Irisin is produced by a proteolytic cleavage of fibronectin type III domain-containing protein 5 (FNDC5) and has emerged as a potential mediator of exercise-induced energy metabolism. The purpose of this study was to review the results of studies that investigated irisin responses to acute and chronic exercise and provide an update. A comprehensive search in the databases of MEDLINE was performed (74 exercise studies). The focus of the analysis was on data concerning FNDC5 mRNA expression in skeletal muscle and circulating irisin concentration relatively to exercise mode, intensity, frequency and duration and the characteristics of the sample used. Circulating irisin levels may either not relate to FNDC5 transcription or expression of the later precedes irisin rise in the blood. Acute speed/strength and endurance exercise protocols represent potent stimuli for irisin release if they are characterized by adequate intensity and/or duration. There are no reports regarding irisin responses to field sport activities. Although animal studies suggest that irisin may also respond to systematic exercise training, the majority of human studies has produced contradictory results. Certain methodological issues need to be considered here such as the analytical assays used to measure irisin concentration in the circulation. Results may also be affected by subjects’ age, conditioning status and exercise intensity. The role of irisin as a moderator of energy metabolism during exercise remains to be seen.
Physical activity (PA) and/or exercise are widely accepted as important interventions not only for the prevention and treatment of various metabolic diseases such as obesity and type 2 diabetes mellitus . Acute and chronic exercise induces extensive metabolic adaptations in skeletal muscle and other organs (e.g. adipose tissue and liver) such as mitochondrial biogenesis . Exercise exerts its effects through various molecular pathways and myokines, which not only act on muscle itself via an autocrine/paracrine manner but also mediate the interaction of muscle with other organs through endocrine mechanisms , . A recently discovered myokine named irisin has been linked to body mass regulation . Irisin, a 112-amino acid glycosylated protein-hormone with a molecular weight of ~12–32 kDa, is a dimer consisting of an N-terminal fibronectin III (FNIII)-like domain that possible binds on fibronectin type III domain-containing protein 5 (FNDC5) receptors .
Exercise upregulates the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a transcriptional coactivator that mediates body’s adaptation to exercise by increasing mitochondria biogenesis, insulin sensitivity, energy expenditure and angiogenesis , . PGC-1α in muscle may trigger a proteolytic cleavage of FNDC5 (a membrane protein) to produce irisin that is subsequently released into the circulation , . Irisin is also expressed in hippocampus in a PGC-1α-dependent manner during exercise where it triggers the expression of several neuroprotective genes . Muscle- or brain-derived irisin release may regulate exercise effects on the body’s energy metabolism via an endocrine action on other tissues, such as adipocytes, heart, bone, kidney, immune system, pancreas, liver and ovaries , .
Irisin may promote the expression of uncoupling protein 1 (UCP1) in white adipose tissue (WAT), probably through p38 mitogen-activated protein kinase (MAPK) signaling, a process called browning, thereby elevating energy expenditure and improving metabolic profile ,  (Figure 1). Consequently, irisin could promote leanness that ultimately may aid the fight against obesity, type 2 diabetes, insulin resistance (IR) and other metabolic diseases , , . Irisin resistance, i.e. a compensatory rise in circulating irisin, has been associated with IR . Reduced circulating irisin levels have been systematically reported in patients with chronic kidney disease, preeclamptic women during gestation, type 2 diabetics and osteoporotic patients . The observation of increased serum irisin levels in healthy centenarians suggested that successful aging may be related to irisin secretion , which is in line with the age-dependent decline of PGC-1α expression .
The exercise-induced upregulation of PGC-1α and the positive correlation of plasma irisin with various obesity-related parameters, disorders and inflammation (e.g. waist-to-hip ratio, body mass index, body fat, C-reactive protein, etc.) ,  made researchers hypothesize that irisin may be a positive regulator of exercise effects on weight management and inflammation . Irisin has also been suspected to mediate various beneficial exercise effects on metabolic regulation such as the upregulation of energy expenditure through the induction of UCP1 in WAT, a process that promotes leanness . In fact, PGC1-α overexpressed by muscle cells secrete one or more molecules that can induce a thermogenic gene program in subcutaneous adipocytes that results in formation of beige adipocytes (known as browning) via a direct muscle-fat cross talk . When researchers searched for proteins as potential PGC1-α target genes in muscle and likely to be secreted, Bostrom et al.  noted that out of five candidate protein molecules, only FNDC5 was capable of inducing UCP1 mRNA and other brown fat genes’ expression. Moreover, immunohistochemistry of FNDC5-treated UCP1-positive cells showed a robust increase in multilocular lipid droplets and areas of higher mitochondrial density . Thus, irisin emerged as a promising therapeutic tool to treat metabolic disorders, and its name was derived from the ancient messenger Greek goddess iris to convey its role as muscle’s messenger to fat cells. If this hypothesis holds, then irisin should respond to various acute and chronic exercise protocols. However, whether an exercise-induced effect on irisin regulation exists or not remains a rather controversial issue because experimental data vary among studies giving rise to a debate that focuses on (i) whether irisin is involved in human metabolism, (ii) whether exercise is a potent stimulus for irisin production, (iii) what are the physiological implications of irisin in exercising humans, (iv) whether exercise induces FNDC5 expression in various tissues and (v) the adequacy of the available methods to quantify circulating irisin in human biological samples. The next sections are describing the current knowledge on the relationship between exercise and irisin as well as evidence on irisin’s role(s) and measurement.
Irisin responses to exercise
Irisin responses to acute exercise
FNDC5 mRNA and plasma irisin did in fact increase in mouse and human muscle following exercise, and this rise was accompanied by positive metabolic adaptations suggesting that following proteolytic cleavage of FNDC5, irisin is released into circulation and probably reaches fat cells where it potentially binds to a receptor to induce browning and heat production . Shortly after, this hypothesis was challenged by another group , who reported no exercise-induced change of irisin in skeletal muscle suggesting that FNDC5 in muscle is not exercise-induced. Since then, more in vivo and in vitro studies investigated the acute irisin responses to various exercise models. This section will describe in detail the effects of a single acute bout of several types of exercise on irisin metabolism. A recent meta-analysis concluded that acute exercise elicits a substantial rise of circulating irisin concentration that was related to participants’ fitness levels . However, this meta-analysis included only 10 published articles, and not all types of exercises were represented adequately .
Acute responses to speed/strength exercise
Speed/strength-type exercise protocols (Table 1) are characterized by efforts of maximal intensity and short duration. Sprint runs induced a marked rise of serum irisin postexercise in moderately trained and untrained males with or without metabolic syndrome , . Findings derived from racing greyhound dogs corroborated that sprint-type exercise does increase peripheral irisin levels acutely . In case of sprinting, irisin rise may be related to the decline of muscle ATP, i.e. a state of metabolic need . Acute sprint-type exercise may represent a potent stimulus for irisin release into the circulation as a part of a compensatory mechanism that attempts to defend ATP homeostasis in muscle , .
|Study||Sex||Age||Conditioning status||Specimen analyzed||Type of exercise||Results|
|Speed-strength forms of exercises|
|Huh et al. ||M||Young humans||Moderately trained||Serum||80-m sprint run||Irisin increased after an 80-m sprint|
|Pekkala et al. ||M||Young and old humans||Untrained||Serum and skeletal muscle biopsy||5 Sets of 10 repetitions in leg press until failure||FNDC5 mRNA increased only in young men postexercise by 1.4-fold but not irisin|
|Huh et al. ||F||Young humans||Untrained||Serum||Whole-body vibration exercise||An acute session of vibration exercise increased irisin by 10%|
|Huh et al. ||M||Young humans||Untrained, healthy and with metabolic syndrome||Serum||Participants alternated treadmill walking (5×4 min at 3 km/h) with treadmill running (4×4 min at 90% HRmax) for a total duration of 36 min||Serum irisin increased for 1 h post-exercise in healthy participants as well as in those with metabolic syndrome|
|Huh et al. ||M||Young humans||Untrained, healthy and with metabolic syndrome||Serum||3 Sets of 8–12 repetitions at 75%–80% of 1 RM in leg extension, chest press, leg curl, lat. pull down, leg press, biceps curls for a total duration of 45 min||Serum irisin increased for 1 h post-exercise in healthy participants as well as in those with metabolic syndrome|
|Löffler et al. ||M and F||Children||Untrained||Serum||30-min physical exercise (10 min jogging, 10 min gymnastics, 10 min sprint)||Irisin increased by 70%|
|Nygaard et al. ||M and F||Young humans||Trained||Plasma and skeletal muscle biopsy||8 Exercises for upper- and lower-body muscle groups (3 sets of 10–12 RM per exercise)||Plasma irisin increased for 1 h post-exercise. FNDC5 gene expression in muscle remained unaltered by exercise|
|Tsuchiya et al. ||M||Young humans||Untrained||Plasma||3–4 Sets of 12 repetitions in eight exercises at 65% of one repetition maximum (1 RM)||Irisin increased 1 h postexercise|
|Bell et al. ||M and F||Greyhound dogs||Trained||Plasma||400 m sprint||Irisin increased by 35% and returned at baseline values 120 min postexercise|
|Kraemer et al. ||M and F||Young humans||Not specified||Plasma||Light (30% 1 RM) or moderate resistance (70% 1 RM) resistance exercise (single biceps curls and calf presses) with partial or no vascular occlusion||Irisin increased by ~5%|
|Cardiovascular or endurance form of exercise|
|Pekkala et al. ||M||Middle-aged humans||Untrained||Serum and skeletal muscle biopsy||1 h cycling 50% of VO2max||No changes in irisin or FNDC5 gene expression in muscle was reported|
|Norheim et al. ||M||Middle-aged humans||Untrained||Plasma and skeletal muscle biopsies||45 min of cycling at 70% of VO2max||Acute exercise increased skeletal muscle FNDC5 mRNA expression and irisin plasma levels immediately postexercise|
|Anastasilakis et al. ||M and F||Young humans||Untrained||Serum||30-min aerobic exercise||Irisin increased postexercise|
|Aydin et al. ||M||Middle-aged humans||Untrained obese and lean||Plasma saliva||Moderate-intensity running for 45 min||Exercise increased irisin in saliva but not in serum|
|Brenmoehl et al. ||M||Young mice||Untrained||Skeletal muscle and serum||Continuous running||Exercise increased irisin but not FNDC5 expression|
|Comassi et al. ||M||Young humans||Trained||Plasma||Ironman triathlon||Irisin increased by ~30% in response to ultra-endurance exercise|
|Czarkowska-Paczek et al. ||M||Young rats||Untrained and trained||Skeletal muscle||Continuous running||FNDC5 mRNA declined in untrained rats but remained stable in trained rats post-exercise. Irisin protein levels increased in the untrained animals but not in the trained ones|
|Daskalopoulou et al. ||M||Young humans||Untrained||Serum||Three exercise trials: (i) maximal workload; (ii) moderate relative intensity (70% VO2max/10 min); (iii) moderate absolute intensity||Irisin increased postexercise with the maximal exercise protocol eliciting the greatest response|
|Huh et al. ||M||Young and old humans||Untrained and trained||serum||Running to exhaustion (time-trial)||Irisin increased by 12% independently of age and fitness status|
|Huh et al. ||M and F||Adolescent humans||Trained||Plasma||Continuous moderate-intensity continuous freestyle swimming (2000 m) and high-intensity interval exercise (six 50 m maximal freestyle swimming bouts every 5 min)||Irisin remained unchanged after continuous swimming but increased following interval swimming by 30% in both sexes 1 h postexercise|
|Kraemer et al. ||M and F||Young humans||Trained||Serum||90 min of running at 60% of VO2max||Irisin transiently increased (~20%) at 54 min of exercise and normalized thereafter in both males and females Stage of the menstrual cycle did not affect irisin responses in women|
|Tsuchiya et al. ||M||Young humans||Untrained||Serum||20-min high-intensity (80% VO2max) running and 40-min low-intensity (40% VO2max) running||Irisin demonstrated a late increase after high-intensity running (6–19 h) and remained unchanged after low-intensity running|
|Huh et al. ||M||Young humans||Untrained, healthy and with metabolic syndrome||Serum||36 min treadmill walking/running at 65% HRmax||Serum irisin increased for 1 h post-exercise in healthy participants as well as in those with metabolic syndrome|
|Liu et al. ||M||Adult mice||Untrained||Skeletal muscle and serum||Treadmill running at speed of 18 m/min and 0° slope for 30, 60, 90 and 120 min||Muscle FNDC5 expression and serum irisin increased|
|Löffler et al. ||M and F||Children||Untrained||Serum||15-min maximal cycling||Irisin increased by 123%|
|Nygaard et al. ||M and F||Young humans||Trained||Plasma and skeletal muscle biopsy||Six 5-min intervals of high-intensity running||Plasma irisin increased for 1 h post-exercise. FNDC5 gene expression in muscle remained unaltered by exercise|
|Quinn et al. ||M||Adult mice||Untrained||Skeletal muscle and serum||Continuous cardiovascular exercise||Both FDNC5 expression in skeletal muscle and serum irisin declined immediately postexercise|
|Tsuchiya et al. ||M||Young humans||Untrained||Plasma||Cycling at 65% of VO2max for 60 min||Irisin remained unaltered|
|Bell et al. ||M and F||Young sled dogs||Trained||Plasma||3.5–5 h of running, daily for 8 days||Irisin remained unaltered from day to day|
|Zugel et al. ||M and F||Young leans and obese||Untrained||Serum||A step-wise incremental exercise trial until exhaustion on a cycling ergometer for the leans and a modified treadmill walking test (to exhaustion) for the obese||Irisin increased by 1.2-fold in leans but not in the obese. There was a greater rise in lean women compared with men|
|Winn et al. ||F||Young||Obese, untrained||Plasma||Continuous treadmill walking (55% VO2peak)||Irisin increased by ~12%|
|Interval type exercise|
|Briken et al. ||M and F||Middle-aged humans||Untrained with multiple sclerosis||Serum||Graded (8–25 W with increases of 8–12.5 W/stage) exercise test on a cycle ergometer||Irisin increased by ~15%|
|Winn et al. ||F||Young||Obese, untrained||Plasma||4 min of high-intensity intervals (80% VO2peak) separated by 3 min of active recovery (50% VO2peak)||Irisin increased by ~12%|
|In vitro models mimicking acute exercise|
|Sánchez et al. ||Differentiated C2C12 myotubes||Exercise mimetics (adrenalin)||No effect on irisin expression|
|Kurdiova et al. ||Human primary muscle cell cultures established from lean, obese prediabetic and type 2 diabetic individuals||In vitro exercise-mimicking treatment (forskolin + ionomycin)||PGC-1a increased (more than doubed). FNDC5 mRNA was reduced by 18% in differentiated muscle cells and irisin in media by 20%|
M, males; F, females; HRmax, maximal heart rate; VO2max, maximal oxygen consumption; RM, repetition maximal; FNDC5, fibronectin type III domain-containing protein 5.
Several studies investigated whether strength-type exercise protocols could alter irisin levels in the blood. When young and old untrained males were subjected to a high-volume resistance exercise protocol for leg extensors only, skeletal muscle FNDC5 increased 1.4-fold in young participants only, whereas serum irisin remained unchanged . By contrast, when young males and females underwent a whole-body resistance exercise protocol (eight exercises for major muscle groups at three to four sets at 10–12 maximal repetitions or RM), FNDC5 remained unchanged in muscle whereas serum irisin increased for 1 h postexercise , , . Irisin also increased by resistance exercise with partial vascular occlusion in young men, suggesting that it may be implicated in muscle growth-related mechanisms . Whole-body vibration exercise also resulted in marked rise (~10%) of irisin in young untrained females .
These findings suggest that irisin may respond to high-intensity protocols that recruit multiple muscle groups such as sprinting or whole-body resistance exercise independent of age, sex, fitness status and clinical profile. This possibility agrees with a previous report of a positive correlation between irisin and follistatin, which is implicated in muscle growth . Evidence suggests that irisin may even be involved in the regulation of muscle hypertrophy-related signaling . Collectively, brief intense exercise may be a potent stimulus for irisin release in young trained or untrained humans of both sexes. These studies measured irisin levels in plasma and serum samples as well as in skeletal muscle biopsies.
Acute responses to endurance exercise
Endurance exercise (Table 1) is characterized by efforts of long duration and low-to-high intensity representing probably a greater metabolic challenge than other types of exercise. Irisin was found to increase in blood or saliva in response to protocols characterized by a prolonged duration (>45 min) , , , , , , ,  and/or moderate-to-high intensity (>60% of maximal oxygen consumption or VO2max) , , , , , , , , , . These increases (12%–123%) peaked in protocols that were characterized by maximal intensity , , . According to Daskalopoulou et al. , subjects that underwent three different exercise regimes (i.e. maximal or submaximal relative and absolute workload) demonstrated significantly higher levels of irisin at 3 min postexercise compared with pre-exercise values, in all exercise conditions. These irisin responses have been observed in both genders, as well in children, adolescents, young adults and middle-aged and older individuals as well as in adults with metabolic syndrome independently of training status , , , , , , , , . Interestingly, protocols of moderate intensity (≤65% VO2max) failed to alter irisin status , , ,  except in one case . These findings were also corroborated by most animal studies , ,  and research that applied exercise mimetics on differentiated C2C12 myotubes . By contrast, in human primary muscle cell cultures, exercise mimetics actually decreased FNDC5 and irisin (Table 1) . An irisin decline was also seen in an animal study . One report suggested that obesity may blunt this exercise-induced increase of irisin compared with leans, but this remains to be confirmed by future studies .
Interestingly, in three occasions, irisin increased post-exercise despite a decline  or lack of change ,  of FNDC5 mRNA expression in both human and animal skeletal muscle and despite a marked rise in PGC-1α expression . These observations suggest that either irisin levels in blood may not relate to FNDC5 transcription or FNDC5 expression precedes irisin rise in the circulation. These two alternatives would not be visible if muscle biopsies and blood sampling occurred at the same time point(s) as it happened in the studies described here.
Collectively, results from most human and animal studies suggest that irisin increases in response to endurance exercise depending on the intensity and duration (and/or their combination) of exercise protocols.
Acute responses to interval-type exercise
Interval exercise training (Table 1) incorporates periods of intense exercise interspersed by resting intervals, and it has been shown to result in high oxygen consumption , substantial enhancement of VO2max  and health-related adaptations such as mitochondrial biogenesis  and improved antioxidant status . This training methodology is characterized by the intensity and duration of work vs. resting intervals as well as the recovery mode . This type of acute exercise protocol was implemented in only two studies. Both of them indicated that irisin increases by 12%–15% in obese  and middle-aged adults with multiple sclerosis .
Responses to in vitro models mimicking acute exercise
Only two studies used in vitro models to mimick acute exercise responses. When adrenalin was applied to differentiated C2C12 myotubes, irisin remained unaltered . By contrast, when forskolin and ionomycin were introduced to human primary muscle cell cultures established from lean, obese prediabetic and type 2 diabetic individuals to simulate exercise, PGC-1a increased (more than doubled), FNDC5 mRNA was reduced by 18% in differentiated muscle cells, irisin in media decreased by 20% whereas PGC-1a expression increased in muscle cells . These discrepancies among these studies may be attributed to the experimental model used.
Conclusions on acute exercise
A total of 35 studies were reviewed to determine whether acute exercise represents a potent stimulus for an irisin rise in the circulation. It appears that all types of acute exercise protocols (i.e. speed/strength, endurance, interval) applied in humans and animals represent potent stimuli for irisin release if they are characterized by adequate intensity and/or duration. The only study that compared resistance exercise with interval- and endurance-type exercise protocols reported that strengthening exercise could induce a greater irisin response than multiple sprints and continuous cardiovascular exercise . However, it would be difficult to directly compare these three different exercise protocols if they are not matched in energy produced and work performed. It would also be interesting to see irisin responses to field sport activities in future studies.
Irisin responses to chronic exercise
The health-related positive adaptations induced by systematic exercise (training) are very well documented especially those that are related to metabolic health, musculoskeletal health and weight management. However, we still have a lot to learn about the systemic, cellular and molecular pathways that regulate these health-promoting adaptations of exercise training. Irisin has emerged as a potential mediator of exercise-induced health benefits as it enhanced health and prolonged life of mice designed to overexpress PGC-1α in skeletal muscle, a response also elicited by exercise training . Although irisin seems to respond to various types of acute exercise, results from chronic exercise studies seem, at least, equivocal so far. However, a meta-analysis that covered the period 2012–2014 (12 studies, three randomized and nine non-randomized trials) reported that resistance exercise training tends to decrease irisin levels in the circulation whereas endurance exercise training demonstrates only a tendency for a similar effect . However, most reviews so far classified exercise interventions as acute or chronic and endurance or resistance. This is a simplistic approach to describe a wide range of different metabolic challenges posed by various types of exercise interventions, i.e. endurance exercise, strength exercise, sprint-type exercise, interval training and PA interventions. This review will attempt to present all current information on this issue by including studies that examined the effects of all different types of exercise training and PA interventions (67 studies).
Evidence from cross-sectional studies
Results of cross-sectional studies (Table 2) provided some evidence that irisin may respond to exercise training. Many studies have reported a reverse relationship between irisin responses and training status, i.e. a higher training, exercise capacity or activity level is associated with a lower irisin concentration in the circulation, i.e. lower irisin values in athletes and physically active individuals compared with non-athletes and sedentary individuals , , , . On the other hand, habitual daily PA was positively associated with fitness status with irisin levels in chronic obstructive pulmonary disease (COPD) patients, overweight individuals and healthy controls , , , , . It appears that irisin may be positively associated with fitness status in females and inversely in males . However, when trained individuals were compared with untrained ones under conditions of mild cold exposure, the former demonstrated a higher FDNC5 expression in skeletal muscle and similar circulating irisin levels with the later, suggesting that irisin may not participate in adipocyte browning assessed by [18F] fluorodeoxyglucose-positron emission tomography-computed tomography . Although irisin was not measured, the expression of its genetic forerunner FNDC5 was more pronounced in trained cardiac patients as compared with untrained cardiac patients . By contrast, under condition of severe energy restrictions, serum irisin was similar in anorexics with either low or high PA levels  and was not correlated with VO2max values . Furthermore, amenorrhoeic female athletes exhibited lower irisin values than their eumenorrheic counterparts and non-athletes further that a chronic energy deficit state and not fitness status may affect irisin values . It must be mentioned that two recent studies also noted no differences in irisin levels between trained and untrained males and females , . Therefore, only 50% of cross-sectional studies suggest that athletes and physically active individuals demonstrate higher circulating irisin levels compared with non-athletes and physically active controls.
|Study||Sex||Age||Conditioning status||Specimen analyzed||Results|
|Lecker et al. ||M||Middle-aged humans||Trained vs. untrained cardiac patients||Skeletal muscle||FNDC5 gene expression was greater in the high-performance group|
|Hofmann et al. ||F||Young humans||Low vs. high physical activity anorexics||Plasma||No differences were detected|
|Huh et al. ||M||Young and old humans||Trained vs. untrained||Serum||Serum irisin was lower in physically active vs. sedentary subjects|
|Pardo et al. ||F||Young humnas||Anorexic vs. normal weight vs. obese individuals||Plasma||Plasma irisin levels were elevated in the obese participants compared with anorexics or normal-weight subjects. Irisin correlated positively with body weight, BMI, fat mass, resting energy expenditure and inversely correlated with daily physical activity|
|Singhal et al. ||F||Young humans||Amenorrheic athletes vs. eumenorrheic athletes vs. non-athletes||Serum||Amenorrheic had lower irisin than eumenorrheic and non-athletes, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with resting energy expenditure and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load|
|Tanisawa et al. ||M||Young, middle-aged, old humans||Fit vs. unfit||Serum||Serum irisin levels were negatively correlated with age but not with the VO2peak|
|Al-Daghri et al. ||M and F||All ages, humans||Active vs. inactive||Serum||Physical activity levels were positively associated with circulating irisin concentration|
|Hew-Butler et al. ||M and F||Young, humans||Trained vs. untrained||Plasma||Plasma irisin was lower in runners compared with non runners both at rest and postexercise|
|Ijiri et al. ||M and F||All ages, humans||Active vs. inactive||Serum||Physical activity levels were positively associated with circulating irisin concentration|
|Kerstholt et al. ||M and F||All ages, humans||Fit vs. unfit||Serum||Irisin concentration was inversely related to exercise capacity|
|Moreno et al. ||M and F||All ages, humans||Active vs. inactive||Plasma||Irisin levels were found to be higher in subjects who do more physical activity|
|Palermo et al. ||M and F||Middle-aged humans||Active vs. inactive||Serum||Physical activity levels were not associated with irisin concentration in the circulation|
|Vosselman et al. ||M||Young humans||Trained vs. untrained||Skeletal muscle and plasma||Under mild cold exposure, trained subjects had higher FNDC5 expression in muscle but a similar irisin concentration with untrained subjects|
|Singhal et al. ||F||Young||Trained vs. untrained||Not reported||No differences were noted between groups|
|Benedini et al. ||M and F||Young humans||Trained vs. untrained||Serum||Although all groups had similar serum irisin levels, a correlation was reported between fitness level and ratio between irisin and HOMA-IR|
|Studies that investigated the effects of speed/strength-form of exercise training|
|Hecksteden et al. ||M and F||30–60 years||Untrained||Serum||3 times/week, 26 weeks, eight machine-based exercises, 2 sets of 15 repetitions with 100% of the 20 repetition maximum performed for each exercise||Irisin remained unaffected by training|
|Raschke et al. ||M||Young||Untrained||Skeletal muscle biopsy||11 weeks, 3 times/week, 8 exercises/session for the whole body, 1–3 sets/exercise, 7–10 RM/set||FNDC5 mRNA expression was not affected by resistance exercise training|
|Bang et al. ||M||Young||Trained||Serum||8 weeks, 6 times/week, 26 exercises for the whole body, 5 sets/exercise of 10–15 reps/set at 60%–80% of 1 RM||Resistance exercise training alone did not affect irisin levels|
|Ellefsen et al. ||F||Young||Untrained||Skeletal muscle biopsy and serum||12 weeks, 3 times/week, 8 exercises for the whole body, either 3 sets for lower body exercise and 1 set for upper body exercises or 1 set for lower body exercise and 3 sets for upper body exercises, 7–10 RM/set||Resistance exercise training did not alter muscle FDNC5 expression or serum irisin levels|
|Greulich et al. ||M and F||Old||Hospitalized patients with stable COPD||Serum||3×2 min/day of vibration training, focused on muscle contractions of the entire flexor and extensor chain of muscles in the legs and the trunk, 12–26 Hz, amplitude 1.5–3||Vibration training increased serum irisin concentration by|
|Huh et al. ||F||Young||Untrained||Serum||6-week vibration training, 2 sessions/week, 11–18.5 min/session, 7 isometric exercises/session for the whole body, frequency was 16–21 Hz, amplitude was 2.5–5 mm||Vibration training failed to alter irisin levels|
|Kim et al. ||M||Old humans and mice||Untrained||Skeletal muscle and serum||Mice performed ladder climbing exercise with tail weight for 3 days/week for 12 weeks – Humans completed a strengthening program with elastic band exercises, 2 days/week for 12 weeks||Irisin increased in muscle and the circulation in response to training in both animals and humans|
|Scharhag-Rosenberger et al. ||M and F||Middle-aged||Untrained||Serum||Participants trained for 24 weeks, 3 times/week, 8 machine-based exercises for the major muscle groups, 2 sets/exercise, 16–20 rep/set at 20 RM||Resistance exercise training did not affect irisin levels|
|Kim et al. ||M and F||Young humans||Obese or overweight, untrained||Plasma||8 weeks, 4 times/week, 60-min sessions, exercises for the whole body at moderate-to-high intensity (65%–80% 1 RM, 10–12 repetitions, 3 sets/exercise)||Plasma irisin levels increased by ~20%|
|Reisi et al. ||M||Adult||Untrained rats||Plasma||8 weeks, 3 days/week on a ladder carrying load (50% of body weight and gradually increased to 200%). 3 sets of five repetitions||Plasma irisin levels, muscle FNDC5 expression, and adipose tissue UCP1 expression increased 5, 4, and threefold, respectively|
|Boeselt et al. ||M and F||Old||Untrained patients with chronic obstructive pulmonary disease||Serum||6 months, 2 time/week for 90 min/time with exercises for major muscle groups performed at 35%–75% of maximal strength (2–4 repetitions and 15–20 series)||Irisin remained unaltered by training|
|Zhao et al. ||M||Old humans||Untrained||Serum||Leg and core muscle strength training program, 2 times/week, 55 min/session for 12 weeks||Training increased circulating irisin by almost twofold|
|Studies that investigated the effects of cardiovascular or endurance form of exercise training|
|Fain et al. ||M||Young||Untrained castrated pigs||Skeletal muscle and serum||Treadmill running at 70% of HRmax, daily, 1 time/day, 5 days/week (35–75 min at 3–7 mph)||Exercise training did not increase FNDC5 mRNA or protein in the deltoid or triceps brachii of pigs but it may increase circulating irisin|
|Hecksteden et al. ||M and F||30–60 years||Untrained humans||Serum||3 times/week, 26 weeks, 45 min walking/running at 60% heart rate reserve||Irisin remained unaffected by training|
|Pekkala et al. ||M||Middle-aged||Untrained humans||Skeletal muscle and serum||High-intensity endurance training, 2 times/week for 21 weeks with cycling, 30–90 min/session at aerobic threshold (below, at or above)||Training did not affect skeletal muscle mRNA of FNDC5 and serum irisin|
|Raschke et al. ||M||Young||Untrained humans||Skeletal muscle biopsy||10 weeks of aerobic interval training, 3 times/week, 4×4 min intervals/session at 90% of peak heart, 3 min active recovery period (70% of peak heart rate)||FNDC5 mRNA expression was not affected by aerobic interval training|
|Besse-Patin et al. ||M||Young obese||Untrained||Skeletal muscle and serum||8-week endurance training program||No change in irisin mRNA level was found in muscle or in irisin protein levels in blood after training|
|Czarkowska-Paczek et al. ||M||Young||Untrained Wistar rats||Skeletal muscle||Treadmill running, 5 days/week, 6 weeks (10–60 min/day and 1200–1680 m/h)||Serum irisin levels remained unchanged following training|
|Peterson et al. ||Male||Young||Untrained Zucker rats||Diaphragm muscle||Running on a level motorized rodent treadmill 5 days/week for 9 weeks||No effect on the expression level of FNDC5 or in muscle protein content of Irisin|
|Seo et al. ||Male||Young||Untrained Sprague-Dawley rats||Skeletal muscle||Treadmill running for 15–60 min, 5 days/week for 4 weeks||Skeletal muscle FNDC-5 levels and plasma irisin concentration were unaffected by training|
|Wu et al. ||M||Adult||Untrained rats||Skeletal muscle, adipose tissue and serum||Endurance running||Training did not alter skeletal muscle FDNC5 expression and circulating irisin concentration but increased subcutaneous white adipose tissue FDNC5 content|
|Bilski et al. ||Male||Young||Untrained Wistar rats with colitis||Plasma||Running on a treadmill at a 20 m/min for 30 min/day, 5 days/week for 6 weeks||Exercise training increased plasma irisin|
|Hew-Butler et al. ||F||Young||Untrained||Plasma||10-week run/walk 5 km training program (3 days/week)||Plasma irisin declined with training|
|Ijiri et al. ||M and F||Middle-aged||Untrained, COPD patients and healthy controls||Serum||Endurance training||Training increased circulating irisin|
|Liu et al. ||M||Adult||Untrained Kunming mice||Skeletal muscle and serum||Treadmill running for 5 days/week for 4 weeks, at speed 18 m/min and incline 0° slope. once/day for 1 h||Muscle FNDC5 expression remained unchanged whereas serum irisin increased|
|Miyamoto-Mikami et al. ||M and F||Young and old humans||Untrained||Serum||8-week endurance-training program (cycling, 60%–70% of V̇O2peak for 45 min, 3 days/week)||Serum irisin increased in the older training group but not in the young training group|
|Samy et al. ||Male Wistar rats||Young||Untrained||Serum||8-week swimming (15 min with increments of additional 15 min daily until a period of 1 hr was attained), 5 times/week||Chronic training failed to alter serum irisin levels|
|Tiano et al. ||Male||Young||Untrained C57BL/6J mice||Serum and skeletal muscle||Free running via voluntary running wheel (3 weeks)||Although FNDC5 and PGC-1α protein levels were increased, there was no increase in serum irisin|
|Male||Young||Untrained C57BL/6J mice||Serum and skeletal muscle||Forced running on a treadmill (90 min/day, 2–3 weeks, 12–18 m/min, 10° incline)||Induced a 33% increase in serum irisin at week 2 along with an increase in the area under the curve over the 3 weeks of exercise. There was also an increase in FNDC5 mRNA expression levels and protein expression in skeletal muscle|
|Male||Young||Untrained C57BL/6J mice||Serum and skeletal muscle||Forced swimming in a countercurrent swim tank (90 min/day, 2–3 weeks, 1.2–1.7 L/min, 30–32°C)||Induced a 33% increase in serum irisin at week 2 along with an increase in the area under the curve over the 3 weeks of exercise. There was no change in FNDC5 mRNA expression levels and protein expression in skeletal muscle|
|Kim et al. ||M and F||Young||Untrained overweight/obese humans||Plasma||5 days/week for 8 weeks with 60-min sessions of whole body exercise (treadmill and cycling) performed at 65%–80% of maximal heart rate||Irisin remained unaltered by training|
|Lu et al. ||M||Adult||Wistar rats fed with a standard or a high-fat diet||Serum||8-week swimming without a load for 15–30 min/session, 5 days/week||Training increased serum irisin in rats receiving both a standard and a high-fat diet|
|Yang et al. ||M||Adult||Untrained rats fed with a high-fat diet||Serum and skeletal muscle||A 16-week swimming intervention, 5 days/week||Exercise increased irisin and PGC-1a skeletal muscle and irisin in serum|
|Bastu et al. ||F||Adult||High-fat diet-induced obesity model of the female C57BL/6J mice||Serum||Freewheel running for 10 weeks||Irisin increased by ~24%|
|Gmiat et al. ||F||Old||Untrained humans||Plasma||12 weeks (35 sessions) of Nordic walking training, 3 times/week for 60 min at an intensity of 60%–70% of maximal (each woman covered a total distance of 107 km). Women also received vitamin D supplementation||Training induced a slight increase of irisin in women who received vitamin D supplementation and the opposite occurred in women with low vitamin D levels|
|Lia et al. ||M||Adult||Mice with cerebral ischemia||Skeletal muscle||Run on a treadmill at 10 m/min for 90 min for 2 weeks. An irisin neutralizing antibody was injected||Irisin increased in skeletal muscle but not in the brain. Irisin contributes to the neuroprotective effect of physical exercise against cerebral ischemia|
|Mazur-Bialy et al. ||M||Adult||Untrained C57BL/6J mice with colitis fed a high-fat diet||Plasma||6-week wheel running||Training increased plasma irisin by 50% only in mice with colitis that were a high-fat diet|
|Studies that investigated the effects of interval form of exercise training|
|Huh et al. ||M||Young||Trained||Skeletal muscle and serum||8-week sprint training, 3 sessions/week (2 or 3 sets of runs with two 80-m sprint runs in each set with a 20-min rest between sets||Irisin levels remained unchanged by exercise training|
|Scalzo et al. ||M and F||Young||Untrained||Skeletal muscle and plasma||9 sessions of sprint interval training over 3 weeks. Each session consisted of 4–8, 30-s bouts of “all-out’” runs separated by 4 min of recovery; each session was separated by 1–2 days||Skeletal muscle FNDC5 protein content and plasma irisin were unaffected by sprint interval training|
|Jedrychowski et al. ||M||Young||Untrained||Plasma||3 days/week cyclic interval training (4×4 min >90% peak aerobic capacity – 3 min rest) separated by 2 days/week of treadmill walking/running (45 min at 70% peak aerobic capacity) for 12 weeks||Plasma irisin increased post-training|
|Briken et al. ||M and F||Middle-aged||Untrained patients with multiple sclerosis||Serum||9 weeks, 2–3 sessions/week of interval endurance training (arm ergometry, rowing and bicycle ergometry) with stepwise progression in intensity and duration||Irisin remained unaltered by training|
|Tsuchiya et al. ||M||Young||Untrained humans||Serum||Participants sprint-trained (cycling) either 1 time/day for 5 days/week, or 2 times/day for 2–3 days/week, all for 20 training sessions over 4 weeks||Sprint training reduced serum irisin by ~77%|
|Witek et al. ||M||Adolescents||Tennis athletes||Serum||Athletes followed their regular training and sampling occurred during their in-season||Irisin levels remained unaltered during the training period|
|Studies that investigated the effects of combination exercise training (endurance plus speed/strength forms of exercise|
|Pekkala et al. ||M||Middle-aged||Untrained||Skeletal muscle and serum||2+2 times/week for 21 weeks. Endurance training: cycling, 30–90 min/session at aerobic threshold (below, at or above). Strength training: 8 exercises for major muscle groups; 21-week training, 60–90 min/session||Training did not affect skeletal muscle mRNA of FNDC5 and serum irisin|
|Kurdiova et al. ||M and F||Young, obese||Untrained||Skeletal muscle and plasma||3 days/week for 3 months. Circuit training combining strength (exercises for major muscle groups – started at 50–60% 1 RM and increased by 2.5% 1 RM per week) and aerobic activities (aerobic dance, running, spinning at 70%–85% of HRmax)||Exercise did not affect FNDC5 and irisin|
|Norheim et al. ||M||Middle-aged||Untrained||Skeletal muscle and plasma||Combined strength (two whole body sessions/week, 60 min/session) and endurance (two endurance bicycle sessions/week of 60 min/session) training for 12 weeks||Training increased skeletal muscle mRNA of FNDC5 and decreased plasma irisin|
|Fukushima et al. ||M and F||Middle-aged||Untrained obese patients without diabetes||Serum||6-month body weight reduction program that included diet, exercise (70 min, included 30 min of endurance exercise and resistance exercises) and cognitive behavioral therapy||Irisin remained unchanged|
|Padilha Bonfante et al. ||M||Middle-aged||Untrained obese humans||Plasma||24-week training, 3 times/week with resistance training (3 sets of 6–10 maximal repetitions) and endurance training (walking/running at 55%–85% of VO2peak) in the same session (~60 min)||Although training did not change irisin levels, it prevented the irsisin decline that was observed in the aged-matched controls|
|Studies that investigated the effects of physical activity interventions|
|Löffler et al. ||M and F||Preadolescents||Untrained||Serum||Increased daily physical activity through sport participation||No effect on irisin levels|
|Palacios-Gonzalez et al. ||M and F||Children||Untrained||Serum||25 min of moderate-intensity exercise, 5 days/week, for 8 months. Exercise included group walking and running (sprints)||No changes in serum irisin levels were detected|
|Kwaśniewska et al. ||M||Middle-aged||Untrained humans||Plasma||Leisure time physical activity||Increased physical activity was associated with reduced plasma irisin levels|
|Morton et al. ||F||Adult||C57BL/6 mice fed a standard or a high-fat diet||Skeletal muscle||Voluntary access to running wheels for 6 weeks||Increased PA increased UCP1, PGC-1a and FNDC5 in muscle|
|Rocha-Rodrigues et al. ||M||Adult||Untrained rats||Plasma and skeletal muscle||Unrestricted access to wheel running for 17 weeks||Irisin remained unaffected by increased PA|
|Seo et al. ||M||Adult||Untrained rats||Plasma||12-week voluntary standing PA: lifting a load equal to their body weight while food height increased progressively every 4 weeks||Irisin levels remained unaltered by increased PA|
M, males; F, females; HRmax, maximal heart rate; VO2peak, peak oxygen consumption; BMI, body mass index; RM, repetition maximal; rep, repetitions; PA, physical activity; FNDC5, fibronectin type III domain-containing protein 5; PGC-1α, peroxisome proliferator-activated receptor γ coactivator-1α; COPD, obstructive pulmonary disease.
Irisin responses to strength exercise training
Studies that examined the effects of speed/strength-type exercise training on irisin responses are shown in Table 2. Five resistance-type exercise interventions , , , , ,  of various durations (11–26 weeks), intensities (50%–80% of maximal strength), volumes (≥8 exercises, 2–5 sets/exercise and 7–20 RM/set) and with a frequency of three sessions/week failed to observe a change in either FNDC5 gene expression or circulating irisin concentration, suggesting that this type of training may not be a potent stimulus for irisin adaptation in young and middle-aged males or females. By contrast, four recent investigations clearly showed that strength training elicited a marked rise (20% to fivefold) of circulating irisin in young and old humans as well as in rats , , , . This rise in irisin was accompanied by a fourfold increase in skeletal muscle FNDC5 expression and a threefold elevation of adipose tissue UCP1 expression . This upregulation of irisin in response to strength training seems to be enhanced by ursolic acid supplementation . Two training studies that used vibration as a resistance exercise mode reported also conflicting results. A vibration training protocol of flexor and extensor muscle groups of trunk and lower limbs of older male and female hospitalized patients with stable COPD increased serum irisin posttraining , whereas a 6-week protocol with two sessions/week with isometric exercises in young untrained females failed to alter irisin concentration in the circulation . Collectively, while earlier human and animal studies suggest that irisin does not respond to resistance exercise training, more recent investigations indicate that this type of training increases irisin in the circulation. We need more data to conclude whether muscle strengthening regimens can stimulate the production and release of irisin.
Irisin responses to chronic endurance training
Based on the results derived from cross-sectional studies, one would expect that irisin responds to endurance training regimens. Unfortunately, almost all human training studies (Table 2) failed to observe a training-induced response of FNDC5 mRNA expression or irisin in the circulation despite the utilization of a wide variety of exercise modes (walking, running, cycling), intensities (60%–90% of peak heart rate), durations (3–21 weeks) and frequencies (2–3 days/week) , , , , , . On the other hand, three other studies reported a rise in circulating irisin in older adults in response to a cardiovascular training program of moderate intensity , , . If age is a crucial factor for irisin response to endurance training remains to be seen.
Interestingly, results from animal training studies (Table 2) were entirely different with nine of them reporting an increase of serum irisin , , , , , , , ,  and five reporting no response , , , , . Strangely, in studies that showed a positive response to training, irisin increase was not always accompanied by a rise in FNDC5 gene expression , . The rise in irisin was paralleled by an increase of irisin and PGC-1a levels in skeletal muscle in only one animal study . Interestingly, in four of the studies that reported a rise in serum irisin, animals were fed a high-fat diet to promote obesity , , , . In these studies, serum irisin was negatively correlated with triglyceride levels, fat mass, total cholesterol levels, IR and restoration of plasma adiponectin , , . In fact, endurance exercise training in one case rescued irisin’s downregulation, a response that was coupled with an elevated activation of adenosine monophosphate-activated protein kinase (AMPK) and a rise in the expression of irisin and PGC-1a in muscle . These results coincide with findings of improved metabolic profile (i.e. insulin sensitivity, fat loss) following pharmacologic administration of irisin in animals .
The reason(s) for these discrepancies among human and animal studies remains to be elucidated. Differences may be attributed to either interspecies variations in irisin response or a higher total training load in animal studies (5 vs. 2–3 sessions/week). Collectively, results from human and animal studies point to different directions, and as such no firm conclusion can be reached on the effects of endurance-type training on irisin responses.
Irisin responses to interval exercise training
Three studies that have examined the effects of interval sprint training on irisin responses (Table 2) have produced conflicting results. Two studies that used an 8- and 9-week sprint interval training intervention with three sessions/week failed to alter irisin levels in the circulation , . Similarly, a shorter period of interval sprint training protocol (3 weeks, nine sessions) did not affect plasma irisin levels and muscle FNDC5 gene expression . In line with these findings, elite adolescent tennis (an interval-type activity) athletes monitored during their yearly training cycle exhibited no variation in serum irisin concentration . By contrast, a study that employed an interval exercise program of greater volume (36 sessions) and measured circulating irisin by quantitative mass spectrometry reported a rise of plasma irisin posttraining, suggesting that irisin may respond to higher training volumes . On the other hand, another study that used high-volume sprint training reported a 77% decline in serum irisin following training . Collectively, most studies suggest that interval-type exercise may not trigger an irisin response despite its intense nature.
Irisin responses to exercise training combining various exercise training protocols
So far, we presented studies that employed a single exercise mode as the training stimulus. What if a combination of exercise mode was used to provide a more intense and thorough muscle and energy system recruitment (Table 2)? When young obese males and females were subjected to mild circuit resistance exercise training that was combined with moderate cardiovascular activities (3 days/week for a total duration of 12 weeks), no changes were detected in skeletal muscle FNDC5 gene expression and serum irisin levels . Similar results were obtained when untrained middle-aged or obese adults trained with a combination of intense prolonged cycling and whole-body strength training for 21–24 weeks , , . By contrast, implementation of a similar training combination for 12 weeks resulted in increased FNDC5 mRNA levels in skeletal muscle and reduced irisin in plasma in middle-aged untrained males . It appears, so far, that only one out of five studies support the notion that a cross-training training protocol upregulates circulating irisin levels in humans.
Irisin responses to PA interventions
Similarly, to human training studies that utilized endurance-type exercise, investigations that manipulated daily PA levels (usually characterized by a significantly lower intensity but implemented daily) failed to observe changes in circulating irisin levels (Table 2). Specifically, a study with children engaged in increased PA by adding either 1 or 12 sports units/week over a period of 3 years reported an absence of irisin response postintervention . Similar results were reported also for preadolescents and middle-aged men who were also subjected to increased daily PA through sport participation and leisure time PA, respectively , . Animal studies, on the other hand, produced contradictory results. When rats were subjected to voluntary wheel running or standing PA in their cages, irisin in plasma and skeletal muscle failed to change , . However, mice fed a high-fat diet and increased their PA through voluntary wheel running upregulated UCP1, PGC-1a and FNDC5 in muscle in response . Hence, it may be concluded that daily PA may not offer a potent stimulus for irisin synthesis and release by skeletal muscle.
The big picture – does irisin has a physiological role in exercise-induced adaptations in humans?
Irisin concentration is most likely regulated by single exercise bouts, as longer training interventions have failed to provide a clear picture, mainly in humans. However, the time frame of exercise-induced irisin responses might be affected by factors such as the age, exercise intensity and/or the individuals’ conditioning level. Although irisin’s resting values are negatively associated with age in cross-sectional studies , , exercise-induced elevations of irisin were not age dependent . Despite individuals with higher PA or cardiovascular conditioning level exhibiting lower resting values of irisin than their sedentary or less fit counterparts, suggesting a negative association between irisin levels and fitness status , , no differences were seen among them in response to an exercise bout . Exercise intensity is critical, as most metabolic and physiological adaptations are intensity dependent. However, studies examining the interaction between exercise intensity and irisin release are lacking, and therefore we cannot come to a clear conclusion. Available data indicate significantly greater increases in circulating irisin levels postexercise with maximal workload (VO2max) as compared with submaximal workloads , .
Irisin is thought to act on subcutaneous WAT to promote browning and thus thermogenesis because FNDC5 overexpression in insulin-resistant animals resulted in fat tissue reduction . Irisin itself has consistently induced browning in brite adipocytes but not in brown adipocytes , , . Interestingly, irisin induced “browning” of mature human primary adipocytes, elevated cellular thermogenesis and inhibited adipogenesis . Although UCP1 expression and serum irisin increased in response to activation by a PPARα agonist , BAT activity may be unresponsive to exercise, and thus irisin may stimulate brite adipocytes only , . Studies suggest that irisin may not act on subcutaneous WAT, but it is rather related to browning at the level of visceral adipose tissue , . Some suggest that FNDC5 and not circulating irisin may be involved in the regulation of exercise-induced browning effect in adipose tissue , , . If irisin is involved in exercise-induced “browning” of fat tissue and increased thermogenesis, then one would expect to see a rise of UCP1 and FNDC5 expression in adipose tissue and muscle, respectively, in response to exercise. Although, increased fitness level has been associated with elevated FNDC5 expression in muscle , , systematic exercise training failed to alter FNDC5, PGC-1a or irisin expression in several cases , , , , , , , , , , , , , ,  and succeeded only in few , , , , . A study that measured the expression of UCP1 in human subcutaneous WAT reported that a combination of endurance and resistance exercise training was ineffective to alter UCP1, FNDC5 mRNAs and circulating irisin . Voluntary PA was ineffective to alter FNDC5 expression in WAT and serum irisin levels, but moderate 3-week exercise training increased irisin-dependent browning of WAT in mice . Therefore, and despite the promising results derived from in vitro and animal studies, exercise training studies are highly inconclusive reporting no apparent link between muscle PGC-1a and FNDC5 expression and circulating irisin in humans.
Irisin may also originate from adipose tissue, a tissue that does produce FNDC5 . Irisin secretion from adipose tissue may be reduced in response to systematic exercise training, indicating a discrete regulation of FNDC5/irisin production by skeletal muscle and adipose tissue . In fact, leptin and other myokines may differentially control FNDC5/irisin expression in muscle and fat, suggesting a cross talk between these tissues to regulate exercise-induced fat browning and thermogenesis and thus energy expenditure . In human studies, however, basal FNDC5 protein levels were lower in WAT compared with muscle, suggesting that higher irisin levels in adipose tissue may be attributed to transport from muscle via the circulation or increased release by other tissues , . Therefore, one should examine both tissues with respect to exercise-induced irisin responses. In conclusion, the controversy remains regarding the role of irisin in exercise-induced thermogenesis through fat browning.
Recent studies have assigned a potential anti-inflammatory role for irisin as well. Irisin seems to provide an anti-inflammatory protection in fat cells  probably by modulating the pro-inflammatory activity of immunocompetent cells such as macrophages through downregulation of reactive oxygen species production  and downstream pathways such as the TLR4/MyD88 , but human studies are lacking.
A metabolic role for FDNC5 and irisin is also supported by data findings , suggesting that defects of carbohydrate and fat metabolism as well as IR were ameliorated in obese animals and lipolysis was increased by an FDNC5/irisin-dependent mechanism. Irisin has also been implicated metabolically in skeletal muscle itself by two investigations that reported an irisin-dependent rise in AMPK phosphorylation and uptake of glucose and fatty acids in cultured human muscle cells (7, 23). Furthermore, irisin administration to cultured murine myocytes increased substrate oxidation, PGC-1α and irisin itself . If irisin is involved in the regulation of carbohydrate and fat metabolism, could irisin be linked to exercise-induced substrate metabolism? Although animal studies suggested that irisin could be a potential regulator of glucose metabolism through actions on tissues such as muscle, adipose tissue and liver, the exact mechanisms (i.e. receptor, signaling pathways) of such a glucoregulatory function at rest or during exercise are still unknown . However, irisin administration resulted in elevation of endothelial progenitor cells (EPCs) in the circulation, enhanced the function of bone marrow derived EPCs of diabetic mice and improved endothelial repair, suggesting that the beneficial effects of exercise on metabolic health may be mediated by irisin .
Emerging evidence suggests that irisin may be implicated in the central regulation of exercise-induced neuroprotection, energy balance and glucose homeostasis. FNDC5 mRNA and FNDC5/irisin immunoreactivity have been detected in different brain areas, and it has been hypothesized that irisin could act as a messenger regulating the cross talk between muscle and brain during exercise . Irisin was found to contribute to the neuroprotective effect of exercise against cerebral ischemia further supporting a role for the PGC-1a/FNDC5 axis in exercise-induced neuroprotection . Furthermore, evidence indicate that irisin may inhibit food intake at hypothalamic level in a dose-dependent manner, thereby contributing to energy balance regulation .
Animal studies have shown that irisin may be essential for musculoskeletal health as well. Treatment with recombinant irisin not only prevented cortical and trabecular bone loss during suspension and accelerated bone mass recovery following bone loss following suspension but also prevented muscle mass loss . Interestingly, low levels of circulating irisin have been proposed as a marker for muscle dysfunction, atrophy and prediction of sarcopenia . Moreover, irisin promoted osteogenesis via lineage-specific differentiation  and osteoblast proliferation/differentiation through P38/ERK/MAPK signaling in vitro . Therefore, evidence suggests that irisin may mediate the beneficial effects of exercise on bone and muscle tissues.
In conclusion, several in vitro and animal studies support that irisin may be a potential mediator of exercise-induced beneficial adaptation on health. However, these findings need to be verified by human studies in the future.
Although several studies provide promising evidence for irisin’s metabolic role, the methodologies used to detect irisin in human or animal circulation have received some criticism due to the limited sensitivity of the commercially available enzyme-linked immunosorbent assay (ELISA) irisin kits. This criticism is mainly focused on the fact that the human FNDC5 gene has an atypical translation start codon (ATA) instead of a typical ATG codon as in mouse or rat . It has been postulated that due to this codon misplacement, human FNDC5 may not even be translated, i.e. human irisin is probably a transcribed pseudogene and its synthesis is not realized in humans , . Another study, however, reported that human irisin is mostly translated from its non-ATG start codon reaching a molecular weight like that of other biologically active peptides in humans such as leptin and insulin .
The range of circulating irisin levels in healthy or unhealthy subjects varies from thousands to <1 ng/mL based on the available commercial ELISA detection kits that use polyclonal antibodies that have not been tested for cross-reactivity with other proteins (e.g. ApoA1) in serum/plasma samples . In the very first study to describe irisin, its detection was achieved by an antibody that binds to the intracellular domains of FNDC5 (hydrophobic and C-terminal) , and thus the protein bands identified as irisin were probably full-length secreted FNDC5 or other proteins with affinity for this antibody thereby questioning the existence of irisin in humans . This antibody was later removed and other novel antibodies binding to irisin’s FNIII domain were introduced . When used in Western blots, these antibodies identified protein bands ranging from ~12 kDa (the anticipated size of irisin) to 35 kDa . When four commercial irisin ELISA kits were validated against Western blotting, a significant cross-reactivity with non-specific proteins was revealed for human and animal serum samples . Moreover, when two commercially available kits were compared, they were both able to detect an exercise-induced irisin rise in the circulation, but there was a 10-fold difference among them  verifying a previous study, suggesting that available ELISA kits tend to bind to various epitopes of the irisin assay . Huh et al.  suggested that a sensitive kit for irisin measurement in blood should measure exclusively circulating irisin without containing epitopes with parts of irisin’s transmembrane or intracellular domains. Interestingly, a 20-kDa FNDC5 signature that was identified by mass spectrometry in human serum samples was not detected by commercial ELISA irisin kits, suggesting that irisin data reported by previous studies using such kits may be questionable . In other words, irisin measurement by such assays may be merely artifacts due to low antibody specificity even questioning the existence of irisin in human blood , , . Antibodies currently used in ELISA kits for irisin detection may seriously overestimate its concentration (5–278 times) compared with data derived from mass spectrometry . Unfortunately, the antibodies or antisera commonly utilized for Western blotting or ELISA assays produced numerous bands which did not correspond to the correct molecular weight of the irisin protein molecule of ~12 kDa . These discrepancies may be attributed to binding of these antibodies to different domains or forms of irisin. Specifically, irisin glycocylation or deglycosylation may affect antibodies’ detection potential , .
Although most studies examining exercise-induced changes in irisin have utilized ELISA assays, the only two studies that used mass spectrometry (with a very small sample size) suggest that irisin is in fact detected in human blood. Lee et al.  did measure an irisin-like peptide in human plasma by mass spectrometry. Jedrychowski et al.  verified Lee’s findings by detecting irisin in human blood using targeted mass spectrometry. These investigators synthesized their own irisin peptides that contained valine residues enriched with carbon 13. Following removal of albumin and immunoglobulins and deglycosylation of plasma samples, they identified a protein band of 12 kDa that corresponded to the size of deglycosylated irisin and verified that human irisin is translated despite the existence of the non-typical ATA start codon . Irisin appeared in the blood of inactive males at a concentration of ~3.6 ng/mL, and this concentration may rise to approximately 4.3 ng/mL in response to exercise training . Although this study used a very limited number of subjects (n=6), its state-of-the-art methodology of irisin measurement provides valuable information on whether irisin exists in humans or not. However, investigators warned that irisin levels might have been underestimated due to protein loss during sample preparation .
Although evidence has been provided for the existence of human irisin in the circulation, results of studies investigating its responses to exercise must be translated with caution due to limitations of commercially available analytical assays. Irisin glycosylation, the existence of irisin in various protein fragments and free or bound forms in the circulation and the extensive cross-reactivity of available antibodies with numerous protein molecules complicate the interpretation of experimental findings . Future efforts need to focus on the production of monoclonal antibodies specific for various forms of irisin (e.g. non-glycosylated vs. glycosylated, free vs. bound), use of negative controls, develop proper matrix in ELISA assays, establish better guidelines for preanalytical conditions to limit treatment-related protein modification (e.g. sample preparation, optimal temperature range to prevent denaturation, storage etc.) and develop resting and exercise reference values for each irisin form , . Scientists should also perform validation trials prior to actual study measurements .
Because of its wide association with a great number of cytokines and receptors associated with diseases, irisin appears as a promising factor to explain numerous metabolic adaptations induced by exercise. However, future well-controlled subjects need to confirm or refute a role of irisin in exercise-induced energy metabolism. Although increased irisin release in response to administration of peroxisome proliferator-activated receptors (PPAR-α) agonists was accompanied by adipose tissue browning, reduced fat tissue and IR in obese animals is exciting and promising news, more research is needed to accept or refute a role of irisin in basal and exercise energy metabolism. It remains to fully elucidate the mode of action as well as the target tissues and end-results of irisin actions during resting and exercise conditions. A recent review concluded that even when irisin was measured with the same ELISA assay (PP, EK-067-52), it was not associated with resting energy expenditure or fatness markers . The validation of ELISA and Western blot assays will aid in this aspect. A wiser approach for experimental exercise studies would be to measure not only circulating irisin but also PGC-1α, FNDC5 and UCP1 mRNA in muscle and adipose tissue. Therefore, based on the current knowledge and methodological shortcomings, this review cannot endorse a specific role for irisin in human metabolism at rest or in response to acute or chronic exercise.
The author wishes to thank Dr. Ioannis Papassoririou for his valuable insight and assistance.
Author contributions: The author has accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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