The p38-PGC-1α-irisin-betatrophin axis: Exploring new pathways in insulin resistance. Sanchis-Gomar Fabian,Perez-Quilis Carme Adipocyte The discovery of irisin as a novel and promising peptidic hormone has raised hopes regarding the hypothesis that irisin may provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions since this hormone may prove to be therapeutically and clinically beneficial. In addition, a new hormone, betatrophin, has recently been identified by Yi and coworkers. Both hormones are connected by a new pathway clearly involved in insulin resistance. We hypothesize here how these hormones may be linked and their possible implications in both aged-reduced restricted regenerative capacity and dedifferentiated β cells of diabetic patients. 10.4161/adip.27370
    Growth Hormone Treatment Increases Plasma Irisin Concentration in Patients with Turner Syndrome. Wikiera B,Zawadzka K,Łaczmański Ł,Słoka N,Bolanowski M,Basiak A,Noczyńska A,Daroszewski J Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme Irisin (Ir) deficiency may be a contributing factor in metabolic disease. This study aimed to investigate the effect of supraphysiological doses of recombinant human growth hormone (rhGH) on Ir plasma concentration in relation to metabolic disorders, including obesity and other components of metabolic syndrome. We studied 36 girls with Turner syndrome (mean age 8.2 years) treated with rhGH (0.05 mg/kg/day). Anthropometric data and fasting blood levels [e. g., Ir, insulin, glucose, glycated hemoglobin (HbA1c), IGF-1, IGFBP-3, cholesterol, insulin resistance (HOMA-IR), and β-cell function (HOMA-β)] were analyzed prior to and following rhGH therapy [mean (SD) follow-up of 1.47 (0.89) years]. Insulin sensitivity (Matsuda index) was calculated before and after the glucose load. Following rhGH therapy, an increase in IGF-1 [mean (SD) of 119.40 (62.47) ng/ml to 439.08 (209.91) ng/ml, p=0.000], Ir [2.10 (1.03) μg/ml to 2.48 (0.78) μg/ml, p=0.036], HOMA-IR [median (IQR) of 0.64 (0.45-1.30) to 0.92 (0.67-2.36), p=0.0206], and HOMA-β values [45.00 (27.69-72.00) to 81.53 (51.43-132.00), p=0.0447] were observed. Multiple regression analysis yielded no associations between Ir and metabolic and hormonal parameters before rhGH treatment; however, on rhGH, the model (R=0.56, adjusted R0.45) showed positive associations between Ir and IGF-1 standard deviation score and HbA1c, and negative associations between Ir and fasting blood glucose, HDL-cholesterol, and triglycerides. Despite manifestation of insulin resistance, rhGH application had a positive effect on Ir regulation, and restored physiological conditions of lipid and glucose metabolism. 10.1055/s-0042-119788
    The Effect of Kinesitherapy Exercises on the Level of Irisin among Females with Cardio-vascular diseases depending on the body mass and hormonal status. Kuznik B I,Davydov S O,Stepanov A V,Morar N V Patologicheskaia fiziologiia i eksperimental'naia terapiia The observation was conducted on 41 female subjects age 32 to 69 with compensated cardio-vascular diseases. 23 of the subjects had an increased body mass index (BMI). It was established that the older the females the less of the irisin muscle hormone is found in the blood. In the subjects with a higher BMI the level of irisin in the blood is also higher. Direct correlations were found between the level of irisin and the level of female sex hormones - estrogen and progesterone. Under the effect of kinesitherapy exercises the level of irisin in females with normal BMI increases; whereas in the females with a higher BMI it generally stays the same or is decreased. The characteristics of irisin’s response to the kinesitherapy exercises depends on its original level, the intensity of physical exercise and the subject’s physique.
    The serum level of irisin, but not asprosin, is abnormal in polycystic ovary syndrome patients. Chang Chia Lin,Huang Shang Yu,Hsu Ya Chiung,Chin Tzu Hsuan,Soong Yung Kuei Scientific reports Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, oligo- or anovulation, and/or polycystic ovary. It frequently presents with dyslipidemia and insulin resistance. Recent studies have shown that the white adipose tissue-derived asprosin is elevated in humans with insulin resistance. Because many PCOS patients have a propensity to develop dyslipidemia and/or insulin resistance, asprosin metabolism could be dysregulated in PCOS patients. Accordingly, we investigated serum levels of asprosin, irisin, GIP, androgens, LH, glucose, insulin, and lipids as well as HOMA-IR, QUICKI and ISI in a cohort of 444 PCOS patients and 156 controls. Patients were stratified based on metabolic syndrome risk factors (ATPIII [+] and [-] groups), or BMI (overweight and lean groups). The irisin level was significantly correlated with body weight, SBP, DBP, Ferriman-Gallwey score, and levels of TSH, triglycerides, glucose and insulin in the overall population, and was elevated in ATPIII(+) and overweight PCOS patients compared to corresponding controls. By contrast, asprosin levels in PCOS, ATPIII(+), or overweight patients were similar to those of corresponding controls. This finding indicated that the regulation of irisin, but not asprosin, metabolism is abnormal in PCOS patients, and this metabolic characteristic is distinctly different from that of diabetes patients. 10.1038/s41598-019-42061-9
    Hypothesis: Irisin is a metabolic trigger for the activation of the neurohormonal axis governing puberty onset. Wahab Fazal,Shahab Muhammad,Behr Rüdiger Medical hypotheses A large body of data suggests that body weight influences puberty onset and adult reproduction. However, the underlying mechanism of how body weight influences puberty onset and fertility is not completely understood. The hypothalamic neuronal circuit regulating reproduction is restrained by inhibitory signals during childhood. At the time of puberty, these inhibitory signals are weakened and supplanted by stimulatory signals that, in turn, stimulate the release of gonadotropin-releasing hormone (GnRH) - a hypothalamic neuropeptide governing reproduction. A number of studies, however, suggest that puberty commencement occurs when body (fat) weight reaches a certain threshold, which is critical for the initiation of puberty and for support of the adult reproductive function. Previously, various signals have been studied which might link body (fat) weight-related information to the hypothalamic neuronal network regulating reproduction. However, the nature of the signal(s) that may link body fat and/or muscle mass with the hypothalamic neuronal network governing reproduction is still unclear. It has been intuitively speculated that augmentation of such signal(s) will cause a restriction of inhibitory input and activation of stimulatory input to GnRH secreting neurons at the time of puberty onset. Therefore, the unveiling of such signal(s) will greatly help in understanding the mechanism of puberty onset. Recently, it has been shown that expression of fibronectin type III domain containing-5 (FNDC5) mRNA in central and peripheral tissues upsurges during postnatal development, especially around the time of puberty onset. Moreover, the systemic level of irisin - one of the protein products of the FNDC5 gene that is secreted as myokine and adipokine - also rises during postnatal development and correlates with the timing of puberty onset. Therefore, we propose here that irisin might serve as a possible signal for linking body fat/muscle mass with the hypothalamic center governing reproductive function. We hypothesize that irisin acts as a trigger for the activation of the hypothalamic neuronal network monitoring the onset of puberty. 10.1016/j.mehy.2016.08.003
    Circulating irisin and glucose-dependent insulinotropic peptide are associated with the development of polycystic ovary syndrome. Chang Chia Lin,Huang Shang Yu,Soong Yung Kuei,Cheng Po Jen,Wang Chin-Jung,Liang I Ting The Journal of clinical endocrinology and metabolism 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 body mass index (healthy-weight and overweight). MAIN OUTCOME MEASURES:We measured serum irisin, GIP, LH, anti-Mullerian hormone (AMH), and androgens as well as metabolic indices including homeostasis model assessment-insulin resistance, Matsuda's sensitivity index, and quantitative insulin-sensitivity check index. 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 development of PCOS and may also represent novel PCOS biomarkers. 10.1210/jc.2014-1180
    Physiological and pharmacological effects of melatonin on remote ischemic perconditioning after myocardial ischemia-reperfusion injury in rats: Role of Cybb, Fas, NfκB, Irisin signaling pathway. Gul-Kahraman Kubra,Yilmaz-Bozoglan Merve,Sahna Engin Journal of pineal research It has been found that remote organ/limb temporary ischemia, known as remote ischemic conditioning, can provide protection against the formation of lethal ischemic outcome. Current evidence suggests that aging and age-releated comorbidities impair the cardioprotective effects of conditionings. In conjuction with aging, decrease in melatonin synthesis from pineal gland can have role in the pathogenesis of aging and age-related cardiovascular diseases. In this study, we investigated the effects of remote ischemic perconditioning (RIPerC) and physiological and pharmacological concentrations of melatonin on the infarct size, Fas gene, cytochrome b-245 beta chain (Cybb) gene, nuclear factor-kappa B (NfκB), and irisin using an in vivo model of myocardial ischemia/reperfusion (I/R) injury. Sprague-Dawley rats that were divided into two groups first as non-pinealectomized (Non-Px) and pinealectomized (Px), and then (a) Control; (b) I/R (30-minute ischemia, 120-minute reperfusion caused by left coronary artery ligation); (c) I/R + RIPerC (when myocardial ischemia initiated, three cycles of 5-minute occlusion followed by 5-minute reperfusion); (d) I/R + Mel; (e) Px; (f) Px + I/R; (g) Px + I/R + RIPerC; (h) Px + I/R + RIPerC + Mel groups. The infarct size was determined by TTC staining and analyzed by the ImageJ program. Molecular parameters were evaluated by qRT-PCR and Western blot. Results showed that increased infarct size in Non-Px groups decreased with RIPerC and melatonin. However, increased infarct size in Px groups was decreased minimally with RIPerC and significantly decreased with RIPerC + Melatonin. Fold change in Fas gene was associated with the infarct size. RIPerC and melatonin reduced expressions of Cybb, NfκB, and irisin genes. The physiological release and pharmacological concentration of melatonin may improve protective effect of RIPerC against I/R-induced infarct size by modulating Cybb, Fas, NfκB, Irisin signaling pathways. 10.1111/jpi.12589
    Elevated circulating levels of irisin and the effect of metformin treatment in women with polycystic ovary syndrome. Li Minyan,Yang Mengliu,Zhou Xiaoxin,Fang Xia,Hu Wenjing,Zhu Wei,Wang Cong,Liu Dongfang,Li Shengbing,Liu Hua,Yang Gangyi,Li Ling The Journal of clinical endocrinology and metabolism 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. Forty seven women with PCOS were randomly assigned to 6 months of oral metformin (850 mg bid). The oral glucose tolerance test (OGTT) and the euglycemic-hyperinsulinemic clamp (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 (body mass index [BMI] ≥ 25 kg/m(2)) and PCOS women (P < .01). Circulating irisin levels correlated with BMI, WHR, FAT%, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), AUC(Insulin), homeostasis model assessment of insulin resistance (HOMA2-IR), M values, and free androgen index (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. 10.1210/jc.2014-2544
    Role of irisin in androgen-deficient muscle wasting and osteopenia in mice. Iemura Shunki,Kawao Naoyuki,Okumoto Katsumi,Akagi Masao,Kaji Hiroshi Journal of bone and mineral metabolism Androgen deficiency plays a crucial role in the pathogenesis of male osteoporosis and sarcopenia. Myokines have recently been identified as humoral factors that are involved in the interactions between muscle and bone; however, the influence of androgen deficiency on these interactions remains unclear. Therefore, we herein investigated the roles of humoral factors linking muscle to bone using orchidectomized mice with sarcopenia and osteopenia. Orchidectomy (ORX) significantly reduced muscle mass, grip strength, and trabecular bone mineral density (BMD) in mice. Among the myokines examined, ORX only significantly reduced fibronectin type III domain-containing 5 (Fndc5) mRNA levels in both the soleus and gastrocnemius muscles of mice. In simple regression analyses, Fndc5 mRNA levels in the soleus muscle positively correlated with trabecular BMD, but not cortical BMD. The administration of irisin, a product of Fndc5, significantly protected against the decrease induced in trabecular BMD, but not muscle mass, by androgen deficiency in mice. In conclusion, the present results demonstrated that androgen deficiency decreases the expression of irisin in the skeletal muscle of mice. Irisin may be involved in muscle/bone relationships negatively affected by androgen deficiency. 10.1007/s00774-019-01043-7
    Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues. Dong Jiangling,Dong Yanjun,Dong Yanlan,Chen Fang,Mitch William E,Zhang Liping International journal of obesity (2005) BACKGROUND/OBJECTIVE:In mice, a high-fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities. SUBJECTS/METHODS:C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using small hairpin RNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their responses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or irisin. Isolated peritoneal macrophages were treated with myostatin or irisin to determine whether myostatin or irisin induce inflammatory mechanisms. RESULTS:In HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In HFD-fed mice, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both the muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue, whereas stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by irisin. Myostatin inhibition increased peroxisome proliferator-activated receptor gamma, coactivator 1α expression and irisin production in the muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types. CONCLUSIONS:These results uncover a metabolic pathway from an increase in myostatin that suppresses irisin leading to the activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well as the shortage of brown/beige fat in obesity. 10.1038/ijo.2015.200
    Serum irisin levels in patients with polycystic ovary syndrome. Bostancı M S,Akdemir N,Cinemre B,Cevrioglu A S,Özden S,Ünal O European review for medical and pharmacological sciences OBJECTIVE: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. PATIENTS AND METHODS: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. RESULTS: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). CONCLUSIONS: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.
    Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Ergul Erkec Ozlem,Algul Sermin,Kara Mehmet Neurological research OBJECTIVES:In this study, we aim to reveal the alterations (due to seizure) in the serum and brain levels of nesfatin-1, ghrelin and irisin after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. METHODS:35 Wistar albino rats were randomly divided into five groups: Control, Acute Pentylenetetrazole group (APTZ), Acute Pentylenetetrazole+ Valproate group (AVPA), PTZ kindling group (PTZk) and PTZ kindling+ Valproate group (KVPA). Serum and brain levels of ghrelin, nesfatin-1 and FNDC5/irisin were determined with ELISA. RESULTS:Serum levels of ghrelin were significantly decreased in APTZ and PTZk groups compared to the control (p < 0.01). There was a statistically significant decrease in brain levels of ghrelin in all groups compared to the control group (p < 0.01). There was a statistically significant increase in serum nesfatin-1 levels in the APTZ and PTZk groups compared to the control (p < 0.05). Serum levels of nesfatin-1 were similar to the control group in both the acute and the chronic treatment groups. There was a statistically significant increase in brain nesfatin-1 levels of the KVPA group compared to the control (p < 0.05). Serum and brain levels of FNDC5/irisin were found significantly increased in APTZ, AVPA and PTZk groups compared to the control (p < 0.01). CONCLUSIONS:Statistically significant alterations were detected in the serum and brain levels of these three peptides in both the PTZ-induced chronic epilepsy model and acute seizure model. The results of this study may suggest that the increase in FNDC5/irisin and nesfatin-1 levels, and the decrease in ghrelin levels may contribute to seizure pathophysiology. However, further studies are needed in order to confirm our hypothesis. 10.1080/01616412.2018.1503992
    Serum and follicular fluid irisin levels in poor and high responder women undergoing IVF/ICSI. Acet M,Celik N,Acet T,Ilhan S,Yardim M,Aktun H L,Basaranoglu S,Deregozu A,Aydin S European review for medical and pharmacological sciences OBJECTIVE:We examined the follicular fluid (FF) and serum levels of irisin in high and poor responders undergoing IVF/ICSI to test whether irisin has a role in the metabolic regulation of energy homeostasis in growing follicle. PATIENTS AND METHODS:Twenty infertile women with PCOS and 20 poor responder participants undergoing controlled ovarian stimulation (COS) with GnRH antagonist protocol for IVF/ICSI treatment were allocated. Blood was obtained at the time of oocyte retrieval. The follicular fluid content of mature follicles was collected from both high and poor responder women. Irisin levels were measured by using EIA. RESULTS:There was no significant difference between serum and FF-irisin levels in women with PCOS. (11.18 ± 5.14 µg/mL vs. 11.06 ± 4.93 µg/mL, p < 0.96). In contrast, serum levels of irisin in poor responders were significantly higher than in the FF-irisin levels (13.13 ± 4.27 µg/mL vs. 10.09 ± 4.14 µg/mL, p < 0.01). FF-irisin levels of PCOS subjects were positively and significantly correlated with serum levels of irisin (r: 0.81, p < 0.00). Serum irisin was positively associated with serum levels of total testosterone but was negatively associated with HOMA-IR in the overall patient population. FF-irisin levels were also noted to be negatively correlated with HOMA-IR. Although there is no correlation between serum irisin and AMH levels, FF irisin levels were negatively correlated with serum AMH levels in PCOS subjects. Contrary to PCOS group there were no significant correlation between serum and FF-irisin levels in poor responder group (r: 0.21; p < 0.35). CONCLUSIONS:The present study is the first attempt to explore the role of irisin in oocyte development by measuring FF and serum levels of this molecules in patients with poor and high responders undergoing IVF/ICSI.
    Circulating Irisin Levels in Children With GH Deficiency Before and After 1 Year of GH Treatment. Ciresi Alessandro,Pizzolanti Giuseppe,Guarnotta Valentina,Giordano Carla The Journal of clinical endocrinology and metabolism Purpose:To evaluate circulating irisin levels in children with GH deficiency (GHD) and any relation with clinical and metabolic parameters. Patients:Fifty-four prepubertal children (mean age, 7.4 ± 0.8 years) with idiopathic GHD treated with GH for at least 12 months and 31 healthy short children as control subjects. Methods:Body height, body mass index (BMI), waist circumference (WC), IGF-I, HbA1c, lipid profile, fasting and after-oral glucose tolerance test glucose and insulin, insulin sensitivity indices, and irisin levels were evaluated at baseline and after 12 months of GH replacement (GHR). Results:At baseline, children with GHD, in addition to having lower growth velocity (P < 0.001), GH peak after stimulation tests (both P < 0.001), and IGF-I (P < 0.001), showed significantly lower irisin (P < 0.001) and higher BMI (P < 0.001) and WC (P = 0.001), without any difference in metabolic parameters, than control subjects. After GHR, children with GHD showed a significant increase in height (P < 0.001), growth velocity (P < 0.001), IGF-I (P < 0.001), fasting glucose (P = 0.002) and insulin (P < 0.001), homeostasis model assessment estimate of insulin resistance (P < 0.001), and irisin (P = 0.005), with a concomitant decrease in BMI (P = 0.001) and WC (P = 0.003). In multivariate analysis, the independent variables significantly associated with irisin were BMI (P = 0.002) and GH peak (P = 0.037) at baseline and BMI (P = 0.005), WC (P = 0.018), and IGF-I (P < 0.001) during GHR. Conclusions:We report that GHR leads to an increase in irisin levels, strongly related to a decrease in BMI and WC, and to an increase in IGF-I; these changes are among the main goals of GHR. These data confirm the favorable effects of GHR in children. 10.1210/jc.2018-01440
    FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle. Varela-Rodríguez B M,Pena-Bello L,Juiz-Valiña P,Vidal-Bretal B,Cordido F,Sangiao-Alvarellos S Scientific reports Irisin is processed from fibronectin type III domain-containing protein 5 (FNDC5). However, a controversy exists concerning irisin origin, regulation and function. To elucidate the relationship between serum irisin and FNDC5 mRNA expression levels, we evaluated plasma irisin levels and FNDC5 gene expression in the hypothalamus, gastrocnemius muscle and different depots of adipose tissue in models of altered metabolism. In normal rats, blood irisin levels diminished after 48-h fast and with leptin, insulin and alloxan treatments, and serum irisin concentrations increased in diabetic rats after insulin treatment and acute treatments of irisin increased blood insulin levels. No changes were observed during long-term experiments with different diets. We suggested that levels of circulating irisin are the result of the sum of the irisin produced by different depots of adipose tissue and skeletal muscle. This study shows for the first time that there are differences in FNDC5 expression depending on white adipose tissue depots. Moreover, a considerable decrease in visceral and epididymal adipose tissue depots correlated with increased FNDC5 mRNA expression levels, probably in an attempt to compensate the decrease that occurs in their mass. Hypothalamic FNDC5 expression did not change for any of the tested diets but increased with leptin, insulin and metformin treatments suggesting that the regulation of central and peripheral FNDC5/irisin expression and functions are different. 10.1038/srep29898
    Circulating Levels of Irisin in Hypopituitary and Normal Subjects. Pena-Bello Lara,Pértega-Diaz Sonia,Sangiao-Alvarellos Susana,Outeiriño-Blanco Elena,Eiras-Leal Raquel,Varela-Rodriguez Bárbara,Juiz-Valiña Paula,Pérez-Fontán Miguel,Cordido María,Cordido Fernando PloS one CONTEXT:The recently identified myokine irisin conveys some of the benefits of exercise. Hypopituitarism with adult growth hormone deficiency (HP) is a situation characterized by decreased GH secretion and an altered body composition. OBJECTIVE:Our aim was to study the skeletal muscle hormone irisin in HP, and compare the results with a similar group of normal subjects. PARTICIPANTS AND METHODS:Seventeen HP patients and fifty-one normal subjects of similar age and sex were studied. The diagnosis of GH deficiency was confirmed by the presence of pituitary disease and a peak GH secretion below 3 μg/L after an insulin tolerance test. The patients were adequately treated for all pituitary hormone deficits, except for GH. Fasting serum irisin was measured with an enzyme immunoassay, and HOMA-IR, QUICKI and HOMA-β were calculated. RESULTS:Fasting irisin levels (ng/ml) were similar in normal [208.42 (168.44-249.23)] and HP patients [195.13 (178.44-241.44)]. In the control group there were moderate significant positive correlations between irisin and BMI, waist circumference, leptin, fasting insulin, HOMA-IR, HOMA-β, triglycerides, and cholesterol. In the control group there were moderate significant negative correlations between irisin and IGF-I and QUICKI. In the hypopituitary group there were moderate significant positive correlations between irisin and body fat and HOMA-β. CONCLUSIONS:We found similar irisin levels in GH deficiency hypopituitary patients when compared with normal subjects. The correlation between irisin and adiposity related factors suggests that that in the case of this clinical model, irisin is regulated by adiposity and not by GH. 10.1371/journal.pone.0160364
    Serum irisin and its regulation by hyperinsulinemia in women with polycystic ovary syndrome. Adamska Agnieszka,Karczewska-Kupczewska Monika,Lebkowska Agnieszka,Milewski Robert,Górska Maria,Otziomek Elzbieta,Nikolajuk Agnieszka,Wolczynski Slawomir,Kowalska Irina Endocrine journal Irisin is an adipokine/myokine which could be connected with insulin sensitivity. Polycystic ovary syndrome (PCOS) is characterized by oligo- or anovulation, polycystic ovary, hyperandrogenism and insulin resistance. The aim of the present study was to determine the relationship between serum irisin concentration and insulin sensitivity (M) as well as the effect of insulin infusion on circulating irisin levels in PCOS women as compared with healthy controls. Seventy seven women were enrolled in the study - 57 with PCOS and 20 healthy controls matched for BMI and age. Hyperinsulinemic euglycemic clamps were performed in all of the study participants. The serum concentrations of irisin at baseline and after the clamp, as well as changes of serum irisin concentration in response to insulin supplied during the clamp (Δ irisin), were estimated. The mean serum concentrations of irisin at baseline and after hyperinsulinemia were higher in PCOS women in comparison to the control group (p=0.01; p=0.006, respectively). Insulin infusion resulted in a decrease of serum irisin concentration only in the PCOS group (p=0.007). In the control group, Δ irisin positively correlated with M (r=0.56, p=0.009). In the entire group, multiple regression analysis showed that Δ irisin (β=0.70, p=0.0002), FFAs 60' during the clamp study (β=-0.22, p=0.01), SHBG (β=0.54, p<0.0001) and the interaction between Δ irisin and PCOS (β=-0.67, p=0.0004) were significantly associated with M. The higher serum irisin concentrations at baseline and in response to insulin infusion might be secondary to insulin resistant conditions in PCOS women. 10.1507/endocrj.EJ16-0249
    Free androgen index and Irisin in polycystic ovary syndrome. Li H,Xu X,Wang X,Liao X,Li L,Yang G,Gao L Journal of endocrinological investigation PURPOSE:PCOS is associated with hyperandrogenism and insulin resistance (IR). Recent studies have shown that circulating Irisin levels increase in PCOS women. However, no report has demonstrated a relationship between Irisin and hyperandrogenism in PCOS women. The purpose of the study was to compare interrelationship between Irisin or androgen excess with IR in PCOS and normal subjects. METHODS:166 PCOS and 103 control women were prospectively studied. Euglycemic- hyperinsulinemic clamps were preformed to assess their insulin sensitivity, which was expressed as M value. Circulating Irisin was determined by ELISA kit. Circulating androgens were measured using ultrasensitive assays. RESULTS:PCOS women with high FAI had significantly higher BMI, FAT%, TC, DHEA-S and HOMA-IR, and significantly lower levels of M values and SHBG than PCOS women with low FAI or the controls. Pearson correlations showed that in the entire population, FAI correlated positively with BMI, WHR, FAT%, blood pressure, TG, DHEA-S, LH/FSH, AUCinsulin, HOMA-IR and Irisin, and negatively with M values. In multiple stepwise regression analysis, only FAT%, DHEA-S and LH/FSH were independent related factors with FAI. CONCLUSION:The elevated Irisin levels in PCOS women were associated with androgen excess. Circulating Irisin is a primary predictor of hyperandrogenism, MetS and IR in PCOS women. 10.1007/s40618-015-0403-7
    The relationships of irisin with bone mineral density and body composition in PCOS patients. Gao Shanshan,Cheng Yan,Zhao Lingling,Chen Yuxin,Liu Yu Diabetes/metabolism research and reviews OBJECTIVE:Our study aims to assay the irisin level and investigate the relationships of irisin level with body mass index (BMI), body composition and bone metabolism in the polycystic ovary syndrome (PCOS) and control women. METHODS:Fifty two PCOS and 39 control women were recruited. Serum sex hormone, fasting insulin and C-peptide were tested. Fasting serum irisin and adiponectin were measured with enzyme-linked immunosorbent assay. Body composition and bone mineral density were assayed by dual energy X-ray absorptiometry. RESULTS:Polycystic ovary syndrome women showed different body compositions compared with controls. Serum irisin level of PCOS did not show significant difference compared with controls although it was decreased. The level of adiponectin in PCOS patients was significantly reduced. BMI had no correlation with irisin level. It indicated a positive correlation between serum irisin levels and bone mineral density in the control group and a negative correlation in the PCOS group after BMI and age adjusted. Furthermore, total lean mass has a significant effect on irisin concentration in the PCOS group. There are no correlations between adiponection and body compositions and bone mineral density in both groups. CONCLUSIONS:The abnormal body composition in PCOS may contribute to the circulation irisin. The crosstalk of irisin in different organs was found and may be related to disease development in PCOS. 10.1002/dmrr.2767
    Irisin inhibition of growth hormone secretion in cultured tilapia pituitary cells. Lian Anji,Li Xin,Jiang Quan Molecular and cellular endocrinology Irisin, the product of fibronectin type III domain-containing protein 5 (FNDC5) gene, is well-documented to be a regulator of energy metabolism. At present, not much is known about its biological function in non-mammalian species. In this study, a full-length tilapia FDNC5 was cloned and its tissue expression pattern has been confirmed. Based on the sequence obtained, we produced and purified recombinant irisin which could induce uncoupling protein 1 (UCP1) gene expression in tilapia hepatocytes. Further, the rabbit polyclonal irisin antiserum was produced and its specificity was confirmed by antiserum preabsorption. In tilapia pituitary cells, irisin inhibited growth hormone (GH) gene expression and secretion and triggered rapid phosphorylation of Akt, Erk1/2, and p38 MAPK. Furthermore, irisin-inhibited GH mRNA expression could be prevented by inhibiting PI3K/Akt, MEK1/2, and p38 MAPK, respectively. Apparently, fish irisin can act directly at the pituitary level to inhibit GH transcript expression via multiple signaling pathways. 10.1016/j.mce.2016.09.030
    The role of sex, adiposity, and gonadectomy in the regulation of irisin secretion. Zügel M,Qiu S,Laszlo R,Bosnyák E,Weigt C,Müller D,Diel P,Steinacker J M,Schumann U Endocrine A sexual dimorphism has been reported for the adipo-myokine irisin at rest and in response to exercise. The effects of male and female sex, adiposity, and gonadectomy on irisin secretion have not been investigated before. The objective of this study was to elucidate the effects of sex, adiposity, and gonadectomy in the regulation of irisin secretion as well as PGC-1α/FNDC5 mRNA and protein expression. We hypothesized that a lack of female sex hormones by ovariectomy reduces irisin levels and inhibits skeletal muscle expression of PGC-1α and FNDC5. Circulating irisin was measured in vivo in serum samples of healthy and obese men and women at rest and in response to acute exercise. The effects of gonadectomy on serum irisin, PGC-1α and FNDC5 muscle mRNA, and protein expression were investigated in ovariectomized (OVX) and orchiectomized (ORX) Wistar rats. Serum irisin at rest was not significantly different between men and women (lean or obese). However, in response to acute aerobic exercise, irisin levels increased significantly more in lean women versus men (p ≤ 0.05). In obese individuals, resting irisin concentrations were significantly higher compared to lean subjects (p ≤ 0.001) and the irisin response to acute exercise was blunted. Only the lack of gonadal hormones in OVX but not ORX rats increased serum irisin levels (p ≤ 0.01) and resulted in significantly increased body weight (p ≤ 0.01), adipose tissue content (p ≤ 0.05), muscle FNDC5 mRNA (p ≤ 0.05), and protein (p ≤ 0.01) expression without altering PGC-1α expression. Testosterone treatment in ORX rats leads to increased PGC-1α mRNA content and reduced PGC-1α protein content without affecting FDNC5 expression or serum irisin levels. We show that a sexual dimorphism exists for the acute irisin response to exercise in normal-weight but not in obese subjects. OVX, which is associated with increased adiposity and insulin insensitivity, increases basal FNDC5 expression and serum irisin, without altering PGC-1α expression. This may be an early sign for metabolic disturbances associated with menopause, such as a developing irisin resistance or an attempt of the organism to improve glucose metabolism. 10.1007/s12020-016-0913-x
    Small interfering RNA mediated knockdown of irisin suppresses food intake and modulates appetite regulatory peptides in zebrafish. Sundarrajan Lakshminarasimhan,Unniappan Suraj General and comparative endocrinology Irisin is a myokine encoded in fibronectin type III domain containing 5 (FNDC5). FNDC5 forms an integral part of the muscle post-exercise, and causes an increase in energy expenditure in mammals. Irisin is abundantly expressed in cardiac and skeletal muscles and is secreted upon activation of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1 alpha). Irisin regulates feeding behaviour and cardiovascular function in mammals. More recently, irisin has gained importance as a potential biomarker for myocardial infarction due to its abundance in cardiac muscle. The goal of this research was to determine whether irisin influences feeding, and regulates appetite regulatory peptides in zebrafish. Intraperitoneal injection of irisin [0.1, 1, 10 and 100ng/g body weight (BW)] did not affect feeding, but its knockdown using siRNA (10ng/g BW) caused a significant reduction in food intake. Knockdown of irisin reduced ghrelin and orexin-A mRNA expression, and increased cocaine and amphetamine regulated transcript mRNA expression in zebrafish brain and gut. siRNA mediated knockdown of irisin also downregulated brain derived neurotrophic factor mRNA in zebrafish. The role of endogenous irisin on food intake is likely mediated by its actions on other metabolic peptides. Collectively, these results indicate that unaltered endogenous irisin is required to maintain food intake in zebrafish. 10.1016/j.ygcen.2017.06.027
    Irisin and Testosterone in Men with Metabolic Syndrome. Kamenov Zdravko,Assyov Yavor,Angelova Petya,Gateva Antoaneta,Tsakova Adelina Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme The beneficial effects of testosterone on the metabolism and body composition of men are well established but the exact mechanisms of these effects are not clearly understood. A potential explanation might lie in the hormones, secreted from skeletal muscles, named "myokines". One such myokine, irisin, has been shown to also have potential beneficial metabolic effects. The aim of this pilot study was to evaluate the association of serum testosterone with circulating serum irisin levels in men with metabolic syndrome. A total 128 men with metabolic syndrome (MS) based on the IDF criteria participated in the study. Irisin serum concentration was determined by means of ELISA. Mean age±SD of the study participants was 51.8±8.3 years. Seventy percent of the subjects had type 2 diabetes mellitus. Circulating irisin was inversely associated with serum testosterone (r=-0.279, p<0.01) and was significantly higher in subjects with hypogonadism - mean±SD 252.0±147.1 vs.172.9±92.2 ng/ml (p=0.002). ROC analysis of serum irisin value was determined for distinguishing subjects with hypogonadism (AUC=0.670). In a multiple linear regression model with BMI, FPG, age, and irisin, only BMI (β=-0.228, p=0.004) and irisin (β=-0.170, p=0.045) were variables independently associated with testosterone concentrations. Irisin is negatively associated with serum testosterone in our population sample of men with MS. This might suggest a possible involvement of myokines and testosterone with regards to the human metabolism. As no such data on this association has been reported in the literature thus far, further prospective studies are required to elucidate this correlation. 10.1055/s-0043-115227
    Central inhibitory effects on feeding induced by the adipo-myokine irisin. Ferrante Claudio,Orlando Giustino,Recinella Lucia,Leone Sheila,Chiavaroli Annalisa,Di Nisio Chiara,Shohreh Rugia,Manippa Fabio,Ricciuti Adriana,Vacca Michele,Brunetti Luigi European journal of pharmacology Irisin, the soluble secreted form of fibronectin type III domain containing 5 (FNDC5)-cleaved product, is a recently identified adipo-myokine that has been indicated as a possible link between physical exercise and energetic homeostasis. The co-localization of irisin with neuropeptide Y in hypothalamic sections of paraventricular nucleus, which receives NPY/AgRP projections from the arcuate nucleus, suggests a possible role of irisin in the central regulation of energy balance. In this context, in the present work we studied the effects of intra-hypothalamic irisin (1μl, 50-200nmol/l) administration on feeding and orexigenic [agouti-related peptide (AgRP), neuropeptide Y (NPY) and orexin-A] and anorexigenic [cocaine and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC)] peptides in male Sprague-Dawley rats. Furthermore, we evaluated the effects of irisin on hypothalamic dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) concentrations and plasma NE levels. Compared to vehicle, irisin injected rats showed decreased food intake, possibly mediated by stimulated CART and POMC and inhibited DA, NE and orexin-A, in the hypothalamus. We also found increased plasma NE levels, supporting a role for sympathetic nervous system stimulation in mediating increased oxygen consumption by irisin. 10.1016/j.ejphar.2016.09.011
    The association between circulating irisin levels and different phenotypes of polycystic ovary syndrome. Zhang L,Fang X,Li L,Liu R,Zhang C,Liu H,Tan M,Yang G Journal of endocrinological investigation PURPOSE: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. METHODS: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. RESULTS: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. CONCLUSIONS:Circulating irisin may allow physicians to establish which women merit screening by a biomarker for PCOS. 10.1007/s40618-018-0902-4
    Serum Irisin and Oxytocin Levels as Predictors of Metabolic Parameters in Obese Children. Binay Çiğdem,Paketçi Cem,Güzel Savaş,Samancı Nedim Journal of clinical research in pediatric endocrinology OBJECTIVE:Irisin and oxytocin can affect energy homeostasis and it has been suggested that they may play an important role in reducing obesity and diabetes. In this study, we aimed to determine the relationship between metabolic parameters (including irisin and oxytocin levels) and anthropometric parameters in obese children. METHODS:Ninety obese children (mean age, 13.85±1.63 years) and 30 healthy controls (mean age, 14.32±1.58 years) were enrolled in this study. Anthropometric and laboratory parameters (glucose, insulin, lipid, oxytocin, and irisin levels) were analyzed. The serum irisin and oxytocin levels were measured by enzyme-linked immunosorbent assay. Bioelectrical impedance was used to determine body composition. RESULTS:Irisin level was higher in the patients than in the controls (p=0.018), and this higher irisin level was correlated with increased systolic blood pressure, body mass index, waist/hip ratio, fat percentage, fat mass, glucose level, insulin level, and homeostasis model assessment of insulin resistance. Serum oxytocin level was significantly decreased in obese children compared to the controls (p=0.049). Also, among the 60 obese patients, oxytocin level was significantly lower in patients with than in those without metabolic syndrome (8.65±2.69 vs. 10.87±5.93 ng/L, respectively), while irisin levels were comparable (p=0.049 and p=0.104, respectively). There were no statistically significant relationships between oxytocin or irisin levels and lipid levels (p>0.05). CONCLUSION:Obese children had significantly higher irisin levels than the healthy controls. Additionally, this study shows for the first time that oxytocin level is significantly lower in obese compared with non-obese children and also lower in obese children with metabolic syndrome compared to those without. 10.4274/jcrpe.3963
    Irisin stimulates gonadotropins gene expression in tilapia (Oreochromis niloticus) pituitary cells. Jiang Quan,Zhang Qianli,Lian Anji,Xu Yue Animal reproduction science The link between energy metabolism and reproduction is well known in vertebrates. Irisin, the product of fibronectin type III domain-containing protein 5 (FNDC5) gene, plays an important role in energy homeostasis. However, biological actions of irisin on reproduction remain elusive. To address this gap, we examined the direct effects of irisin on luteinizing hormone β (LHβ) and follicle-stimulating hormone β (FSHβ) gene expression in tilapia pituitary cells. As a first step, the transcripts of FNDC5 were detected in the proximal pars distalis (PPD), but not in the rostral pars distalis (RPD) and neurointermediate lobe (NIL) of the tilapia pituitary by RT-PCR. In the tilapia pituitary, irisin immunoreactive signals were also detected in PPD region. In primary cultures of tilapia pituitary cells, irisin was effective in stimulating both LHβ and FSHβ mRNA levels in vivo and in vitro. In cultured pituitary cells of tilapia, removal of endogenous irisin by immunoneutralization using irisin antiserum inhibited LHβ and FSHβ gene expression. Salmon gonadotrophin releasing hormone (sGnRH) increased LHβ and FSHβ mRNA levels in tilapia pituitary but these stimulatory actions were not either enhanced by treatment with irisin or blocked by irisin antiserum. Furthermore, the stimulation on LHβ and FSHβ mRNA expression was coincident with the enhancement of LHβ and FSHβ mRNA stability after irisin treatment. These results provide evidence that irisin may serve as a novel intrapituitary factor maintaining gonadotropins gene expression in tilapia pituitary. 10.1016/j.anireprosci.2017.06.018
    Reproductive effects of irisin: Initial in vitro studies. Poretsky Leonid,Islam Julie,Avtanski Dimiter,Lin Yu Kuei,Shen Yi-Ling,Hirth Yael,Lesser Martin,Rosenwaks Zev,Seto-Young Donna Reproductive biology The recently discovered myo- and adipokine irisin affects insulin sensitivity in classical insulin target tissues (adipose tissue, skeletal muscle and liver), but the reproductive effects of this hormone, if any, remain largely unexplored. We hypothesized that irisin may have effects on the hypothalamic-pituitary-gonadal axis. To test this hypothesis, we used murine pituitary mPit12 and human ovarian granulosa cells. GnRH treatment resulted in significant (up to 2.5-fold, p<0.0005) and dose-dependent stimulation of LH production by the mPit12 cells. Treating these cells with irisin alone showed a significant stimulatory effect on LH synthesis only at irisin concentration of 100ng/ml. When used together with GnRH, irisin abolished the stimulatory effect of GnRH on LH production. Human ovarian granulosa cells were treated with insulin, irisin or a combination of both and the estradiol (E2) production was measured. Both insulin or irisin stimulated granulosa cell E2 production (1.4-fold, p<0.05 and 2.5-fold, p=0.0002, respectively), but when insulin and irisin were used in combination, this stimulatory effect on E2 production was abolished. We conclude that irisin may have reproductive axis effects in the pituitary and in the ovary. Further studies are needed to confirm these initial observations and to explore the mechanisms of irisin effects in the reproductive system. 10.1016/j.repbio.2017.05.011
    Circulating irisin in patients with polycystic ovary syndrome: a meta-analysis. Cai Xue,Qiu Shanhu,Li Ling,Zügel Martina,Steinacker Jürgen Michael,Schumann Uwe Reproductive biomedicine online 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. 10.1016/j.rbmo.2017.10.114
    Higher circulating irisin levels in patients with polycystic ovary syndrome:a meta-analysis. Wang Chuan,Zhang Xin-Yue,Sun Yu,Hou Xin-Guo,Chen Li Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 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. 10.1080/09513590.2017.1393065
    Serum irisin concentrations in lean adolescents with polycystic ovary syndrome. Bacopoulou Flora,Athanasopoulos Nikos,Efthymiou Vasiliki,Mantzou Aimilia,Aravantinos Leon,Vlahopoulos Spiros,Deligeoroglou Efthymios Clinical endocrinology OBJECTIVE:To explore differences in irisin concentrations between lean adolescents with PCOS and age- and body mass index (BMI)-matched controls and examine the associations of irisin with core features of the syndrome. DESIGN:Cross-sectional study. PATIENTS:Lean females with PCOS, aged 13-21 years. MEASUREMENTS:Physical, hormonal and sonographic assessment. Irisin concentrations were measured with ELISA. RESULTS:Participants included in total 39 sedentary females (mean ± SD; age 17.3 ± 2.1 years, BMI 20.7 ± 1.3 Kg/m ), 23 adolescents with PCOS and 16 controls. Adolescents with PCOS compared to controls had significantly elevated concentrations of fasting serum irisin (mean ± SD; PCOS, 1.7 ± 1.0 μg/mL vs controls, 1.0 ± 0.4 μg/mL; P = .007), luteinizing hormone (LH), oestradiol, testosterone, Δ4-androstenedione, 17-hydroxyprogesterone, glucose, as well as free androgen index, Ferriman-Gallwey score and mean ovarian volume (MOV). For the total sample, circulating irisin was positively correlated with MOV (r = .332, P = .041), glucose (r = .428, P = .007), insulin (r = .369, P = .021) and HOMA-IR (r  = .422, P = .007) and negatively correlated with QUICKI (r = -.329, P = .041). Follicle-stimulating hormone (B = 0.295, Beta = .342, P = .042) and MOV (B = 0.182, Beta = 0.821, P = .001) were positive predictors, and LH (B = -0.108, Beta = -0.523, P = .010) and testosterone (B = -0.431, Beta = -0.457, P = .032) were negative predictors of irisin concentrations, whereas irisin positively predicted fasting glucose (B = 0.262, Beta = 0.428, P = .007). In the PCOS group, irisin concentrations were positively correlated with HOMA-IR (r  = .416, P = .048) but negatively correlated with LH (r  = -.499, P = .015), testosterone (r = -.585, P = .003), free androgen index (r = -.426, P = .048) and Ferriman-Gallwey score (r = -.533, P = .015). CONCLUSIONS:Irisin was associated with the adolescents' metabolic and reproductive characteristics and the hyperandrogenic phenotype of the syndrome. Much research is needed to ascertain mechanisms of elevated serum irisin in adolescent PCOS. 10.1111/cen.13555
    Effects of Irisin and Exercise on Metabolic Parameters and Reproductive Hormone Levels in High-Fat Diet-Induced Obese Female Mice. Bastu Ercan,Zeybek Umit,Gurel Gurevin Ebru,Yüksel Ozgor Bahar,Celik Faruk,Okumus Nazli,Demiral Irem,Dural Ozlem,Celik Cem,Bulut Huri,Ilkay Armutak Elif,Baysal Bulent,Buyru Faruk,Yeh John Reproductive sciences (Thousand Oaks, Calif.) It has been documented that exogenously administered irisin (10 fibronectin-type III domain-containing 5 [FNDC5]), which is a new polypeptide hormone, induces the browning of subcutaneous fat and thermogenesis. In this study, effects of physical activity and exogenous administration of irisin were investigated on parameters related with reproduction and metabolism in the high-fat diet-induced obesity model of the female C57BL/6J mice. Sixty mice were gathered at age approximately 5 to 6weeks and were divided into 3 groups. Control group remained sedentary. Irisin group remained also sedentary but intravenously received 10 FNDC5-expressing adenovirus after 20 weeks. Exercise group performed treadmill after 6 weeks. All mice were sacrificed 22 to 23 weeks after the start of the study. There was a significantly greater Δ weight in the controls compared with the irisin and exercise groups ( P < .05). Glucose and insulin levels were significantly higher in the controls ( P < .05). The serum irisin level was significantly higher in the exercise group ( P < .05). Serum luteinizing hormone levels were significantly increased in the irisin group ( P < .05). Serum anti-Müllerian hormone levels were significantly higher in irisin and exercise groups ( P < .05). There were significant negative correlations between serum irisin levels and Δ weight and homeostatic model assessment of insulin resistance ( r = -0.327, r = -0.297, respectively; P < .05 for both). The numbers of primordial follicles per ovary were similar ( P > .05), whereas primary and secondary follicles per ovary were higher in the irisin and exercise groups compared with controls ( P < .05). Pharmacologic introduction of irisin may improve metabolic factors such as insulin sensitivity and obesity by promoting weight loss and consequently improving the reproductive potential. 10.1177/1933719117711264
    Effect of Metformin Treatment on Insulin Resistance Markers, and Circulating Irisin in Women with Polycystic Ovarian Syndrome (PCOS). Masaeli Asiyeh,Nayeri Hashem,Mirzaee Mohammadreza Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme Polycystic ovarian syndrome (PCOS) is considered as a common endocrinal dysfunction among adult women characterized by polycystic ovaries, anovulation, and hyperandrogenism. Irisin is associated with metabolic parameters and insulin resistance. However, the association of irisin with PCOS remains poorly delineated. This study was aimed to examine circulating irisin levels and effects of metformin on this parameter in women with PCOS. Moreover, the association of irisin with insulin resistance markers was determined. Thirty-nine females with PCOS, aged 20-40 years, participated in this study and received 500 mg of metformin once daily for 3 months. Serum creatinine, blood urea nitrogen, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL), cholesterol, triglyceride, fasting blood sugar, testosterone, 17-hydroxyprogesterone, and irisin were assayed in the studied groups. Circulating irisin was significantly higher in PCOS women. Circulating irisin levels correlated with 17-hydroxyprogesterone, testosterone, and insulin. Three months metformin treatment decreased circulating irisin in PCOS women and improved IR. Circulating irisin is directly associated with insulin resistance in PCOS women and may be used as a biomarker for IR in these patients. Moreover, metformin as a confounding therapy in metabolic diseases can be used to regulate circulating irisin levels in PCOS women. 10.1055/a-0896-1130
    Irisin as a Novel Marker for Insulin Resistance in Iraqi Women with Polycystic Ovary Syndrome Before and After Metformin Therapy. Farhan Fatin Shallal,Hussien Shatha Sami Journal of obstetrics and gynaecology of India Background:Polycystic ovarian syndrome affects 5-10% of women; it represents the most common cause of hyperinsulinemia with anovulation. Many biomarkers are used to assess insulin resistance. Irisin is a newly discovered myokine associated with insulin resistance and other metabolic syndromes. Objective:To measure the serum level of irisin in polycystic ovary syndrome patients and assess the effect of metformin treatment on its level. Method:This study was a prospective interventional study conducted in a private clinic and Al-Yarmouk Teaching Hospital in Baghdad City from January 1, 2017, till April 1, 2018. A hundred women were enrolled in the study. Fifty of them suffered from PCOS and other fifty were normal. They were randomly selected according to computer-based randomization and assigned as a control group. Hormonal, biochemical and oral glucose tolerance tests were performed on all patients, including Irisin. The results have been compared for both groups. Twenty-nine women of PCOS patients received metformin for a course period of 4 months as the changes in their biochemical results were evaluated. Result:Serum irisin level was higher in patients group compared to control group (312 ± 134.3 and 188.4 ± 53.8 μg/l, respectively), and the difference was statistically significant as the value < 0.001. After 4 months treatment with metformin for twenty-nine polycystic patients, there was a significant reduction in irisin level by (165.8 ± 55.6 μg/l) and the value was significant. Conclusion:Irisin might be used as a simple test for the prediction of insulin resistance in PCOS patients. 10.1007/s13224-018-1176-7
    Serum irisin levels in polycystic ovary syndrome after ovarian drilling. Foda Ashraf A,Foda Engy A,El-Said Zeinab H Diabetes & metabolic syndrome BACKGROUND:Many cases of Poly-Cystic Ovary Syndrome (PCOS) are overweight and presenting with insulin resistance. MAIN OBJECTIVE:was to evaluate the effects of ovarian drilling on the serum levels of Irisin in women with polycystic ovaries. STUDY DESIGN AND SETTING:Serum Irisin levels were investigated in 100 cases with PCOS before ovarian drilling and 3 months after drilling, and in 80 control cases. Serum Irisin, hormonal profile and HOMA-IR were estimated in PCOS cases before and after ovarian drilling. Statistical analysis was performed by using Statistical Package for Social Scientists (SPSS). RESULTS:The serum irisin levels in overweight and in normal weight PCOS cases before ovarian drilling were significantly higher as compared with the corresponding control cases. Fasting serum Irisin levels were found to be significantly elevated in PCOS patients before ovarian drilling as compared to the levels after drilling. The serum irisin levels in overweight and in normal weight PCOS cases before ovarian drilling were found to be significantly positively correlated with BMI, insulin levels, and HOMA-IR. CONCLUSION:Elevated serum Irisin levels in PCOS may contribute to the development of insulin resistance. Ovarian drilling for polycystic ovaries results in a significant decrease in the serum Irisin levels. The analysis of ROC curves may suggest that serum Irisin may be a valuable biomarker for diagnosis and for monitoring cases with PCOS during treatment. 10.1016/j.dsx.2019.02.019
    Abnormal irisin level in serum and endometrium is associated with metabolic dysfunction in polycystic ovary syndrome patients. Wang Wei,Guo Ying,Zhang Xinxian,Zheng Jiahua Clinical endocrinology INTRODUCTION:Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive-age women. Irisin is considered to play a role in metabolic disorder and PCOS. However, correlation between irisin and metabolic disorder in PCOS is not clear. MATERIAL AND METHODS:This is a prospective study. Forty patients with PCOS and thirty patients without PCOS were recruited for in vitro fertilization and embryo transfer (IVF-ET). All PCOS women fulfilled all three Rotterdam consensus criteria. In each group, patients were also divided into obese and nonobese patients, and patients with or without dyslipidaemia. RESULTS:Serum irisin level in PCOS patients was significantly reduced. Irisin level in obese PCOS patients was significantly lower than in nonobese PCOS patients. Irisin level in PCOS patients with dyslipidaemia was significantly higher than in PCOS patients with normal blood lipid profile. In both PCOS and control patients, serum irisin level was negatively correlated with body weight and waist-hip ratio (WHR). Moreover, serum irisin level was positively correlated with body fat rate, BAI, fasting plasma glucose (FPG) and HOMA-IR in PCOS patients. In addition, serum irisin level was positively correlated with HOMA-IR in control patients. In PCOS patients, body weight and HOMA-IR could predict the level of irisin. In control patients, body mass index (BMI) could predict the level of irisin. Expression of irisin in PCOS patients was lower than that in control patients. However, there was no significant difference of irisin expression between the subdivided groups in PCOS and control patients. CONCLUSIONS:Taken together, the present findings enriched the knowledge about the role of irisin in metabolic dysfunction in PCOS patients. 10.1111/cen.13805
    Irisin in the primate hypothalamus and its effect on GnRH in vitro. Wahab Fazal,Khan Ikram Ullah,Polo Ignacio Rodriguez,Zubair Hira,Drummer Charis,Shahab Muhammad,Behr Rüdiger The Journal of endocrinology Irisin, encoded by the FNDC5 gene, is a recently discovered endocrine factor mainly secreted as a myokine and adipokine. However, irisin/FNDC5 expression has also been reported in different other organs including components of the reproductive axis. Yet, there is the scarcity of data on FNDC5/irisin expression, regulation and its reproductive effects, particularly in primates. Here, we report the expression of FNDC5/irisin, along with PGC1A (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and ERRA (estrogen-related receptor alpha), in components of the reproductive axis of marmoset monkeys. Hypothalamic FNDC5 and ERRA transcript levels are developmentally regulated in both male and female. We further uncovered sex-specific differences in FNDC5, ERRA and PGC1A expression in muscle and the reproductive axis. Moreover, irisin and ERRα co-localize in the marmoset hypothalamus. Additionally, in the arcuate nucleus of rhesus monkeys, the number of irisin+ cells was significantly increased in short-term fasted monkeys as compared to ad libitum-fed monkeys. More importantly, we observed putative interaction of irisin-immunoreactive fibers and few GnRH-immunoreactive cell bodies in the mediobasal hypothalamus of the rhesus monkeys. Functionally, we noted a stimulatory effect of irisin on GnRH synthesis and release in mouse hypothalamic neuronal GT1-7 cells. In summary, our findings show that FNDC5 and irisin are developmentally, metabolic-status dependently and sex-specifically expressed in the primate hypothalamic-pituitary-gonadal axis and exert a stimulatory effect on GnRH expression and release in mouse hypothalamic cells. Further studies are required to confirm the reproductive effects of irisin in vivo and to illuminate the mechanisms of its regulation. 10.1530/JOE-18-0574
    Serum and follicular fluid irisin levels in women with polycystic ovaries undergoing ovarian stimulation: correlation with insulin resistance and lipoprotein lipid profiles. Bousmpoula Artemis,Benidis Evangelos,Demeridou Styliani,Kapeta-Kourkouli Rachil,Chasiakou Anthia,Chasiakou Stamatia,Kouskouni Evangelia,Baka Stavroula Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology Irisin, a novel exercise-induced myokine, has been implicated in different aspects of human metabolism and could be connected to polycystic ovary syndrome (PCOS). This study aimed to investigate serum and follicular fluid (FF) irisin levels in PCOS and normal women undergoing controlled ovarian stimulation and correlate them to the lipid and lipoprotein levels as well as with other metabolic parameters. Serum and FF irisin, together with serum lipid and lipoprotein levels were assessed in 70 women with diagnosed PCOS and 70 non-PCOS controls, under fertilization (IVF) treatment. Regardless of BMI, PCOS women had a significantly increased number of oocytes retrieved, fertilized oocytes and transferred embryos, although the number of women achieving pregnancies did not differ between groups. No correlation between FF irisin levels and pregnancy could be established. Serum and FF irisin levels were significantly higher in PCOS and overweight women and were positively associated with BMI and dyslipidemia. FF irisin levels correlated positively to and were lower than serum irisin levels. Further research would be helpful to analyze irisin's role in female reproduction, if any, as well as in human metabolism and the pathophysiology of PCOS. 10.1080/09513590.2019.1594761
    Effect of irisin on endometrial receptivity of rats with polycystic ovary syndrome. Li Chenggang,Zhou Li,Xie Yong,Guan Chuang,Gao Haifeng Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology To investigate the influence of irisin on endometrial receptivity of rats with polycystic ovarian syndrome (PCOS). PCOS rats were randomly divided into PCOS group and irisin group, and normal rats were used as control group. The PCOS group and control group were injected intraperitoneally with normal saline while the irisin group with recombinant irisin. The serum and uterus were obtained. Detect serum sex hormones, including Testosterone (T), Estradiol (E), Progesterone (P), and glucose, insulin levels. Observe endometrial morphology by hematoxylin-eosin staining. Then evaluate the expression of leukemia inhibitory factor (LIF) and integrin αvβ3 in endometrium using ELISA, immunohistochemistry and Real-time PCR. (1) Levels of serum T, glucose and insulin in PCOS group were significantly higher than those in control and irisin group. (2) For the endometrial morphology, levels of equivalent diameter, area of uterine glands and gland cavity and endometrial average thickness were lower in PCOS group than those in control and irisin group. (3) LIF and integrin αvβ3 mRNA were basically consistent with protein expression. Levels of LIF and integrin αvβ3 were decreased in PCOS group when compared with control and irisin group. Irisin may improve endometrial receptivity by promoting expression of LIF and integrin αvβ3. 10.1080/09513590.2018.1529158
    Effects of intracerebroventricular administration of irisin on the hypothalamus-pituitary-gonadal axis in male rats. Tekin Suat,Beytur Ali,Erden Yavuz,Beytur Asiye,Cigremis Yilmaz,Vardi Nigar,Turkoz Yusuf,Tekedereli Ibrahim,Sandal Suleyman Journal of cellular physiology Irisin is a product of fibronectin type III domain-containing protein 5 (FNDC5) and plays an important role in energy homeostasis. In this study, we aimed to determine effects of intracerebroventricular administration of irisin on the hypothalamus-pituitary-gonadal axis by molecular, biochemical, and morphological findings. Fourty male Wistar-Albino rats were used and divided into four groups including control, sham (vehicle), 10, and 100 nM irisin infused groups (n = 10). Hypothalamic gonadotropin releasing hormone (GnRH) level and serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were determined. Testicular tissue histology and spermiogram analysis were also performed. Both irisin concentrations significantly reduced hypothalamic GnRH messenger RNA (mRNA) and protein levels (p < 0.05). It was found that serum LH, FSH, and testosterone levels and Sertoli and Leydig cell numbers were decreased by irisin administration (p < 0.05). In addition, irisin administration reduced sperm density and mobility (p < 0.05). However, it did not cause any change in testicular and epididymis weights and tubular diameter. Our results reveal that irisin can play a role in the central regulation of reproductive behavior and also reduces testosterone levels by suppressing LH and FSH secretion. These results suggest that the discovery of irisin receptor antagonists may be beneficial in the treatment of infertility. 10.1002/jcp.27541
    Irisin increases the expression of anorexigenic and neurotrophic genes in mouse brain. Natalicchio Annalisa,Marrano Nicola,Biondi Giuseppina,Dipaola Lucia,Spagnuolo Rosaria,Cignarelli Angelo,Perrini Sebastio,Laviola Luigi,Giorgino Francesco Diabetes/metabolism research and reviews BACKGROUND:Irisin, a newly discovered muscle-derived hormone, acts in different organs and tissues, improving energy homeostasis. In this study, we assessed, for the first time, the effects of intraperitoneal irisin injections on circulating levels of leptin and ghrelin, mRNA expression of the major hypothalamic appetite regulators and brain neurotrophic factors, as well as feeding behaviour in healthy mice. METHODS:Twelve male 6-week-old C57BL/6 mice were randomized into two groups and intraperitoneally injected daily with irisin (0.5 μg/g body weight) or vehicle (phosphate-buffered saline [PBS]) for 14 days. On the last day of observation, leptin and ghrelin levels were measured with an enzyme-linked immunosorbent assay (ELISA). mRNA levels of genes of interest were analysed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in brain extracts. RESULTS:Irisin administration did not change leptin or ghrelin serum concentrations. However, irisin injection increased CART, POMC, NPY, and BDNF mRNA levels, without affecting the mRNA expression of AgRP, orexin, PMCH, and UCP2. Finally, over the time frame of irisin treatment, body weight and feeding behaviour were unaltered. CONCLUSIONS:These results suggest that intraperitoneal injection of irisin, although without effects on feeding behaviour and body weight, can increase the expression of anorexigenic and neurotrophic genes in mouse brain. 10.1002/dmrr.3238