FNDC5 is a transmembrane protein present in cells both within and outside of the central nervous system, with PGC1a (an exercise dependent transcriptional coactivator) dependent expression1]. It was discovered in 2012 by Bostrom et al.[2], and found to be cleaved into a water soluble protein called irisin which has been detected in both human plasma and CSF[3]. FNDC5 and Irisin have been linked to many peripheral phenomena including brown fat adipogenesis[2] and telomere length maintenance[4], as well as neurological effects such as BDNF release.[1] This makes both FNDC5 and irisin key protein targets in future treatment plans for metabolic diseases like obesity, and neurodegenerative diseases such as Alzheimer's Disease. Potential irisin receptors, the downstream effects of irisin, and the effects of membrane bound FNDC5 all require further investigation.
////////Browning of white fat: does irisin play a role in humans? [Elsen M et al. (2014) The discovery of irisin as an exercise-regulated myokine inducing browning of WAT has gained interest as a potential new strategy to combat obesity and its associated disorders, such as type 2 diabetes. However, there are inconsistencies regarding the relevance of irisin in humans. The regulation of FNDC5 mRNA expression by exercise and contraction could not be reproduced by a number of human studies using several exercise protocols and in vitro approaches. Furthermore, the nature of FNDC5 fragments and the presence of irisin in humans are questionable and probably contribute to conflicting data obtained with commercially available ELISA kits. Most importantly, the information regarding the concentration of circulating irisin in humans is not clear, as different studies using different kits measure irisin levels in a wide range. Data about the role of irisin in states of human obesity and metabolic diseases are conflicting and, in some cases, changes in irisin levels have been observed; they were only moderate in 10-20%. Independent of the presence and regulation of FNDC5/irisin in humans, the application of recombinant irisin could still represent a therapeutic strategy to fight obesity. However, the current data obtained from human cell models reveal that FNDC5/irisin has no effect on browning of the major WAT depots in humans and is likely to selectively target a small subpopulation of adipocytes, which are located in classical BAT regions, such as the supraclavicular adipose tissue. Thus, other candidates, such as BMP7 or CNPs, seem to be more prominent candidates as inducers of browning in humans.//////////////////
A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Boström P et al. (2012) Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-γ co-activator-1 α (PGC1-α). Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.//////////////////
Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry. Jedrychowski MP et al. (2015) Exercise provides many health benefits, including improved metabolism, cardiovascular health, and cognition. We have shown previously that FNDC5, a type I transmembrane protein, and its circulating form, irisin, convey some of these benefits in mice. However, recent reports questioned the existence of circulating human irisin both because human FNDC5 has a non-canonical ATA translation start and because of claims that many human irisin antibodies used in commercial ELISA kits lack required specificity. In this paper we have identified and quantitated human irisin in plasma using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. This precise state-of-the-art method shows that human irisin is mainly translated from its non-canonical start codon and circulates at ∼3.6 ng/ml in sedentary individuals; this level is increased to ∼4.3 ng/ml in individuals undergoing aerobic interval training. These data unequivocally demonstrate that human irisin exists, circulates, and is regulated by exercise.//////////////////
NCBI Summary:
This gene encodes a secreted protein that is released from muscle cells during exercise. The encoded protein may participate in the development of brown fat. Translation of the precursor protein initiates at a non-AUG start codon at a position that is conserved as an AUG start codon in other organisms. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]
General function
Ligand
Comment
origin of ligand
Cellular localization
Secreted
Comment
Higher circulating irisin levels in patients with polycystic ovary syndrome:a meta-analysis. Wang C et al. (2017) Insulin resistance (IR) has been reported to be highly associated with the pathogenesis of polycystic ovary syndrome (PCOS). Although irisin, a newly identified myokine that may be closely associated with IR, has been implicated in the development of PCOS, the results are still ambiguous. We performed this meta-analysis to compare the circulating irisin levels between PCOS and healthy women and assess the association of irisin with IR. Published works were retrieved from PubMed and Embase databases using combinations of 'irisin' and ('polycystic ovary syndrome' or 'PCOS'). Eight studies involving 1918 PCOS patients and 528 controls were included in the meta-analysis. Publication bias was observed using a funnel plot and Egger's regression asymmetry test. The pooled data indicated that the levels of irisin were at least 45.78 ng/ml [95% confidence interval (CI)] (12.45, 79.12, p = .007) higher in patients with PCOS than that in the healthy controls. Additionally, we did not observe a significant correlation between circulating irisin levels and IR in study populations, although the results may not be reliable for small sample sizes. The current meta-analysis suggested that irisin might contribute to the development of PCOS independent of IR.//////////////////
Ovarian function
Steroid metabolism
Comment
The myokine irisin: localization and effects in swine late medium and large antral ovarian follicle. Basini G et al. (2020) Irisin is mainly synthesized by skeletal muscle tissue, where it is believed to be responsible for the benefits of exercise on metabolism and cardiovascular system. In adipose tissue, its best-known effect is the browning of white adipocytes, resulting in the increase of thermogenesis and energy expenditure. As it has been largely documented that metabolic dysfunctions can frequently be associated with reductions in fertility, the possible involvement of this molecule in the regulation of reproductive processes represents an issue to be addressed. On this basis, the first aim of this work was the evaluation of the presence of irisin in the swine ovary; then, we investigated the expression of the associated molecules FNDC5, PGC-1α, and PPAR-γ. To verify a potential modulatory role both on ovarian function and on redox status, cell growth, steroidogenesis, production of superoxide anion and nitric oxide, the nonenzymatic antioxidant scavengers, were assessed in vitro on granulosa cells treated with increasing concentrations of irisin (50, 100, and 150 ng/mL). The data collected demonstrate the presence of irisin in swine ovarian follicle. Moreover, the highest concentrations tested stimulated metabolic activity and inhibited cell proliferation (P < 0.05); the peptide exerted a biphasic effect on progesterone (P < 0.01) production and, at the highest concentrations, inhibited nitric oxide while stimulated the nonenzymatic antioxidant power (P < 0.05). Superoxide anion and estradiol 17β were unaffected. The demonstration of the local presence of irisin at the ovarian level and the highlighted effects allow us to qualify this molecule as a potential physiological regulator of follicular function.//////////////////
The association between circulating irisin levels and different phenotypes of polycystic ovary syndrome. Zhang L et al. (2018) The diagnosis of polycystic ovary syndrome (PCOS) is based on a combination of various clinical phenotypes in each patient. However, insulin resistance (IR) and dysmetabolism are not included in the diagnostic criteria of PCOS. Therefore, the definition of PCOS is controversial. The objective of this study is to investigate whether some PCOS phenotypes can be predicted by a circulating biomarker related to IR and metabolic dysfunction in PCOS women. One hundred and seventeen women with PCOS and 95 healthy women were recruited for this study. All individuals were assessed by the phenotypic and metabolic characteristics related to PCOS. A euglycemic-hyperinsulinemic clamp was performed to assess insulin sensitivity. Circulating irisin concentrations were determined with ELISA. In our PCOS cohort, 65.8% of individuals were found to have hyperandrogenism. 83.8% had chronic oligoanovulation, and 80.3% of subjects showed polycystic ovaries. According to the diagnostic criteria of PCOS, 30.8% of PCOS subjects were diagnosed with the classic phenotype. In addition, 65.8% of PCOS women had insulin resistance. Serum irisin levels were significantly higher in PCOS women compared with healthy women. However, PCOS women with a normoandrogenic phenotype had similar circulating irisin levels as healthy women. PCOS women with the normoandrogenic phenotype had a low homeostasis model assessment of insulin resistance (HOMA-IR) and higher M-values than PCOS women with other phenotypes. Circulating irisin levels were associated with hyperandrogenism, but not with oligoanovulation or PCO morphology. Circulating irisin may allow physicians to establish which women merit screening by a biomarker for PCOS.//////////////////
Elevated Circulating Levels of Irisin and the Effect of Metformin Treatment in Women with Polycystic Ovary Syndrome. Li M et al. (2015) Context: Polycystic ovary syndrome (PCOS) is an insulin resistance (IR) state, like obesity and type 2 diabetes mellitus (T2DM). Although previous studies have suggested a correlation between irisin and the metabolic parameters associated with obesity and T2DM, the results have been inconsistent. Objective: Our objective was to 1) determine circulating irisin levels in women with PCOS and control subjects, 2) examine the relationship of irisin and conventional markers of insulin resistance, and 3) examine irisin changes with interventions modulating IR in PCOS women. Patients and Design: This study was comprised of a series of cross-sectional and interventional studies of 178 PCOS and 123 healthy women from the general population and outpatients of the Internal Medicine Department at the Second Affiliated Hospital, Chongqing Medical University, China. 47 women with PCOS were randomly assigned to 6 months of oral metformin (850 mg bid). OGTT and EHC were performed to assess glucose tolerance and insulin sensitivity. Outcome measures were IR (AUC Insulin and M values) on an OGTT and EHC, irisin levels, and metabolic markers. Results: Circulating irisin was significantly higher in both overweight/obese (BMI≥25 kg/ m(2)) and PCOS women (P<0.01). Circulating irisin levels correlated with BMI, WHR, FAT%, TG, TC, LDL-C, AUC Insulin, HOMA2-IR, M values and FAI. During EHC, short-term hyperinsulinemia exhibited an inhibitory effect on irisin levels. After 6 months of metformin treatment, there was a significant decrease in circulating irisin in PCOS women following improved IR. Conclusions: These data suggest that irisin may be a useful marker of IR in PCOS women.//////////////////
Expression regulated by
Comment
Ovarian localization
Comment
Circulating irisin in patients with polycystic ovary syndrome: a meta-analysis. Cai X et al. (2017) There is growing interest in exploring circulating (plasma/serum) irisin in polycystic ovary syndrome (PCOS) patients. This meta-analysis aimed to summarize the evidence assessing circulating irisin changes in this population. A systematic search was conducted in three databases: PubMed, Cochrane Library and Web of Science, for studies reporting irisin in PCOS patients compared with healthy controls or stratified by body mass index (BMI), or assessing irisin response to hyperinsulinemia. Effect sizes (Cohen's d with 95% confidence intervals CI]) were calculated using random-effects models. Eight studies with 918 PCOS patients and 528 healthy controls were included. Results showed that circulating irisin was higher in PCOS patients than in overall healthy controls (d = 0.37, 95% CI 0.05 to 0.70), but not compared with BMI-matched or age- and BMI-matched controls. Circulating irisin was higher in PCOS patients with higher BMI than lower (d = 0.36, 95% CI 0.16 to 0.56). Circulating irisin decreased 2 h later in response to euglycemic hyperinsulinemia in PCOS patients with a larger magnitude than healthy controls (d = -0.32, 95% CI -0.53 to -0.11). In summary, with adjustment for BMI, circulating irisin in PCOS patients seems comparable to healthy controls, but its response to hyperinsulinemia might be impaired.//////////////////
Serum irisin levels in patients with polycystic ovary syndrome. [Bostancı MS et al. (2015) Polycystic ovary syndrome (PCOS) is clinically heterogeneous endocrine disorders. Insulin resistance-related proteins play a role in the etiopathogenesis of PCOS. Irisin is a newly identified myokine which act like adipokines. Irisin has been shown to be associated with the insulin resistance and metabolic syndrome. The purpose of this study was to determine the serum levels of irisin in PCOS patients and evaluate the correlations with other metabolic and hormonal parameters. Thirty-five PCOS patients and 35 matched healthy controls were enrolled to study. Serum irisin levels, anthropometric, hormonal and metabolic parameters including HOMA-IR were measured. Linear regression analysis was employed to study the relationship between irisin and hormonal and metabolic parameters. Serum irisin level in PCOS patients (mean value; 0.491±0.145 µg/mL) was significantly elevated when compared to control group (mean value 0.281±0.138 µg/mL) (p < 0.001). Linear regression analysis showed that serum irisin was positively associated with body mass index, luteinizing hormone, fasting insulin and total cholesterol in the overall patient population but not for PCOS group alone (p < 0.05). Serum irisin level of PCOS patients was high compared to that of healthy control subjects. In patients with PCOS, this situation may be due to insulin resistance, when there is leptin resistance or metabolic syndrome.//////////////////
Circulating irisin and GIP are associated with the development of polycystic ovary syndrome. Chang CL 2014 et al.
Context: Polycystic ovary syndrome (PCOS) is characterized by oligo- or anovulation, polycystic ovary, and/or hyperandrogenism. In addition, many PCOS patients present with dyslipidemia, insulin resistance, and obesity. Due to the complexity of this disorder, the causes of PCOS remain to be identified. Objectives: Because many PCOS patients have a propensity to develop dyslipidemia, we hypothesized that the brown adipose-differentiation factor, irisin, and the glucose-dependent insulinotropic peptide (GIP) play a role in the development of PCOS. Design and Setting: Serum hormone levels in 202 PCOS patients and 47 healthy women were investigated. Patients or Other Participants: Patients were stratified based on the presence/absence of metabolic syndrome risk factors, as defined by the National Cholesterol Education Program's Adult Treatment Panel III report (ATPIII [+] and ATPIII [-]), or BMI (healthy-weight and overweight). Main Outcome Measures: We measured serum irisin, GIP, luteinizing hormone (LH), anti-Mullerian hormone (AMH), and androgens as well as metabolic indices including HOMA-IR, ISI Matsuda, and QUICKI. Results: PCOS patients exhibited hyperandrogenism, dyslipidemia, and hyperinsulinism as well as elevated LH and AMH levels. In addition, fasting irisin level (p < .001) and glucose-induced GIP response (p = .013) in PCOS patients were significantly elevated as compared to those of control women. Remarkably, levels of fasting irisin and glucose-induced GIP response remained significantly elevated in ATP III [-] PCOS and healthy-weight PCOS patients when compared to matched controls. Analysis of the effect size indicated that both fasting irisin and glucose-induced GIP response are significant risk factors for PCOS with odds ratios of 6.63 and 4.21, respectively. Conclusion: Although there is as yet no evidence for a causal link between irisin and/or GIP and PCOS, it is conceivable that irisin and GIP might contribute to the the develpment of PCOS and may also represent novel PCOS biomarkers.
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Follicle stages
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Irisin deletion induces a decrease in growth and fertility in mice.
Reprod Biol Endocrinol. 2021 Feb 13;19(1):22.Bone mineral content in smokers. McDermott MT et al. (1988) We did a cross-sectional evaluation of the effect of heavy cigarette smoking on bone mass using single photon absorptiometry (SPA) of the radius in 35 smokers (24 women, 11 men) and 35 nonsmokers (24 women, 11 men). Individuals from the two groups were carefully matched for sex, age, weight, height, calcium intake, and, for women, menopausal history and estrogen use. We found no differences between smokers and nonsmokers at the middle or distal portion of the radius. This suggests that smoking has no direct effect on appendicular bone mass; however, it may still influence bone loss indirectly through effects on other factors such as age at menopause, body weight, diet, and possibly physical activity.//////////////////