5 24.9 ± 3.4

29.0 ± 2.4

23.5 ± 2.0

24.2 ± 2.7

23.5 ± 3.9

29 ± 3

21 ± 2

30 ± 4

23 ± 3

BMI (kg/m2)

Serum Serum Serum

Plasma

Plasma

Plasma

Plasma

Serum

Serum

Serum

Serum

Sample

C C C

C

C

C

C

C

C

C

C

Method

188 ± 75 ng/ml 201 ± 52 ng/ml 196 ± 51 ng/ml

Basal 160 ng/ml (SD not shown)

Post-Ex 143 ng/ml (SD not shown)

Basal 71.0 ± 41.6 ng/ Post-Ex ml 73.3 ± 36.0 ng/ml Basal 101.3 ± 12.5 ng/ml

Data only shown in ● ▶ Fig. 1. No accurate data reported. Minimum concentrations around 750 ng/ml Maximum concentrations around 1 500 ng/ml

Mean irisin concentration

A training-induced increase in circulating irisin could not be confirmed

Hemodialysis patients have lower plasma irisin when compared to healthy subjects. Resistance exercise was unable to augment plasma irisin despite increasing muscle mass. No enhancing effect of long-term training on circulating irisin levels

Serum irisin did not change after acute aerobic, long-term endurance training or endurance training combined with resistance exercise (RE) training, or associated with metabolic disturbances.

Main results

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NAFLD: Nonalcoholic fatty liver disease; Post-Ex: Post exercise; SD: Standard deviation

A: ELISA, Aviscera Biosciences, Santa Clara, CA, USA; B: ELISA, USCN Life Science, Wuhan, China; C: ELISA, Phoenix Pharmaceuticals, Burlingame, CA, USA; BMI: Body mass index; IGF-1: Insulin-like growth factor 1; IHTG: Intrahepatic triglyceride contents;

Normal glucose response or overweight with abnormal glucose metabolism

Healthy and physically inactive ( < 1 bout of exercise/ week the previous year) men

Controls with normal weight

50.9 ± 6.6

43 ± 15

Obese subjects

Healthy subjects

40 ± 15

Lean subjects

44.8 ± 14.1

49 ± 13

Metabolic syndrome

26 patients undergoing hemodialysis

37 ± 15

Age (years)

Healthy subjects

Subjects

[25]

[24]

[23]

(Ref)

Study

Table 1 Characteristics of the studies in which circulating levels of irisin are determined. Continued.

594 Commentary

▶ Table 1. ■ ELISA, Aviscera Biosciences, Santa Clara, CA, USA; ▲ ELISA, USCN Fig. 1 Graphic representation of the results obtained in the studies shown in ● Life Science, Wuhan, China; ● ELISA, Phoenix Pharmaceuticals, Burlingame, CA, USA. Solid symbols: plasma; void symbols: serum. Each letter corresponds to a reference: a [17], b [22], c [21], d [19], e [18], f [14], g [15], h [16], i [23], j [24], k [25], l [26]. Error bars represent SD.

FNDC5 peptide to demonstrate the browning effect on fat cell cultures of irisin. It is debatable whether this truncated peptide possesses any biological activity. Erickson states that the fraction of FNDC5, which is protein cleaved and released to the media is not well known and therefore, whether FNDC5 proteolytic cleavage, and in turn irisin secretion, is a major biological pathway, is also unknown. More recently, Schumacher et al. described that irisin exists as a preformed dimer [33]. This fact has important implications for its function as a highly conserved ectodomain of FNDC5-like receptors as well as a putative myokine ligand. Thus, the structure of irisin suggests a mechanism for myokine ligand signaling via binding of a preformed dimer [33]. These concerns also demonstrate that it is necessary to reconsider the physiological function of irisin. Likewise, Raschke et al. have demonstrated in humans that the start codon of the FNDC5 gene is mutated and is not activated by contraction, the ATA start codon of the FNDC5 gene is essentially not translated, and recombinant FNDC5 and irisin have no effect on the brite differentiation of preadipocytes [27]. Accordingly, they suggested that humans do not produce the FNDC5 protein and therefore cannot have plasma irisin [27]. Therefore, the mutated start codon may affect the translation rate and further the circulating concentrations of irisin. In addition, if the translation rate varies individually, it may cause differences in irisin measurement. If all the above findings are correct, all assays of human plasma or serum irisin must be measuring only cross-reacting antigens and irisin cannot possibly be a physiologically significant human hormone. To conclude, in our opinion, further research is recommended to clarify whether:  i. irisin levels are really associated with BMI, reflecting primarily muscle or fat mass; ii. irisin levels are related to other biological variables; iii. the differences observed only reflect inter-population or methodological variations, assay discrepancies and/or preanalytical variability (i. e., blood collection, handling, storage, repeated melting, etc…); iv. there are plasma vs. serum differences; v. irisin ELISA assays really measure circulating irisin levels or only cross-reacting antigens; vi. irisin really exists.

Conflict of Interest



The authors state that there are no conflicts of interest in the publication of this article.

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 prostatecancer 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

Sanchis-Gomar F et al. Irisin Measurement … Horm Metab Res 2014; 46: 591–596

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Commentary 595

17

18

19

20

21

22

23

24

25

Obesity and Insulin Resistance. J Clin Endocrinol Metab 2013; 98: E769–E778 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 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 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 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 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 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 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 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 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

Sanchis-Gomar F et al. Irisin Measurement … Horm Metab Res 2014; 46: 591–596

26

27

28

29

30 31 32 33

adipose tissue in human. FEBS J 2013, doi:10.1111/febs.12619 [epub ahead of print] 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 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 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, doi:10.1055/s-0033-1355381 [epub ahead of print] 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 Hojlund K, Bostrom P. Irisin in obesity and type 2 diabetes. J Diabetes Complications 2013; 27: 303–304 Timmons JA, Baar K, Davidsen PK, Atherton PJ. Is irisin a human exercise gene? Nature 2012; 488: E9–E10 discussion E10–E11 Erickson HP. Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor? Adipocyte 2013; 2: 289–293 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

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596 Commentary

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Inconsistency in circulating irisin levels: what is really happening?

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, g...
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