Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors.
Kim Hyeonwoo,Wrann Christiane D,Jedrychowski Mark,Vidoni Sara,Kitase Yukiko,Nagano Kenichi,Zhou Chenhe,Chou Joshua,Parkman Virginia-Jeni A,Novick Scott J,Strutzenberg Timothy S,Pascal Bruce D,Le Phuong T,Brooks Daniel J,Roche Alexander M,Gerber Kaitlyn K,Mattheis Laura,Chen Wenjing,Tu Hua,Bouxsein Mary L,Griffin Patrick R,Baron Roland,Rosen Clifford J,Bonewald Lynda F,Spiegelman Bruce M
Irisin-encoding gene (FNDC5) variant is associated with changes in blood pressure and lipid profile in type 2 diabetic women but not in men.
Brondani Letícia A,Boelter Gabriela,Assmann Taís S,Leitão Cristiane B,Canani Luís H,Crispim Daisy
Metabolism: clinical and experimental
INTRODUCTION:Irisin has recently been described as a novel myokine, which reduces visceral obesity and improves glucose metabolism in mice. Thus, polymorphisms in the gene encoding irisin, fibronectin type III domain containing 5 (FNDC5), may be associated with type 2 diabetes mellitus (T2DM) and related disorders. However, to date, no study has investigated the association between FNDC5 polymorphisms and susceptibility to T2DM. OBJECTIVE:To investigate the association of FNDC5 rs3480 (A/G) and rs1746661 (G/T) polymorphisms, alone or in combination, with T2DM and its clinical features. METHODS:We analyzed 1006 T2DM patients and 434 nondiabetic subjects. Polymorphisms were genotyped by real-time PCR using TaqMan MGB probes. Haplotypes constructed from the combination of rs1746661 and rs3480 polymorphisms were inferred using the Phase 2.1 program. RESULTS:Genotype, allele and haplotype frequencies of rs1746661 and rs3480 polymorphisms did not differ significantly between nondiabetic subjects and T2DM patients. Women with T2DM carrying the G allele of rs3480 showed increased HbA1c levels compared with A/A carriers, adjusted for age. The T allele of rs1746661 was associated with increased systolic blood pressure, total cholesterol and LDL-cholesterol and decreased HDL-cholesterol in women with T2DM, adjusted for covariates. Moreover, prevalence of hypercholesterolemia was higher in women carrying the T allele of rs1746661 than in G/G carriers (72.4% vs. 58.7%, OR=2.010, 95% CI=1.210-3.390), but it was not significantly different in men. CONCLUSIONS:These results indicate that, although not associated with T2DM, the G allele of rs3480 appears to be associated with increased HbA1c, while the T allele of rs1746661 appears to be associated with higher systolic blood pressure and dyslipidemia in women with T2DM.
The effects of green cardamom on blood glucose indices, lipids, inflammatory factors, paraxonase-1, sirtuin-1, and irisin in patients with nonalcoholic fatty liver disease and obesity: study protocol for a randomized controlled trial.
Daneshi-Maskooni Milad,Keshavarz Seyed Ali,Mansouri Siavash,Qorbani Mostafa,Alavian Seyed Moayed,Badri-Fariman Mahtab,Jazayeri-Tehrani Seyed Ali,Sotoudeh Gity
BACKGROUND:The relationship between dietary components and nonalcoholic fatty liver disease (NAFLD) needs to be further investigated. The potential health benefits of cardamom have been found in some studies. Cardamom showed beneficial effect on hepatomegaly, dyslipidemia, and fasting hyperglycemia in animals. However, some adverse effects of cardamom have been reported in animals. No previous human study had been conducted on the effects of cardamom in NAFLD. This study aims to determine the effects of green cardamom (Elettaria cardamomum) supplementation on blood glucose indices, lipids, inflammatory profiles, and liver function, especially by examining irisin, paraxonase-1 (PON1) and sirtuin-1 (Sirt1) in obese patients with NAFLD. METHODS:This trial is to be conducted at the polyclinic of the National Iranian Oil Company (NIOC) Central Hospital, Tehran. Eighty obese patients with NAFLD will be selected according to the eligibility criteria. The NAFLD diagnosis method is ultrasonography. Patients will be randomly divided into two groups by a random-number table (cardamom and placebo groups, two 500-mg capsules, three times/day, taken with meals for 3 months, follow-up monthly). General characteristics, dietary intakes (at the beginning, middle, and end), and physical activity (at the beginning and end) will be assessed using a general, 24-h food recall, and short-form International Physical Activity Questionnaires (IPAQ), respectively. Lifestyle advice will be presented to both groups identically. At the beginning and the end, anthropometrics (weight, height, and waist circumference), blood pressure, extent of fatty liver, and blood biomarkers, including serum glucose indices (fasting blood sugar (FBS)) and insulin (FBI), homeostasis model assessment-insulin resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (QUICKI)), lipids (triglyceride (TG), low-density lipoprotein-cholesterol (LDL-c), high-density lipoprotein-cholesterol (HDL-c), total cholesterol (TC)), inflammatory markers (highly sensitive C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)), liver enzymes (alanine transaminase (ALT), aspartate transaminase (AST)), irisin, PON1, and Sirt1, will be determined. DISCUSSION:This trial would be the first to assess the effects of green cardamom on several blood factors, including glucose indices, lipids, inflammatory markers, liver enzymes, irisin, PON1, and Sirt1, and blood pressure and anthropometry in obese patients with NAFLD. Further study of cardamom's potential in improving NAFLD is suggested. TRIAL REGISTRATION:Iranian Registry of Clinical Trials (IRCT), ID number: IRCT2015121317254N4 . Registered on 27 December 2015.
Irisin as a muscle-derived hormone stimulating thermogenesis--a critical update.
Hofmann Tobias,Elbelt Ulf,Stengel Andreas
The recently described myokine, irisin is cleaved from fibronectin type III domain containing protein 5 (FNDC5) and has been proposed to be secreted upon exercise to promote the browning of beige fat cells in white adipose tissue that results in enhanced thermogenesis and increased energy expenditure. The initial studies suggested irisin as a treatment option for obesity and associated diseases such as type 2 diabetes mellitus and stimulated further research. However, the results of subsequent studies investigating the regulation of irisin by different types of exercise are partly conflicting and effects were only shown in highly selective patient populations so far. Moreover, other parameters like body weight or fat free mass were shown to influence irisin adding more complexity to the mechanisms regulating this hormone. The present review will describe the discovery of irisin, its potential role in adipose tissue-mediated thermogenesis, its regulation by exercise and lastly, discuss current controversies and highlight gaps of knowledge to be filled by future studies.
Plasma irisin depletion under energy restriction is associated with improvements in lipid profile in metabolic syndrome patients.
de la Iglesia Rocio,Lopez-Legarrea Patricia,Crujeiras Ana B,Pardo Maria,Casanueva Felipe F,Zulet Maria A,Martinez Jose A
OBJECTIVE:A recently discovered myokine, irisin, may have an important role in energy metabolism. This study aimed to evaluate the relationship between this hormone and the lipid profile of patients with metabolic syndrome (MetS) following a hypocaloric diet. DESIGN:Ninety-three Caucasian adults (52 men/41 women) diagnosed with MetS followed an 8-week-long energy-restricted programme (-30% of the energy requirements). Anthropometric measurements, biochemical markers and plasma irisin levels were analysed before and after the nutritional intervention. RESULTS:Global plasma irisin levels were significantly reduced at the end of the study (-72.0 ± 100.9 ng/ml, P < 0.001) accompanying the weight loss (-6.9%). The depletion of irisin significantly correlated with changes in some atherogenic-related variables: total cholesterol (B = 0.106, P = 0.018), total cholesterol/high-density lipoprotein cholesterol ratio (B = 0.002, P = 0.036), low-density lipoprotein cholesterol (B = 0.085, P = 0.037) and apolipoprotein B (B = 0.052, P = 0.002), independently of changes in body weight. CONCLUSIONS:An association between the reduction in plasma irisin levels and the depletion of important lipid metabolism biomarkers was observed in patients with MetS undergoing an energy-restricted programme.
Elevated skeletal muscle irisin precursor FNDC5 mRNA in obese OLETF rats.
Roberts Michael D,Bayless David S,Company Joseph M,Jenkins Nathan T,Padilla Jaume,Childs Thomas E,Martin Jeffrey S,Dalbo Vincent J,Booth Frank W,Rector R Scott,Laughlin M Harold
Metabolism: clinical and experimental
OBJECTIVE:There is debate as to whether fibronectin type III domain containing 5 (FNDC5) and its protein product irisin are therapeutic targets for obesity-associated maladies. Thus, we sought to examine FNDC5 mRNA within skeletal muscle of obese/diabetic-prone Otsuka Long-Evans Tokushima Fatty (OLETF) rats versus lean/healthy Long Evans Tokushima Otsuka (LETO) rats. We hypothesized that FNDC5 expression would be greater in obese (OLETF) versus lean (LETO) animals. MATERIALS/METHODS:Triceps muscle of 30-32week old OLETF and LETO rats were assayed for FNDC5 and PGC1α mRNA levels. Body composition and circulating biomarkers of the OLETF and LETO rats were also correlated with skeletal muscle FNDC5 mRNA expression patterns in order to examine potential relationships that may exist. RESULTS:OLETF rats exhibited twice the amount of triceps FNDC5 mRNA compared to LETO rats (p<0.01). Significant positive correlations existed between triceps muscle FNDC5 mRNA expression patterns versus fat mass (r=0.70, p=0.008), as well as plasma leptin (r=0.82, p<0.001). PGC1α mRNA levels were also highly correlated with FNDC5 mRNA (r=0.85, p<0.001). In subsequent culture experiments, low and high physiological doses of leptin had no effect on PGC1α mRNA or FNDC5 mRNA levels in C2C12 myotubes. Paradoxically, circulating irisin concentrations tended to be higher in a second cohort of LETO versus OLETF rats (p=0.085). CONCLUSION:These results reveal a positive association between total body adiposity and skeletal muscle FNDC5 gene expression. Of interest, circulating irisin levels tended to be lower in OLETF rats. Further research is needed to examine whether other adipose tissue-derived factors up-regulate FNDC5 transcription and/or inhibit irisin biosynthesis from FNDC5.
Irisin mRNA and circulating levels in relation to other myokines in healthy and morbidly obese humans.
Vamvini Maria T,Aronis Konstantinos N,Panagiotou Grigorios,Huh Joo Young,Chamberland John P,Brinkoetter Mary T,Petrou Michael,Christophi Costas A,Kales Stefanos N,Christiani David C,Mantzoros Christos S
European journal of endocrinology
OBJECTIVE:Skeletal muscle is considered to be an endocrine organ that secretes a number of myokines including follistatin (FST), myostatin (MSTN), activin A, and the newly identified irisin. Irisin's biology and function exhibit similarities with the functions of the FST-MSTN-activin A axis. It remains unknown whether there is any interplay among these molecules. The aim of this study is to examine potential associations of irisin with the FST, MSTN, and activin A axis. METHODS:Two observational studies were performed to evaluate the associations of irisin with the other three peptides. Study A included 150 healthy males aged 18.48±0.16 years with BMI 23.18±3.75 kg/m(2). Fasting serum samples were used to measure the levels of the molecules of interest. Study B included 14 morbidly obese individuals, candidates for bariatric surgery, aged 53.14±8.93 years with BMI 50.18±10.63 kg/m(2). Blood samples were obtained after an overnight fast. Eight out of the 14 participants consented to an optional thigh biopsy during their bariatric surgery. Using the above blood and tissue samples, we measured circulating levels and muscle mRNA of irisin, FST, MSTN, and activin A. RESULTS:We report that FNDC5 mRNA in muscle is positively correlated with FST mRNA expression in morbidly obese subjects (ρ=0.93, P<0.001). We also found that circulating irisin is positively correlated with FST circulating levels among lean subjects (ρ=0.17, P=0.05) while this association was suggestive among the obese (ρ=0.56, P=0.07). CONCLUSION:The newly identified myokine irisin may be positively associated with FST at both the mRNA and circulating protein level.
The whole body cryostimulation modifies irisin concentration and reduces inflammation in middle aged, obese men.
Dulian Katarzyna,Laskowski Radosław,Grzywacz Tomasz,Kujach Sylwester,Flis Damian J,Smaruj Mirosław,Ziemann Ewa
The anti-inflammatory effect induced by exposure to low temperature might trigger the endocrine function of muscle and fat tissue. Thus, the aim of this study was to investigate the influence of the whole body cryostimulation (CRY) on irisin, a myokine which activates oxygen consumption in fat cells as well as thermogenesis. In addition, the relationship between hepcidin (Hpc) - hormone regulating iron metabolism, and inflammation was studied. A group of middle aged men (n = 12, 38 ± 9 years old, BMI > 30 kg m(-2)) participated in the study. Subjects were exposed to a series of 10 sessions in a cryogenic chamber (once a day at 9:30 am, for 3 min, at temperature -110 °C). Blood samples were collected before the first cryostimulation and after completing the last one. Prior to treatment body composition and fitness level were determined. The applied protocol of cryostimulation lead to rise the blood irisin in obese non-active men (338.8 ± 42.2 vs 407.6 ± 118.5 ng mL(-1)), whereas has no effect in obese active men (371.5 ± 30.0 vs 343.3 ± 47.6 ng mL(-1)). Values recorded 24 h after the last cryo-session correlated significantly with the fat tissue, yet inversely with the skeletal muscle mass. Therefore, we concluded the subcutaneous fat tissue to be the main source of irisin in response to cold exposures. The applied cold treatment reduced the high sensitivity C-reactive protein (hsCRP) and Hpc concentration confirming its anti-inflammatory effect.
Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans.
Lee Paul,Linderman Joyce D,Smith Sheila,Brychta Robert J,Wang Juan,Idelson Christopher,Perron Rachel M,Werner Charlotte D,Phan Giao Q,Kammula Udai S,Kebebew Electron,Pacak Karel,Chen Kong Y,Celi Francesco S
Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.
Lack of Adipocyte-Fndc5/Irisin Expression and Secretion Reduces Thermogenesis and Enhances Adipogenesis.
Pérez-Sotelo D,Roca-Rivada A,Baamonde I,Baltar J,Castro A I,Domínguez E,Collado M,Casanueva F F,Pardo M
Irisin is a browning-stimulating molecule secreted from the fibronectin type III domain containing 5 precursor (FNDC5) by muscle tissue upon exercise stimulation. Despite its beneficial role, there is an unmet and clamorous need to discern many essential aspects of this protein and its mechanism of action not only as a myokine but also as an adipokine. Here we contribute to address this topic by revealing the nature and role of FNDC5/irisin in adipose tissue. First, we show that FNDC5/irisin expression and secretion are induced by adipocyte differentiation and confirm its over-secretion by human obese visceral (VAT) and subcutaneous (SAT) adipose tissues. Second, we show how secreted factors from human obese VAT and SAT decrease PGC1α, FNDC5 and UCP1 gene expression on differentiating adipocytes; this effect over UCP1 is blunted by blocking irisin in obese secretomes. Finally, by stable gene silencing FNDC5 we reveal that FNDC5-KO adipocytes show reduced UCP1 expression and enhanced adipogenesis.
FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise.
Huh Joo Young,Panagiotou Grigorios,Mougios Vassilis,Brinkoetter Mary,Vamvini Maria T,Schneider Benjamin E,Mantzoros Christos S
Metabolism: clinical and experimental
OBJECTIVE:In mouse, PGC1-α overexpression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. One prior study has shown that FNDC5 induces browning of subcutaneous fat in mice and mediates beneficial effects of exercise on metabolism, but a more recent study using gene expression arrays failed to detect a robust increase in FNDC5 mRNA in human muscles from exercising subjects. No prior study has reported on the physiological regulation and role of circulating irisin and FNDC5 in humans. MATERIALS/METHODS:A. FNDC5 gene expression studies: We first examined tissue distribution of FNDC5 in humans. B. Cross-sectional studies: Predictors of FNDC5 mRNA expression levels were examined in muscle tissues from 18 healthy subjects with a wide range of BMI. Assays were optimized to measure circulating FNDC5 and irisin levels, and their associations with anthropometric and metabolic parameters were analyzed in two cross-sectional studies that examined 117 middle-aged healthy women and 14 obese subjects, respectively. C. Interventional studies: The effect of weight loss on FNDC5 mRNA and/or circulating irisin levels was examined in 14 obese subjects before and after bariatric surgery. The effect of acute and chronic exercise was then assessed in 15 young healthy adults who performed intermittent sprint running sessions over an 8 week period. RESULTS:Tissue arrays demonstrated that in humans, the FNDC5 gene is predominantly expressed in muscle. Circulating irisin was detected in the serum or plasma of all subjects studied, whereas circulating FNDC5 was detected in only a distinct minority of the subjects. Cross-sectional studies revealed that circulating irisin levels were positively correlated with biceps circumference (used as a surrogate marker of muscle mass herein), BMI, glucose, ghrelin, and IGF-1. In contrast, irisin levels were negatively correlated with age, insulin, cholesterol, and adiponectin levels, indicating a possible compensatory role of irisin in metabolic regulation. Multivariate regression analysis revealed that biceps circumference was the strongest predictor of circulating irisin levels underlying the association between irisin and metabolic factors in humans at baseline. Both muscle FNDC5 mRNA levels and circulating irisin levels were significantly downregulated 6 months after bariatric surgery. Circulating irisin levels were significantly upregulated 30 min after acute exercise and were correlated mainly with ATP levels and secondarily with metabolites related to glycolysis and lipolysis in muscle. CONCLUSIONS:Similar to mice, the FNDC5 gene is expressed in human muscle. Age and muscle mass are the primary predictors of circulating irisin, with young male athletes having several fold higher irisin levels than middle-aged obese women. Circulating irisin levels increase in response to acute exercise whereas muscle FNDC5 mRNA and circulating irisin levels decrease after surgically induced weight loss in parallel to decrease in body mass. Further studies are needed to study the regulation of irisin levels and its physiological effects in humans and to elucidate the mechanisms underlying these effects.
Synergistic effect of carnosine on browning of adipose tissue in exercised obese rats; a focus on circulating irisin levels.
Schaalan Mona F,Ramadan Basma K,Abd Elwahab Azza H
Journal of cellular physiology
The recent appreciation of the energy burning capacity of brown adipose tissue turns it to an attractive target for anti-obesity therapy. We sought to evaluate the effect of L-carnosine on browning of white adipose tissue in exercised obese rats. Sixty adult male Wistar albino rats, 7-8 week-old weighing 130-150 g, were allocated into six groups; with 10 rats in each, for an experimentation period of 12 weeks: (i) normal control rats fed a standard fat diet (SFD/control), (ii) normal control rats fed a standard diet and injected with L-carnosine (250 mg/kg, i.p,) for 6 weeks (SFD/CAR), (iii) high-fat diet (HFD)-induced obese rats for 12 weeks, (iv) HFD rats subjected to exercise training (HFD/EXE) for 6 weeks, (v) HFD rats injected with L-carnosine (250 mg/kg,i.p.) for 6 weeks (HFD/CAR) and, (vi) HFD rats subjected to exercise training and L-carnosine (HFD/EXE/CAR). At the end of the 12-week-experiment, the body weights and the serum levels of lipid profile, oxidative stress, and inflammatory markers as well as circulating myokines were investigated. Gastrocnemius muscles and inguinal adipose tissues were excised for the measurement of gene expression of muscle irisin, adipose tissue uncoupling protein1 (UCP1), CD137 and the protein level of p38MAPK. In addition, histopathological examination for the studied groups was performed. Both exercise training for 6 weeks and carnosine treatment significantly decreased body weight gain, ameliorated obesity-induced dyslipidemia, reduced the thiobarbituric acid reactive species (TBARS) and TNF-α, while increased total antioxidant capacity and IL-10. Furthermore, increases in serum irisin levels and the expression of adipose uncoupling protein-1 (UCP-1), adipose CD137, p38 MAPK, and muscular fibronectin type III domain-containing protein 5(FNDC5), the precursor of irisin gene expression, were correlated with these carnosine- and exercise-induced physiological improvements. The highest improvement was evident in the combined exercise and carnosine group which indicates that their beneficial effects in obese animals were synergistic. These findings suggest that L-carnosine may induce browning of adipose tissue through irisin stimulation, a phenomenon that could be related to its antioxidant, anti-inflammatory, and anti-obesity effects.
Modulation of Irisin and Physical Activity on Executive Functions in Obesity and Morbid obesity.
Fagundo A B,Jiménez-Murcia S,Giner-Bartolomé C,Agüera Z,Sauchelli S,Pardo M,Crujeiras A B,Granero R,Baños R,Botella C,de la Torre R,Fernández-Real J M,Fernández-García J C,Frühbeck G,Rodríguez A,Mallorquí-Bagué N,Tárrega S,Tinahones F J,Rodriguez R,Ortega F,Menchón J M,Casanueva F F,Fernández-Aranda F
Whether the executive profile is different between obesity (OB) and morbid obesity (MO) remains unclear. Recent evidence suggests that physical activity (PA) can act as a cognitive enhancer. Irisin is a recently discovered hormone associated with some of the positive effects of PA. The objective of the study was to investigate the executive profile in OB and MO, and to explore the role of PA and irisin. 114 participants were included (21 OB, 44 MO and 49 healthy controls-HC) in the study and assessed with the Wisconsin Card Sorting Test, Stroop Color and Word Test, and Iowa Gambling Task. All participants were female, aged between 18 and 60 years. Results showed a similar dysfunctional profile on decision making in OB and MO compared with HC. Thus, no specific neuropsychological profiles between OB and MO can be clearly observed in our sample. However, a negative correlation was found between irisin and executive functioning. These results demonstrate a specific executive profile in OB and a relevant and negative modulation of irisin on executive functioning. Although irisin might be a promising target for the treatment of obesity, its effects on cognition might be considered when thinking about its therapeutic use.
Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity--correlation with body mass index.
Stengel Andreas,Hofmann Tobias,Goebel-Stengel Miriam,Elbelt Ulf,Kobelt Peter,Klapp Burghard F
Irisin was recently identified as cleavage product of fibronectin type III domain containing 5 (FNDC5) and shown to increase energy expenditure in mice and humans and therefore was discussed as potential treatment option in obesity. However, the regulation of irisin under conditions of severely altered body weight such as anorexia nervosa and obesity remains to be investigated. We analyzed circulating irisin levels over a broad spectrum of body weight in 40 patients with anorexia nervosa (mean body mass index, BMI 12.6±0.7 kg/m(2)), normal weight controls (22.6±0.9 kg/m(2)) and obese patients with BMI of 30-40 (36.9±1.2 kg/m(2)), 40-50 (44.9±1.1 kg/m(2)) and >50 (70.1±2.7 kg/m(2), n=8/group). Correlation analyses were performed between irisin and different body indices, parameters of body composition and hormones involved in various homeostatic processes. Obese patients showed higher circulating irisin levels compared to normal weight and anorexic patients (p<0.05) resulting in a correlation of irisin with body weight (r=0.47, p<0.01) and BMI (r=0.50, p<0.001). Plasma irisin was also positively correlated with fat mass (r=0.48, p<0.01), body cell mass (r=0.45, p<0.01) and fat free mass (r=0.40, p<0.05). Insulin levels were positively correlated with irisin (r=0.45, p<0.01), whereas circulating ghrelin, cortisol, thyroid-stimulating hormone or C-reactive protein were not (p>0.05). These data indicate that circulating irisin is affected under conditions of altered BMI with highest levels in severely obese patients. The increase of irisin under conditions of obesity may indicate a physiological function to improve glucose tolerance which is often impaired in obese subjects.
Endurance training-induced increase in circulating irisin levels is associated with reduction of abdominal visceral fat in middle-aged and older adults.
Miyamoto-Mikami Eri,Sato Koji,Kurihara Toshiyuki,Hasegawa Natsuki,Fujie Shumpei,Fujita Satoshi,Sanada Kiyoshi,Hamaoka Takafumi,Tabata Izumi,Iemitsu Motoyuki
To elucidate the effects of endurance training on circulating irisin levels in young and middle-aged/older adults, and to determine the association between endurance training-induced alteration of irisin and reduction in body fat. Twenty-five healthy young (age 21 ± 1 years; 16 men, 9 women) and 28 healthy middle-aged/older adults (age 67 ± 8 years; 12 men, 16 women) participated in the study. Each age cohort was divided into two groups: the endurance-training group (14 young, 14 middle-aged/older) and the control group. Subjects in the training groups completed an 8-week endurance-training program (cycling at 60-70% peak oxygen uptake [V̇O2peak] for 45 min, 3 days/week). Before and after the intervention, we evaluated serum irisin level, V̇O2peak, and body composition. The increase in V̇O2peak in the young and middle-aged/older training groups after the intervention period was significantly greater than those in the young and middle-aged/older control groups (P < 0.05). Serum irisin level was significantly increased in the middle-aged/older training group after the intervention period (P < 0.01), but not in the young training group. Furthermore, in the middle-aged/older training group, the endurance training-induced reduction in visceral adipose tissue area was negatively correlated with the change in serum irisin level (r = -0.54, P < 0.05). These results suggest a possible role for secreted irisin in the exercise-induced alteration of abdominal visceral fat in middle-aged and older adults.
Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects.
Lopez-Legarrea P,de la Iglesia R,Crujeiras A B,Pardo M,Casanueva F F,Zulet M A,Martinez J A
Nutrition & diabetes
Irisin is assumed to be a relevant link between muscle and weight maintenance as well as to mediate exercise benefits on health. The aim of this study was to assess the possible associations between irisin levels and glucose homeostasis in obese subjects with metabolic syndrome (MetS) following an energy-restricted treatment. Ninety-six adults with excessive body weight and MetS features underwent a hypocaloric dietary pattern for 8 weeks, within the RESMENA randomized controlled trial (www.clinicaltrials.gov; NCT01087086). After the intervention, dietary restriction significantly reduced body weight and evidenced a dietary-induced decrease in circulating levels of irisin in parallel with improvements on glucose homeostasis markers. Interestingly, participants with higher irisin values at baseline (above the median) showed a greater reduction on glucose (P=0.022) and insulin (P=0.021) concentrations as well as on the homeostasis model assessment index (P=0.008) and triglycerides (P=0.006) after the dietary intervention, compared with those presenting low-irisin baseline values (below the median). Interestingly, a positive correlation between irisin and carbohydrate intake was found at the end of the experimental period. In conclusion, irisin appears to be involved in glucose metabolism regulation after a dietary-induced weight loss.
Irisin has no effect on lipolysis in 3T3-L1 adipocytes or fatty acid metabolism in HepG2 hepatocytes.
Wang Chuan,Wang Lingshu,Li Wenjuan,Yan Fei,Tian Meng,Wu Chuanlong,Qi Lin,Wang Xuping,Song Jun,Hou Xinguo,Chen Li
Irisin, a newly identified myokine responsible for browning of white or beige adipocytes, has been reported to be present at reduced levels in diabetic patients and associated with obesity, serum triglyceride (TG) levels, and intrahepatic TG levels. We wondered whether irisin could directly affect fatty acid and TG metabolism in adipocytes and hepatocytes. We examined the effects of various concentrations of irisin on lipolysis (according to Oil Red O staining, free fatty acid release, and glycerol release), protein expression of HSL and ATGL, and mRNA expression of other lipid-related genes (UCP-1, PPARγ, FABP-4, HSL, ATGL, PPARα, and CPT-1) in mature 3T3-L1 adipocytes, as well as mRNA levels of genes involved in the synthesis (SREBP-1C and FAS) and β-oxidation (PPARα and CPT-1) of fatty acids in HepG2 hepatocytes under physiological or hyperglycemic conditions. Our results revealed that although irisin significantly increased the mRNA levels of UCP-1 and PPARα, it failed to show detectable effects on lipolysis, HSL or ATGL protein levels, or the mRNA expression of other lipid-related genes in mature 3T3-L1 adipocytes. In HepG2 hepatocytes, high glucose induced the upregulation of SREBP-1C and FAS and the downregulation of PPARα; however, no significant effect of irisin on gene expression was observed under either physiological or hyperglycemic conditions. We therefore conclude that irisin has no significant direct effect on lipolysis in 3T3-L1 adipocytes or on fatty acid metabolism in HepG2 hepatocytes.
Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance.
Moreno-Navarrete José María,Ortega Francisco,Serrano Marta,Guerra Ester,Pardo Gerard,Tinahones Francisco,Ricart Wifredo,Fernández-Real José Manuel
The Journal of clinical endocrinology and metabolism
CONTEXT:Recently irisin (encoded by Fndc5 gene) has been reported to stimulate browning and uncoupling protein 1 expression in sc adipose tissue of mice. OBJECTIVE:The objective of the study was to investigate FNDC5 gene expression in human muscle and adipose tissue and circulating irisin according to obesity, insulin sensitivity, and type 2 diabetes. DESIGN, PATIENTS, AND MAIN OUTCOME MEASURE:Adipose tissue FNDC5 gene expression and circulating irisin (ELISA) were analyzed in 2 different cohorts (n = 125 and n = 76); muscle FNDC5 expression was also evaluated in a subcohort of 34 subjects. In vitro studies in human preadipocytes and adipocytes and in induced browning of 3T3-L1 cells (by means of retinoblastoma 1 silencing) were also performed. RESULTS:In both sc and visceral adipose tissue, FNDC5 gene expression decreased significantly in association with obesity and was positively associated with brown adipose tissue markers, lipogenic, insulin pathway-related, mitochondrial, and alternative macrophage gene markers and negatively associated with LEP, TNFα, and FSP27 (a known repressor of brown genes). Circulating irisin and irisin levels in adipose tissue were significantly associated with FNDC5 gene expression in adipose tissue. In muscle, the FNDC5 gene was 200-fold more expressed than in adipose tissue, and its expression was associated with body mass index, PGC1α, and other mitochondrial genes. In obese participants, FNDC5 gene expression in muscle was significantly decreased in association with type 2 diabetes. Interestingly, muscle FNDC5 gene expression was significantly associated with FNDC5 and UCP1 gene expression in visceral adipose tissue. In men, circulating irisin levels were negatively associated with obesity and insulin resistance. Irisin was secreted from human adipocytes into the media, and the induction of browning in 3T3-L1 cells led to increased secreted irisin levels. CONCLUSIONS:Decreased circulating irisin concentration and FNDC5 gene expression in adipose tissue and muscle from obese and type 2 diabetic subjects suggests a loss of brown-like characteristics and a potential target for therapy.
Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling.
Zhang Yuan,Li Rui,Meng Yan,Li Shiwu,Donelan William,Zhao Yan,Qi Lei,Zhang Mingxiang,Wang Xingli,Cui Taixing,Yang Li-Jun,Tang Dongqi
The number and activity of brown adipocytes are linked to the ability of mammals to resist body fat accumulation. In some conditions, certain white adipose tissue (WAT) depots are readily convertible to a ''brown-like'' state, which is associated with weight loss. Irisin, a newly identified hormone, is secreted by skeletal muscles into circulation and promotes WAT "browning" with unknown mechanisms. In the current study, we demonstrated in mice that recombinant irisin decreased the body weight and improved glucose homeostasis. We further showed that irisin upregulated uncoupling protein-1 (UCP-1; a regulator of thermogenic capability of brown fat) expression. This effect was possibly mediated by irisin-induced phosphorylation of the p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-related kinase (ERK) signaling pathways. Inhibition of the p38 MAPK by SB203580 and ERK by U0126 abolished the upregulatory effect of irisin on UCP-1. In addition, irisin also promoted the expression of betatrophin, another newly identified hormone that promotes pancreatic β-cell proliferation and improves glucose tolerance. In summary, our data suggest that irisin can potentially prevent obesity and associated type 2 diabetes by stimulating expression of WAT browning-specific genes via the p38 MAPK and ERK pathways.
Association between circulating irisin levels and the promotion of insulin resistance during the weight maintenance period after a dietary weight-lowering program in obese patients.
Crujeiras Ana B,Zulet M Angeles,Lopez-Legarrea Patricia,de la Iglesia Rocío,Pardo María,Carreira Marcos C,Martínez J Alfredo,Casanueva Felipe F
Metabolism: clinical and experimental
OBJECTIVE:Weight regain is associated with the promotion of insulin resistance. The newly discovered myokine irisin, which was proposed to be involved in the management of insulin sensitivity, could play a role in this process. This study aimed to investigate the association between irisin and reduced insulin sensitivity induced by weight regain. MATERIALS/METHODS:Insulin sensitivity was evaluated according to the homeostasis model assessment of insulin resistance (HOMA-IR) in 136 obese patients who followed an eight-week hypocaloric diet (30% reduced energy expenditure) to lose weight and was re-evaluated four or six months after treatment. Irisin plasma levels, as well as the levels of leptin, adiponectin, ghrelin and TNF-α, were quantified in a sub-cohort (n=73) from the initially studied patients at baseline (T0), at the diet endpoint (T1) and after the follow-up period (T2). RESULTS:After a successful dietary intervention to lose weight, 50% of the patients who regained the lost weight during the follow-up period were categorized as insulin resistant (HOMA-IR≥2.5) compared with only 25% of patients who maintained the weight loss (p=0.018). Importantly, in addition to the well-studied hormones leptin and adiponectin, irisin plasma levels were statistically associated with several risk factors for insulin resistance. Indeed, the increased risk of insulin resistance during the follow-up period was related to high irisin levels at baseline (odds ratio=4.2; p=0.039). CONCLUSIONS:Circulating irisin predicts the insulin resistance onset in association with weight regain. Therefore, irisin could be secreted as an adaptive response to counteract the deleterious effect of excess adiposity on glucose homeostasis.
Effects of lipid-lowering drugs on irisin in human subjects in vivo and in human skeletal muscle cells ex vivo.
Gouni-Berthold Ioanna,Berthold Heiner K,Huh Joo Young,Berman Reena,Spenrath Nadine,Krone Wilhelm,Mantzoros Christos S
CONTEXT AND OBJECTIVE:The myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs). DESIGN AND PARTICIPANTS:A randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. RESULTS:Baseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage. CONCLUSIONS:Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress. TRIAL REGISTRATION:ClinicalTrials.gov NCT00317993 NCT00317993.
Irisin: A Hope in Understanding and Managing Obesity and Metabolic Syndrome.
Arhire Lidia I,Mihalache Laura,Covasa Mihai
Frontiers in endocrinology
White adipose tissue (WAT) is an endocrine organ highly integrated in homeostasis and capable of establishing ways of communicating and influencing multiple metabolic processes. Brown adipose tissue promotes energy expenditure by incorporating the uncoupling protein 1 (UCP1), also known as thermogenin, which decouples cellular respiration and heat production, in the mitochondrial membranes. Recent data suggest the presence of a thermogenic cell formation from white adipocytes (beige or brite cells) with a potential role in preventing obesity and metabolic syndrome. The formation of these cells is influenced by physical exertion that induces expression of PPARγ coactivator-1 (PGC1) and downstream membrane protein, fibronectin type III domain-containing protein 5 (FNDC5) in skeletal muscle. Irisin, a thermogenic adipomyokine produced by FNDC5 cleavage is involved in the browning of adipose tissue. While animal studies are congruent with regard to the relationship between physical exertion and irisin release, the results from human studies are less than clear. Therefore, this review focuses on recent advances in our understanding of muscle and adipose tissue thermogenesis. Further, it describes the molecular mechanisms by which irisin impacts exercise, glucose homeostasis and obesity. Finally, the review discusses current gaps and controversies related to irisin release, its mode of action and its future potential as a therapeutic tool in managing obesity and metabolic syndrome.
Plasma irisin in runners and nonrunners: no favorable metabolic associations in humans.
Hew-Butler Tamara,Landis-Piwowar Kristin,Byrd Gregory,Seimer Max,Seigneurie Nicole,Byrd Brigid,Muzik Otto
Irisin is a hormone which mimics the favorable metabolic effects associated with regular exercise, by converting subcutaneous white fat into brownish fat, in rodents. Thirty-three human subjects (16 runners, 17 nonrunners) were measured for: resting energy expenditure (REE), body composition, VO2 Peak test, [irisin]p, and plasma metabolic profile. Nine female nonrunners then participated in a 10-week supervised 5 km training program and tested after the race. Two runners underwent (18)F-FDG-PET scans to quantify brown fat. No gender or age (28 ± 10 years) differences noted between matched cohorts. Runners averaged 58 ± 26 miles/week for 13 ± 6 years and had lower bodyweight (63 vs. 88 kg; P < 0.001), BMI (21 vs. 30 kg/m(2); P < 0.0001), triglycerides (58 vs. 123 mg/dL; P < 0.01), total (white) fat (14 vs. 32%; P < 0.0001), and had higher VO2 Peak (63 vs. 34 mL/kg-min; P < 0.0001) and HDL (65 vs. 48 mg/dL; P < 0.01) compared with nonrunners. [Irisin]p was lower in runners versus nonrunners both before (179 vs. 197 ng/mL; NS) and after (207 vs. 226 ng/mL; NS) the VO2 Peak test. Significant (P < 0.05) positive correlations were noted between [irisin]p versus BMI (r(2) = 0.15), triglycerides (r(2) = 0.40), and total body fat(g) (r(2) = 0.24) with a significant negative correlation between [irisin]p versus respiratory quotient (r(2) = 0.33). Total lean mass significantly correlated with REE (r(2) = 0.58) while total fat mass inversely correlated with VO2 Peak (r(2) = 0.64). Nonrunners had lower [irisin]p after completion of the training program (194 vs.181 ng/mL; pre- to post-training; P > 0.05). Neither runner selected for (18)F-FDG-PET scans had brown fat. Runners demonstrated significantly healthier metabolic and body composition profiles compared with nonrunners. None of these favorable exercise effects were positively associated with [irisin]p..
Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue: in vivo and in vitro studies.
Kurdiova Timea,Balaz Miroslav,Vician Marek,Maderova Denisa,Vlcek Miroslav,Valkovic Ladislav,Srbecky Miroslav,Imrich Richard,Kyselovicova Olga,Belan Vitazoslav,Jelok Ivan,Wolfrum Christian,Klimes Iwar,Krssak Martin,Zemkova Erika,Gasperikova Daniela,Ukropec Jozef,Ukropcova Barbara
The Journal of physiology
Irisin was identified as a myokine secreted by contracting skeletal muscle, possibly mediating some exercise health benefits via 'browning' of white adipose tissue. However, a controversy exists concerning irisin origin, regulation and function in humans. Thus, we have explored Fndc5 gene and irisin protein in two clinical studies: (i) a cross-sectional study (effects of type 2 diabetes (T2D) in drug-naive men) and (ii) an intervention study (exercise effects in sedentary, overweight/obese individuals). Glucose tolerance and insulin sensitivity were assessed. Maximal aerobic capacity and muscle strength were measured before and after training. Body composition (magnetic resonance imaging), muscle and liver fat content (1H-magnetic resonance spectroscopy (MRS)) and in vivo muscle metabolism (32P-MRS) were determined. Skeletal muscle and subcutaneous abdominal adipose tissue samples were taken in the fasted state and during euglycaemic hyperinsulinaemia (adipose tissue) and before/after exercise training (muscle). We found that muscle Fndc5 mRNA was increased in prediabetes but not T2D. Fndc5 in adipose tissue and irisin in plasma were reduced in T2D by 40% and 50%, respectively. In contrast, T2D-derived myotubes expressed/secreted the highest levels of Fndc5/irisin. Neither hyperinsulinaemia (adipose tissue/plasma) nor exercise (muscle/plasma) affected Fndc5/irisin in vivo. Circulating irisin was positively associated with muscle mass, strength and metabolism and negatively with fasting glycaemia. Glucose and palmitate decreased Fndc5 mRNA in myotubes in vitro. We conclude that distinct patterns of Fndc5/irisin in muscle, adipose tissue and circulation, and concordant in vivo down-regulation in T2D, indicate that irisin might distinguish metabolic health and disease. Moreover, Fndc5/irisin was discordantly regulated in diabetic muscle and myotubes in vitro, suggesting that whole body factors, such as glucose and fatty acids, might be important for irisin regulation. Exercise did not affect Fndc5/irisin. However, irisin was positively linked to muscle mass, strength and metabolism, pointing to common regulatory factors and/or the potential for irisin to modify muscle phenotype.
Association of serum irisin with metabolic syndrome in obese Chinese adults.
Yan Bing,Shi Xiulin,Zhang Huijie,Pan Lingling,Ma Zhimin,Liu Suhuan,Liu Yongwen,Li Xiaoying,Yang Shuyu,Li Zhibin
Irisin, a recently identified novel myokine, drives brown-fat-like conversion of white adipose tissues and has been proposed to mediate beneficial effects of exercise on metabolism. Circulating irisin was significantly reduced in type 2 diabetes patients; however, no evidence is available about its association with metabolic syndrome (MetS) and effects of adiposity and muscle mass on circulating irisin have been controversial. Cross-sectional data on socio-demographic, lifestyle, clinical characteristics and serum irisin were collected for 1,115 community-living Chinese adults with central obesity. Associations of serum irisin with MetS (central obesity plus any two of the following four factors (raised blood pressure (BP), raised fasting plasma glucose (FPG), raised triglyceride (TG), and reduced HDL cholesterol) and each component of MetS were analyzed using multivariable logistic regression. Among the 1,115 obese Chinese adults with a mean age of 53.2(±7.2) years, serum irisin levels (log-transformed) were significantly reduced in subjects with MetS and raised FPG than their control groups (p = 0.034 and 0.041, respectively). After adjustment for potential confounders, serum irisin was significantly associated with reduced risks of MetS and raised FPG, with odds ratios (ORs) (95% CI) per standard deviation of log-transformed irisin of 0.796 (0.505-0.959, p = 0.027) and 0.873 (0.764-0.998, p = 0.046), respectively. Associations of irisin with raised BP, raised TG and reduced HDL were not statistically significant ((ORs) (95% CI): 0.733(0.454-1.182, p = 0.202), 0.954(0.838-1.086, p = 0.478) and 1.130(0.980-1.302, p = 0.092), respectively). Stepwise multivariable linear regression analysis showed that fasting insulin, HbA1c and albumin/globulin ratio were negatively associated with serum irisin level with statistical significance (all p-values <0.05) and waist circumference was negatively associated with serum risin with marginally statistical significance (p = 0.055). These results imply that irisin may play an important role in insulin resistance and MetS and should be confirmed in future prospective studies.
The relationship between circulating irisin, retinol binding protein-4, adiponectin and inflammatory mediators in patients with metabolic syndrome.
Tabak Omur,Simsek Gonul,Erdenen Fusun,Sozer Volkan,Hasoglu Tuna,Gelisgen Remise,Altunoglu Esma,Muderrisoglu Cuneyt,Senyigit Abdulhalim,Uzun Hafize
Archives of endocrinology and metabolism
OBJECTIVE:We wanted to investigate whether there is a relationship between circulating irisin, retinol binding protein-4 (RBP-4), adiponectin and proinflammatory mediators implicated in the development of insulin resistance (IR) in metabolic syndrome (MetS). SUBJECTS AND METHODS:In 180 individuals, including controls and patients with MetS, we measured fasting plasma insulin, high sensitivity C-reactive protein (hsCRP), pentraxin-3 (PTX-3), interleukin-33 (IL-33), irisin, RBP-4, and adiponectin using ELISA kits. RESULTS:While fasting plasma hsCRP, PTX-3, IL-33, irisin, RBP-4 concentrations were higher, adiponectin levels were lower in patients with MetS than in controls. A correlation analysis revealed that plasma irisin levels were positively associated with MetS components such as waist circumference and waist-hip ratio, low density lipoprotein (LDL) and markers of systemic inflammation such as PTX-3, hsCRP, uric acid, and RBP-4. Adiponectin levels were negatively associated with waist circumference, waist-hip ratio, PTX-3 and LDL. CONCLUSIONS:Although the precise mechanisms are still unclear, irisin, RBP-4, adiponectin and PTX-3 are hallmarks of the MetS, which is related to low-grade inflammation. It is conceivable that irisin and adiponectin might contribute to the development of MetS and may also represent novel MetS components. Future clinical studies are needed to confirm and extend these data.
Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo.
Amengual Jaume,García-Carrizo Francisco J,Arreguín Andrea,Mušinović Hana,Granados Nuria,Palou Andreu,Bonet M Luisa,Ribot Joan
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND/AIMS:All-trans retinoic acid (ATRA) has protective effects against obesity and metabolic syndrome. We here aimed to gain further insight into the interaction of ATRA with skeletal muscle metabolism and secretory activity as important players in metabolic health. METHODS:Cultured murine C2C12 myocytes were used to study direct effects of ATRA on cellular fatty acid oxidation (FAO) rate (using radioactively-labelled palmitate), glucose uptake (using radioactively-labelled 2-deoxy-D-glucose), triacylglycerol levels (by an enzymatic method), and the expression of genes related to FAO and glucose utilization (by RT-real time PCR). We also studied selected myokine production (using ELISA and immunohistochemistry) in ATRA-treated myocytes and intact mice. RESULTS:Exposure of C2C12 myocytes to ATRA led to increased fatty acid consumption and decreased cellular triacylglycerol levels without affecting glucose uptake, and induced the expression of the myokine irisin at the mRNA and secreted protein level in a dose-response manner. ATRA stimulatory effects on FAO-related genes and the Fndc5 gene (encoding irisin) were reproduced by agonists of peroxisome proliferator-activated receptor β/δ and retinoid X receptors, but not of retinoic acid receptors, and were partially blocked by an AMP-dependent protein kinase inhibitor. Circulating irisin levels were increased by 5-fold in ATRA-treated mice, linked to increased Fndc5 transcription in liver and adipose tissues, rather than skeletal muscle. Immunohistochemistry analysis of FNDC5 suggested that ATRA treatment enhances the release of FNDC5/irisin from skeletal muscle and the liver and its accumulation in interscapular brown and inguinal white adipose depots. CONCLUSION:These results provide new mechanistic insights on how ATRA globally stimulates FAO and enhances irisin secretion, thereby contributing to leaning effects and improved metabolic status.
Chronic Exercise Training and Circulating Irisin in Adults: A Meta-Analysis.
Qiu Shanhu,Cai Xue,Sun Zilin,Schumann Uwe,Zügel Martina,Steinacker Jürgen Michael
Sports medicine (Auckland, N.Z.)
BACKGROUND:Irisin is a newly discovered hormone that is proposed to be a promising therapeutic target in obesity and type 2 diabetes. It has received remarkable attention recently, while inconsistent results have been shown regarding its association with chronic exercise training in adults. OBJECTIVE:The aim of this study was to evaluate the effects of chronic exercise training on circulating (plasma/serum) irisin in adults by meta-analyzing randomized controlled trials (RCTs) and non-randomized studies (NRSs) separately. METHODS:We conducted a search of the PubMed, Web of Science and Cochrane Library databases from January 2012 to September 2014 for studies published in English. Studies were included if they had an assessment of chronic (≥8 weeks) exercise training effects on circulating irisin in the general or clinical population (mean age ≥18 years) with reported outcomes of circulating irisin, and involved more than five participants. Pooled effect sizes (Cohen's d) with 95 % confidence intervals (CIs) for changes in circulating irisin were calculated by a random-effects model. Subgroup analyses were performed to evaluate the association between exercise modes and changes in circulating irisin. RESULTS:Of the 181 articles screened, 12 studies in eight articles were included, of which three were RCTs and nine were NRSs. In the three RCTs (a total of 173 healthy, untrained participants), chronic exercise training was associated with a moderate and significant overall effect in decreasing circulating irisin compared with the control (d = -0.46; 95 % CI -0.76 to -0.15). Chronic resistance exercise training showed a moderate and significant effect in decreasing circulating irisin compared with the control (d = -0.41; 95 % CI -0.75 to -0.06), while endurance exercise training only had a trend (d = -0.64; 95 % CI -1.32 to 0.04). In the nine NRSs (a total of 113 intervention participants), chronic exercise training was associated with a trivial and non-significant overall effect in decreasing circulating irisin compared with baseline (d = -0.04; 95 % CI -0.30 to 0.23). CONCLUSIONS:Chronic exercise training leads to significantly decreased circulating irisin levels in the RCTs, while evidence remains inconclusive in the NRSs. Well-designed RCTs that measure dietary intake and report changes of body fat percentage or insulin sensitivity/resistance index following chronic exercise training are required to confirm these findings.
Irisin levels in relation to metabolic and liver functions in Egyptian patients with metabolic syndrome.
Rizk Fatma H,Elshweikh Samah A,Abd El-Naby Amira Y
Canadian journal of physiology and pharmacology
Irisin is a new myokine that is suspected to influence metabolic syndrome (MetS). However, there is a great controversy with respect to its level in cases of MetS and its correlation with different metabolic parameters. The present study assesses irisin levels in MetS patients and studies its relationship to metabolic and liver functions to evaluate the possible role of the liver in regulation of this level. Sixty subjects were included in this experiment, who were divided into 3 groups: group I (normal control), group II (MetS patients with normal liver enzymes), and group III (MetS with elevated liver enzymes and fatty liver disease). Serum irisin levels showed significant increases in groups II and III compared with group I, and significant increases in group III compared with group II. Also, irisin levels were positively correlated with body mass index, serum triglycerides, homeostatic model assessment of insulin resistance index (HOMA-IR), and liver enzymes. We concluded that serum irisin levels increased in patients with MetS, especially those with elevated liver enzymes, and had a positive correlation with parameters of lipid metabolism and glucose homeostasis with the possibility of hepatic clearance to irisin.
ROCK1 reduces mitochondrial content and irisin production in muscle suppressing adipocyte browning and impairing insulin sensitivity.
Zhou Xiaoshuang,Li Rongshan,Liu Xinyan,Wang Lihua,Hui Peng,Chan Lawrence,Saha Pradip K,Hu Zhaoyong
Irisin reportedly promotes the conversion of preadipocytes into "brown-like" adipocytes within subcutaneous white adipose tissue (WAT) via a mechanism that stimulates UCP-1 expression. An increase in plasma irisin has been associated with improved obesity and insulin resistance in mice with type 2 diabetes. But whether a low level of irisin stimulates the development of obesity has not been determined. In studying mice with muscle-specific constitutive ROCK1 activation (mCaROCK1), we found that irisin production was down-regulated and the mice developed obesity and insulin resistance. Therefore, we studied the effects of irisin deficiency on energy metabolism in mCaROCK1 mice. Constitutively activation of ROCK1 in muscle suppressed irisin expression in muscle resulting in a low level of irisin in circulation. Irisin deficiency reduced heat production and decreased the expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) and subcutaneous WAT. Moreover, mCaROCK1 mice also displayed impaired glucose tolerance. Notably, irisin replenishment in mCaROCK1 mice partially reversed insulin resistance and obesity and these changes were associated with increased expression of UCP1 and Pref-1 in subcutaneous WAT. These results demonstrate that irisin mediates muscle-adipose tissue communication and regulates energy and glucose homeostasis. Irisin administration can correct obesity and insulin resistance in mice.
Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway.
Xin C,Liu J,Zhang J,Zhu D,Wang H,Xiong L,Lee Y,Ye J,Lian K,Xu C,Zhang L,Wang Q,Liu Y,Tao L
International journal of obesity (2005)
BACKGROUND/OBJECTIVES:It has been reported that irisin regulated exercise-mediated adipocyte browning; however, the systematical effects of irisin on the metabolism of glucose and lipid in diabetes are largely unknown. In the present study, we investigated the role and underlying mechanism of irisin in glucose utilization and lipid metabolism in diabetic mice. METHODS:A mouse model of diabetes was established by feeding C57BL/6 mice with high-fat diet. The diabetic mice were then treated with irisin. To mimic type 2 diabetes in vitro, myocytes and hepatocytes were cultured in a medium of high glucose and high fat. Glucose uptake, fatty acid oxidation and the expression of related protein were evaluated. RESULTS:Irisin improved glucose tolerance and glucose uptake as evidenced by increased (18)F-FDG accumulation and GLUT4 translocation in diabetic skeletal muscle. Irisin also increased glucose uptake in myocytes cultured in high glucose/high fatty acid medium. In contrast, irisin reduced the expression of PEPCK and G6Pase, which are involved in gluconeogenesis, in diabetic liver. Consistently, irisin reduced fat weight and serum total cholesterol and triglyceride levels in diabetic mice, but increased acetyl coenzyme A carboxylase-β phosphorylation in muscle tissue and uncoupling protein 1 expression in fat tissue. In addition, irisin increased the oxidation of fatty acid in myocytes. Knockdown of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) attenuated the effects of irisin on glucose uptake and fatty acid β-oxidation in myocytes. Similarly, inhibition of AMPK by a specific inhibitor reduced the effects of irisin on PEPCK and G6Pase expression in hepatocytes. CONCLUSIONS:Our results suggest that irisin has an essential role in glucose utilization and lipid metabolism, and irisin is a promising pharmacological target for the treatment of diabetes and its complications.
FNDC5 overexpression and irisin ameliorate glucose/lipid metabolic derangements and enhance lipolysis in obesity.
Xiong Xiao-Qing,Chen Dan,Sun Hai-Jian,Ding Lei,Wang Jue-Jin,Chen Qi,Li Yue-Hua,Zhou Ye-Bo,Han Ying,Zhang Feng,Gao Xing-Ya,Kang Yu-Ming,Zhu Guo-Qing
Biochimica et biophysica acta
Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5), and contributes to the beneficial effects of exercise on metabolism. Here we report the therapeutical effects of FNDC5/irisin on metabolic derangements and insulin resistance in obesity, and show the lipolysis effect of irisin and its signal molecular mechanism. In obese mice, lentivirus mediated-FNDC5 overexpression enhanced energy expenditure, lipolysis and insulin sensitivity, and reduced hyperlipidemia, hyperglycemia, hyperinsulinism, blood pressure and norepinephrine levels; it increased hormone-sensitive lipase (HSL) expression and phosphorylation, and reduced perilipin level and adipocyte diameter in adipose tissues. Subcutaneous perfusion of irisin reduced hyperlipidemia and hyperglycemia, and improved insulin resistance. Either FNDC5 overexpression or irisin perfusion only induced a tendency toward a slight decrease in body weight in obese mice. In 3T3-L1 adipocytes, irisin enhanced basal lipolysis rather than isoproterenol-induced lipolysis, which were prevented by inhibition of adenylate cyclase or PKA; irisin increased the HSL and perilipin phosphorylation; it increased PKA activity, and cAMP and HSL mRNA levels, but reduced perilipin expression. These results indicate that FNDC5/irisin ameliorates glucose/lipid metabolic derangements and insulin resistance in obese mice, and enhances lipolysis via cAMP-PKA-HSL/perilipin pathway. FNDC5 or irisin can be taken as an effective therapeutic strategy for metabolic disorders.
Circulating Irisin Concentrations Are Associated with a Favourable Lipid Profile in the General Population.
Oelmann Simon,Nauck Matthias,Völzke Henry,Bahls Martin,Friedrich Nele
BACKGROUND/AIMS:Irisin is a myokine, which is mainly inversely associated with the risk for non-communicable diseases. Irisin improves cellular energy metabolism by uncoupling the mitochondrial respiratory chain resulting in increased energy expenditure using lipids. To date potential associations between irisin concentration and lipid profile are poorly understood. Therefore, this investigation aimed to evaluate potential associations between irisin and lipid levels in the general population. METHODS:Data of 430 men and 537 women from the population-based Study of Health in Pomerania (SHIP-TREND) with available irisin and lipid concentrations were used. Analyses of variance, linear and logistic regression models adjusted for age, HBA1c, waist circumference, physical activity, smoking, alcohol consumption, systolic blood pressure, ALAT were calculated. RESULTS:We detected significantly inverse associations between irisin and circulating levels of total [beta coefficient 0.21 (standard error 0.08), p = 0.01], low-density cholesterol [-0.16 (0.07), p = 0.03] and triglycerides [-0.17 (0.08), p = 0.02] for men. Females without lipid lowering medication had an inverse association between irisin and total cholesterol [-0.12 (0.06), p = 0.05]. Further, male subjects with irisin concentrations in the third tertile had an increased odds for elevated low-density cholesterol [odds ratio 1.96 (95% confidence interval 1.07-3.48), p = 0.03) and triglyceride [1.95 (1.09-3.47), p = 0.02] levels, even after exclusion of subjects with lipid lowering medication. In addition, our data revealed an annual rhythm of serum irisin levels with peak levels arise in winter and summer months. CONCLUSION:This is the first investigation to report a significant association between circulating irisin and a favourable lipid profile in the general population. This may infer that higher irisin concentrations are associated with a reduced risk for non-communicable diseases.
Plasma irisin is increased following 12 weeks of Nordic walking and associates with glucose homoeostasis in overweight/obese men with impaired glucose regulation.
Korkmaz Ayhan,Venojärvi Mika,Wasenius Niko,Manderoos Sirpa,Deruisseau Keith C,Gidlund Eva-Karin,Heinonen Olli J,Lindholm Harri,Aunola Sirkka,Eriksson Johan G,Atalay Mustafa
European journal of sport science
Irisin is a myokine that is thought to be secreted in response to exercise that may help to prevent obesity and maintain normal glucose metabolism. In this study we investigated the associations between irisin and glucose homeostasis in middle-aged, overweight and obese men (n = 144) with impaired glucose regulation, and the impact of exercise training on these relationships. The participants underwent 12 weeks of resistance or aerobic (Nordic walking) exercise training three times per week, 60 minutes per session. Venous blood (n = 105) and skeletal muscle samples (n = 45) were obtained at baseline and post-intervention. Compared to controls, Nordic walking, but not resistance training, increased irisin levels in plasma (9.6 ± 4.2%, P = 0.014; 8.7 ± 4.9%, P = 0.087; respectively) compared to controls. When considering all subjects, baseline irisin correlated positively with atherogenic index of plasma (r = 0.244, P = 0.013) and 2-hour insulin levels (r = 0.214, P = 0.028), and negatively with age (r = -0.262, P = 0.007), adiponectin (r = -0.240, P = 0.014) and McAuley index (r = -0.259, P = 0.008). Training-induced FNDC5 mRNA changes were negatively correlated with HbA1c (r = -0.527, P = 0.030) in the resistance training group and with chemerin in the Nordic walking group (r = -0.615, P = 0.033). In conclusion, 12-weeks of Nordic walking was more effective than resistance training in elevating plasma irisin, in middle-aged men with impaired glucose tolerance. Thus, the change in irisin in response to exercise training varied by the type of exercise but showed limited association with improvements in glucose homeostasis.
Circulating irisin levels are associated with lipid and uric acid metabolism in a Chinese population.
Tang Shanshan,Zhang Rong,Jiang Feng,Wang Jie,Chen Miao,Peng Danfeng,Yan Jing,Wang Shiyun,Bao Yuqian,Hu Cheng,Jia Weiping
Clinical and experimental pharmacology & physiology
Irisin is a novel hormone secreted by skeletal muscle after exercise, which may ameliorate insulin resistance. In this study, we aimed to explore the relationship between circulating irisin levels and type 2 diabetes mellitus (T2DM) as well as related metabolic traits in a Chinese population. A total of 203 subjects were recruited. Of these, 68 subjects with normal glucose tolerance (NGT), 63 subjects with impaired glucose regulation (IGR) and 72 subjects with new-onset T2DM. Circulating irisin levels were measured by enzyme-linked immunosorbent assay (ELISA). Detailed clinical investigations and biochemistry measurements were carried out in all of the subjects. Multivariate linear regression analysis was performed to assess the association between irisin levels and related metabolic characteristics. All subjects were classified into normal weight and overweight/obese subgroups according to body mass index (BMI). No significant differences in circulating irisin levels were identified among the three groups (P = 0.9741). After adjusting for covariates, multiple linear regression analysis revealed that serum irisin level was independently and significantly associated with total cholesterol (P = 0.0005), low-density lipoprotein cholesterol (P = 0.0014), fasting fatty acids (P = 0.0402) and uric acid (P = 0.0062). By dividing the serum irisin levels into three tertile groups, the values of total cholesterol, low-density lipoprotein cholesterol, fasting fatty acids and uric acid were all increased significantly with the increase of irisin (P < 0.05). Moreover, serum irisin levels remain closely related to total cholesterol in both normal weight and overweight/obese subgroups. Our study suggests that circulating irisin concentrations are significantly associated with lipid and uric acid metabolism in a Chinese population.
Association of Circulating Irisin with Insulin Resistance and Oxidative Stress in Obese Women.
Belviranli M,Okudan N,Çelik F
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
Irisin is a myokine/adipokine with potential role in obesity and diabetes. The purpose of the present study was to assess irisin levels and its association with insulin resistance and oxidative stress markers in premenopausal normal-weight and obese women. Ten obese (mean body mass index, 32.65±3.04 kg m) and 10 normal-weight (23.00±2.23 kg m) premenopausal women were involved in the present study. Anthropometric, and body composition parameters, blood chemistry, oxidative stress markers, and irisin concentrations of different groups were measured. Correlation analyses were performed between irisin and other measured parameters. Plasma irisin levels were lower in the obese group than the normal-weight group (p<0.05). Glucose, homeostasis model assessment index (HOMA-IR), and MDA levels in the obese group were higher than that in the normal-weight group (p<0.05). Plasma irisin was negatively correlated with insulin (r=-0.648, p<0.05), HOMA-IR (r=-0.664, p<0.05) and MDA (r=-0.690, p<0.05). These data suggest that irisin levels are decreased with obesity, and irisin may have an antidiabetic and antioxidant effects.
Swimming exercise increases serum irisin level and reduces body fat mass in high-fat-diet fed Wistar rats.
Lu Yun,Li Hongwei,Shen Shi-Wei,Shen Zhen-Hai,Xu Ming,Yang Cheng-Jian,Li Feng,Feng Yin-Bo,Yun Jing-Ting,Wang Ling,Qi Hua-Jin
Lipids in health and disease
BACKGROUND:It has been shown that irisin levels are reduced in skeletal muscle and plasma of obese rats; however, the effect of exercise training on irisin level remains controversial. We aim to evaluate the association of swimming exercise with serum irisin level and other obesity-associated parameters. METHODS:Forty healthy male Wistar rats were randomly assigned to 4 groups: a normal diet and sedentary group (ND group), normal diet and exercise group (NDE group), high-fat diet and sedentary group (HFD group), and high-fat diet and exercise group (HFDE group. After 8 consecutive weeks of swimming exercise, fat mass and serum irisin level was determined. RESULTS:Higher serum irisin levels were detected in the HFDE group (1.15 ± 0.28 μg/L) and NDE group (1.76 ± 0.17 μg/L) than in the HFD group (0.84 ± 0.23 μg/L) or the ND group (1.24 ± 0.29 μg/L), respectively (HFDE group vs. HFD group, P < 0.05; NDE group vs. ND group, P < 0.01). Pearson's correlation analysis showed that serum irisin level negatively correlated with TG level (r = -0.771, P < 0.05), percentage fat mass (r = -0.68, P < 0.05), fat mass (r = -0.576, P < 0.05), visceral fat mass (r = -0.439, P < 0.05) and TC level (r = -0.389, P < 0.05). The fat mass, visceral fat mass and percentage fat mass were lower in the HFDE group than the HFD group (all P values < 0.01). CONCLUSION:Swimming exercise decreases body fat mass in high-fat-fed Wistar rats, which may be attributable to elevated irisin levels induced by swimming exercise.
Relation of serum irisin level with metabolic and antropometric parameters in obese children.
Çatlı Gönül,Küme Tuncay,Tuhan Hale Ünver,Anık Ahmet,Çalan Özlem Gürsoy,Böber Ece,Abacı Ayhan
Journal of diabetes and its complications
OBJECTIVE:This study aimed to investigate the relationship between serum irisin level and metabolic and anthropometric parameters in obese children. METHODS:The study included 36 obese children with a body mass index (BMI) of ≥95th percentile and 30 healthy children with a BMI ranging from the 5th to the 85th percentile. Healthy and obese children had similar age, gender and pubertal stage distribution. Anthropometric and biochemical parameters (fasting glucose, insulin, lipid profile, leptin and irisin levels) were measured. Bioelectric impedance analysis was used to determine the body composition parameters, including body fat percentage and fat mass. RESULTS:Serum irisin and leptin levels of the obese children were significantly higher than those of the healthy children [median irisin levels, 141.2 & 107.6ng/mL, p=0.024; median leptin levels, 10.9 & 2.9pg/mL, P<0.001, respectively). No statistically significant difference was found when leptin and irisin levels were compared among obese patients in terms of the presence of insulin resistance. Irisin levels significantly correlated with high-density lipoprotein cholesterol (HDL-C), fasting insulin and homeostasis model assessment-insulin resistance (HOMA-IR) with adjustment for age and BMI. The multivariate regression analysis showed that age, HOMA-IR and HDL-C had a significant association with the serum irisin level, which explained 30.6% of the variance. CONCLUSION:This study demonstrated that obese children had significantly higher irisin levels than healthy children. Additionally, it provides evidence regarding the role of irisin on insulin sensitivity and lipid metabolism in childhood obesity.
The Exercise-Induced Irisin Is Associated with Improved Levels of Glucose Homeostasis Markers in Pregnant Women Participating in 8-Week Prenatal Group Fitness Program: A Pilot Study.
Szumilewicz Anna,Worska Aneta,Piernicka Magdalena,Kuchta Agnieszka,Kortas Jakub,Jastrzębski Zbigniew,Radzimiński Łukasz,Jaworska Joanna,Micielska Katarzyna,Ziemann Ewa
BioMed research international
Background:Both exercise and pregnancy influence serum irisin concentration. Aim:To determine how the interaction of pregnancy and exercise affects irisin level and whether various patterns of exercise adherence had different effect on irisin concentration. Methods:It was a one-group pretest-posttest study among 9 Caucasian nulliparous healthy women in normal pregnancy (age 23 ± 3 years, 21 ± 2 weeks of gestation; mean ± SD) who participated in 8-week group fitness program. Before and after exercise intervention, we determined serum concentrations of irisin and selected parameters of lipid profile and glucose homeostasis markers. Results:In active women, irisin slightly decreased with the development of pregnancy. After 8 weeks of exercising, irisin correlated negatively with fasting glucose ( = -0.922; = 0.001), glycated hemoglobin ( = -0.784; = 0.012), and insulin concentrations ( = -0.845; = 0.004). In women exercising below recommended level, we observed a significant drop in irisin concentration, whereas in women exercising at least three times a week this myokine slightly increased (31% difference; 90% confidence limits ±28; a large, clear effect). Conclusions:Irisin stimulated by prenatal exercise may improve glucose homeostasis markers in healthy women and compensate for metabolic changes induced by pregnancy. Moreover, the frequency of exercise may regulate the changes in exercise-induced irisin concentration.
Relationships between serum irisin levels and metabolic parameters in Japanese patients with obesity.
Fukushima Yaeko,Kurose Satoshi,Shinno Hiromi,Cao Thi Thu Ha,Tamanoi Atsuko,Tsutsumi Hiromi,Hasegawa Takaaki,Nakajima Toshiaki,Kimura Yutaka
Obesity science & practice
BACKGROUND/PURPOSE:Irisin is a skeletal muscle myokine that causes the brown coloration of white fat, promotes fat burning, inhibits weight gain and may be useful for treatment of obesity. Irisin is also related to glucose/lipid metabolism and may prevent onset of diabetes, but a consensus on irisin secretion has not been reached. The purpose of this study was to determine the relationships between serum irisin levels and physical factors in untreated Japanese men and women with obesity. METHODS:The subjects were 66 untreated patients with obesity (body mass index ≥30 kg m) who visited our obesity clinic. The subjects included 19 men and 47 women with a mean age of 45.7 ± 13.4 years, mean body weight of 93.8 ± 17.6 kg, and mean body mass index of 36.5 ± 4.7 kg m. At the initial visit, blood sampling was performed, body composition was evaluated using dual energy X-ray absorptiometry, and exercise tolerance was determined in a cardiopulmonary exercise test. Homeostasis model of assessment - insulin resistance (HOMA-IR), an index of insulin resistance, and the serum level of irisin were measured. RESULTS:In men, serum irisin was positively correlated with fasting blood glucose (r = 0.491, < 0.05), immunoreactive insulin (r = 0.536, < 0.05), HOMA-IR (r = 0.635, < 0.01), body weight (r = 0.491, < 0.05), lean body mass of the trunk (r = 0.579, < 0.05) and whole lean body mass (r = 0.489, < 0.05). In women, serum irisin was positively correlated with immunoreactive insulin (r = 0.502, < 0.01) and HOMA-IR (r = 0.385, < 0.01). In both sexes, HOMA-IR was an independent variable associated with obesity (men: β = 0.635, R = 0.369, < 0.01; women: β = 0.385, R = 0.129, < 0.01). CONCLUSION:The serum level of irisin was positively correlated with HOMA-IR in Japanese patients with obesity of both sexes. This suggests that compensatory enhancement of irisin secretion may occur in response to insulin resistance.
The influence of bariatric surgery on serum levels of irisin and nesfatin-1.
Majorczyk Marta,Staszkiewicz Magdalena,Szklarczyk Joanna,Major Piotr,Pisarska Magdalena,Wysocki Michał,Stefura Tomasz,Kacprzyk Artur,Droś Jakub,Hołda Mateusz K,Pędziwiatr Michał,Budzyński Andrzej,Jaworek Jolanta
Acta chirurgica Belgica
Bariatric surgery is associated with multiple endocrine and metabolic changes. Irisin and nesfatin-1 have recently been described as regulatory peptides involved in obesity-related insulin resistance. Our aim was to analyze the changes of those two molecules observed in patients after bariatric procedures. This prospective study involved 40 patients treated for morbid obesity. Irisin and nesfatin-1 were measured before, 6 months and 1 year after surgical intervention. We also gathered demographic data, information concerning comorbidities, factors related to the surgery and outcomes of bariatric treatment. Twenty-seven patients completed the study (15 females). The mean age of the group was 43.5 ± 10.4 years. Six (22.2%) patients were submitted to Laparoscopic Sleeve Gastrectomy and 21 (77.8%) patients were submitted to Laparoscopic Roux-en-Y Gastric Bypass. The participants in our study achieved significant weight loss. The irisin level remained stable in the whole study group during all three measurements included in our study protocol ( = .71). Our study group presented a reduction of the nesfatin-1 level 6 months after bariatric surgery and a slight further decrease after one-year observation, although these changes were also not significant ( = .17). We did not find any significant correlation between changes of irisin or nesfatin-1 level and bariatric surgery, as an aid in the regulation of glucose metabolism.
Serum irisin levels in patients with psoriasis.
Baran Anna,Myśliwiec Hanna,Kiluk Paulina,Świderska Magdalena,Flisiak Iwona
The Journal of dermatological treatment
BACKGROUND:Irisin has been proposed to regulate metabolic diseases such as obesity, diabetes or metabolic syndrome which are common comorbidities in psoriasis. OBJECTIVES:The aim of this study was to evaluate the serum irisin level in psoriasis and elucidate possible associations with disease activity, inflammatory or metabolic parameters and topical treatment. METHODS:Thirty-seven individuals with active plaque-type psoriasis and 15 healthy controls were enrolled. Blood samples were collected before and after two weeks of therapy. Serum irisin concentrations were examined by enzyme-linked immunosorbent assay (ELISA). The results were correlated with psoriasis area and severity index (PASI), body mass index (BMI), inflammatory and biochemical markers, lipid profile and effectiveness of topical treatment. RESULTS:Irisin serum levels were insignificantly increased in psoriatic patients in comparison to the controls (p = 0.38). No significant correlations between investigated adipokine and several indicators of metabolic disorders, nor BMI (p = 0.37) or PASI (p = 0.5) were found. Significant positive correlations with C-reactive protein (CRP) (0.009), lipocalin-2 (p = 0.02), age (p = 0.02) and disease duration (p = 0.008) were noted. After topical treatment, serum irisin level did not significantly change (p = 0.31), despite clinical improvement. CONCLUSIONS:Irisin might be a marker of inflammation in psoriatic patients, but may not be a reliable indicator of metabolic conditions, severity of psoriasis nor efficacy of antipsoriatic treatment.
Physiology and role of irisin in glucose homeostasis.
Perakakis Nikolaos,Triantafyllou Georgios A,Fernández-Real José Manuel,Huh Joo Young,Park Kyung Hee,Seufert Jochen,Mantzoros Christos S
Nature reviews. Endocrinology
Irisin is a myokine that leads to increased energy expenditure by stimulating the 'browning' of white adipose tissue. In the first description of this hormone, increased levels of circulating irisin, which is cleaved from its precursor fibronectin type III domain-containing protein 5, were associated with improved glucose homeostasis by reducing insulin resistance. Consequently, several studies attempted to characterize the role of irisin in glucose regulation, but contradictory results have been reported, and even the existence of this hormone has been questioned. In this Review, we present the current knowledge on the physiology of irisin and its role in glucose homeostasis. We describe the mechanisms involved in the synthesis, secretion, circulation and regulation of irisin, and the controversies regarding the measurement of irisin. We also discuss the direct effects of irisin on glucose regulatory mechanisms in different organs, the indirect effects and interactions with other hormones, and the important open questions with regard to irisin in those organs. Finally, we present the results from animal interventional studies and from human clinical studies investigating the association of irisin with obesity, insulin resistance, type 2 diabetes mellitus and the metabolic syndrome.
Circulating serum irisin levels in obesity and type 2 diabetes mellitus.
Shoukry Amira,Shalaby Sally M,El-Arabi Bdeer Shereen,Mahmoud Amira A,Mousa Mayada M,Khalifa Ashraf
Irisin is an exercise-regulated myokine inducing browning of white adipose tissue and has gained interest as a potential new strategy to combat obesity and its associated disorders, such as type 2 diabetes mellitus (T2DM). The aim of this study is to evaluate the circulating serum irisin levels in obesity and T2DM and also to elucidate possible relationships between serum irisin levels with anthropometric and metabolic parameters of obesity and T2DM. One hundred fifty newly diagnosed T2DM patients as well as 150 nondiabetic control subjects were enrolled in this study. Nondiabetic controls were then stratified according to their body mass index (BMI) into three subgroups; lean, overweight, and obese. Serum irisin levels were evaluated by enzyme-linked immunosorbent assay. Serum irisin levels were significantly decreased in T2DM patients compared with nondiabetic controls. Obese nondiabetic controls had significantly higher serum irisin levels compared with lean nondiabetic controls. In both nondiabetic controls and T2DM patients, serum irisin was significantly positively correlated with BMI (r = 0.985, P < 0.001 and r = 0.218, P = 0.007, respectively), fat mass (r = 0.959, P < 0.001 and r = 0.202, P = 0.013, respectively), fat-free mass (r = 0.606, P < 0.001 and r = 0.194, P = 0.017, respectively), fat-free mass index (r = 0.820, P < 0.001 and r = 0.179, P = 0.028, respectively), waist-to-hip ratio (r = 0.880, P < 0.001 and r = 0.194, P = 0.017, respectively), fasting insulin (r = 0.989, P < 0.001 and r = 0.207, P = 0.011, respectively), and HOMA-IR (r = 0.989, P < 0.001 and r = 0.185, P = 0.023, respectively), whereas; significantly negatively correlated with insulin sensitivity (r = -0.992, P < 0.001 and r = -0.187, P = 0.022, respectively). In this study, we demonstrated that circulating serum irisin levels were increased in obese nondiabetic subjects, while decreased in T2DM patients. Moreover, serum irisin levels were correlated with anthropometric and metabolic markers of obesity and T2DM. © 2016 IUBMB Life, 68(7):544-556, 2016.
SNPs in FNDC5 (irisin) are associated with obesity and modulation of glucose and lipid metabolism in Saudi subjects.
Al-Daghri Nasser M,Mohammed Abdul Khader,Al-Attas Omar S,Amer Osama E,Clerici Mario,Alenad Amal,Alokail Majed S
Lipids in health and disease
BACKGROUND:Irisin is a recently identified myokine that plays an important role in preventing obesity and insulin resistance. We investigated whether the common FNDC5 (irisin precursor) gene variants influence susceptibility to obesity and type 2 diabetes (T2D) and verified the impact of FNDC5 gene variants on serum irisin levels, glucose and lipid metabolism in a Saudi population. METHODS:Genomic DNA from 814 (394 T2DM and 414 controls) subjects were genotyped for the five common SNPs (rs3480A/G, rs1746661G/T, rs1298190A/G, rs726344A/G and rs1570569G/T) of the FNDC5 gene using the TaqMan genotyping assay. Biochemical parameters and hematic concentrations of irisin and insulin as well as anthropometric indices were collected. RESULTS:Serum irisin levels were higher in T2DM patients compared to controls (p < 0.0001). Analyses of FNDC5 SNPs showed that: 1) The rs3480 GG associates with decreased risk of obesity (p = 0.005; odds ratio: 0.48) and lower body mass index (BMI) values (p = 0.03). In addition, GGAAG was identified as the protective haplotype against risk of obesity (p = 0.001; odds ratio: 0.23). 2) The rs1746661 G allele associates with higher triglyceride (TG) levels (p = 0.019). 3) The rs157069 TT genotype associates with higher fasting insulin (p = 0.029) and HOMA-IR (p = 0.002) as well as with lower circulating irisin levels (p = 0.016). CONCLUSIONS:SNPs in FNDC5 gene correlates with obesity and glucose-lipid metabolism possibly because they modulate the serum levels of irisin.
Irisin Inhibits Hepatic Cholesterol Synthesis via AMPK-SREBP2 Signaling.
Tang Hong,Yu Ruili,Liu Shiying,Huwatibieke Bahetiyaer,Li Ziru,Zhang Weizhen
Irisin, a myokine released during exercise, promotes browning of subcutaneous adipose tissue and regulates energy homeostasis. Although exercise constantly reduces blood cholesterol, whether irisin is involved in the regulation of cholesterol remains largely unknown. In the present study, subcutaneous infusion of irisin for 2weeks induced a reduction in plasma and hepatic cholesterol in high fat diet-induced obese (DIO) mice. These alterations were associated with an activation of 5' AMP-activated protein kinase (AMPK) and inhibition of sterol regulatory element-binding transcription factor 2 (SREBP2) transcription and nuclear translocation. In primary hepatocytes from either lean or DIO mice, irisin significantly decreased cholesterol content via sequential activation of AMPK and inhibition of SREBP2. Suppression of AMPK by compound C or AMPKα1 siRNA blocked irisin-induced alterations in cholesterol contents and SREBP2. In conclusion, irisin could suppress hepatic cholesterol production via a mechanism dependent of AMPK and SREBP2 signaling. These findings suggest that irisin is a promising therapeutic target for treatment of hypercholesterolemia.
The Levels of Serum Irisin as a Predictor of Insulin Resistance in Han Chinese Adults with Metabolically Healthy Obesity.
Liu Bo-Wei,Yin Fu-Zai,Qi Xi-Ming,Fan Dong-Mei,Zhang Yue
BACKGROUND:The aim of this study was to evaluate serum irisin levels and analyze its related factors in Han adults with metabolically healthy obesity. METHODS:This cross-sectional study included 75 metabolically healthy, non-obese adults and 51 metabolically healthy, obese adults. Anthropometric measurements, including height, weight, waist circumference (WC), and blood pressure, were performed. All patients underwent an oral glucose tolerance test (OGTT) after 8 hours of fasting, and the levels of glucose, insulin, lipids, and serum irisin were measured. RESULTS:The levels of serum irisin (5.40 ± 1.69 vs. 6.46 ± 1.37 µg/mL) were significantly lower in the metabolically healthy obese group (p < 0.05). Irisin correlated positively with high density lipoprotein cholesterol (HDL-C) (r = 0.303) and correlated negatively with body mass index (BMI) (r = -0.389), WC (r = -0.324), fasting plasma glucose (FPG) (r = -0.441), HOMA-IR (r = -0.429), triglycerides (TG) (r = -0.185), total cholesterol (TC) (r = -0.209), low density lipoprotein cholesterol (LDL-C) (r = -0.157) (p < 0.05). Multiple regression analysis revealed that FPG (β = -1.720, p = 0.001) and HOMA-IR (β = -0.399, p = 0.006) were still significantly associated with irisin. Serum irisin (β = -0.246, p = 0.005) and BMI (β = 0.078, p = 0.043) were significant independent predictors for HOMAIR. CONCLUSIONS:Serum irisin levels were reduced in metabolically healthy, obese Han adults. Irisin reduction appears to be associated with elevated FPG and insulin resistance but not obesity. In additional, falling irisin may increase the occurrence of insulin resistance in metabolically healthy Han adults and should be examined in future studies.
Association of circulating irisin levels with normal weight obesity, glycemic and lipid profile.
Mehrabian Sarvenaz,Taheri Ehsaneh,Karkhaneh Maryam,Qorbani Mostafa,Hosseini Saeed
Journal of diabetes and metabolic disorders
BACKGROUND:Irisin, a recently identified myokine/adipokine, has potential role in type 2 diabetes and obesity. Normal weight obesity (NWO) is associated with a significantly higher risk of developing metabolic syndrome and cardiometabolic dysfunction. The aim of this study was to investigate association of irisin level with NWO, glycemicand lipid profile in women. METHODS:In this matchedcase-control study, 38 subjects with NWO (body mass index (BMI) <25 kg/m2 and BF % > 30) as case and 26 controls (BMI <25 kg/m2 and BF % < 30) were selected randomly from sport clubs in the East area of Tehran, Iran. In addition to anthropometric variables, including BMI and body composition, fasting blood sugar (FBS), fasting levels of irisin andinsulin, triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were measured. All statistical analyses were performed with SPSS 18.0. RESULTS:In univariate analysis, levels of irisin were significantly higher in subjects with NWO compared to controls (0.81 ± 0.41vs. 0.58 ± 0.26 ng/ml, P = 0.009). This association remained significant after adjusting for confounders (adjusted for energy intake, physical activity, waist circumference and BMI) (P = 0.049). In NWO, irisin level was not significantly correlated with all glycemic and lipid profile. In control group, only correlation ofirisin with insulin was statistically significant (P = 0.03). CONCLUSION:Serum irisin levels were higher in NWO subjects than controls. In control group, only the negative association between irisin and insulin levels was statistically significant. Further studies with larger sample size are clearly needed to evaluate the potential role of irisin in NWO subject and other disturbed metabolic conditions.
Association of plasma fatty acid composition with plasma irisin levels in normal weight and overweight/obese children.
Viitasalo A,Ågren J,Venäläinen T,Pihlajamäki J,Jääskeläinen J,Korkmaz A,Atalay M,Lakka T A
BACKGROUND:Irisin has been suggested to protect against overweight. There are no previous data on the association of plasma fatty acid (FA) composition with plasma irisin. OBJECTIVES:We studied the association of FA composition with plasma irisin in normal weight and overweight/obese children. METHODS:This cross-sectional study included pre-pubertal children (388 normal weight children and 55 overweight/obese children); 6-9 years of age, taking part in the Physical Activity and Nutrition in Children Study. After an overnight fast, we measured plasma FA composition by gas chromatography and plasma irisin levels by enzyme-linked immunosorbent assay. RESULTS:Higher proportion of total monounsaturated fatty acids in plasma cholesteryl esters (CEs) (β = 0.139, P = 0.003) and phospholipids (PLs) (β = 0.147, P = 0.002) and lower proportion of total polyunsaturated fatty acids in plasma CE (β = -0.130, P = 0.006) and PL (β = -0.165, P < 0.001) were associated with higher plasma irisin level in the whole study group. The association of plasma FA composition with plasma irisin level was stronger among overweight/obese children compared to normal weight children. Higher proportion of γ-linolenic acid (β = 0.324, P = 0.017) and lower proportion of linoleic acid (β = -0.397, P = 0.005) in plasma CE were related to higher plasma irisin level among overweight/obese children, indicating the direct association of estimated D6D activity in plasma CE (β = 0.343, P = 0.011) with plasma irisin. Furthermore, higher proportion of oleic acid in plasma CE (β = 0.345, P = 0.012) and PL (β = 0.292, P = 0.033) and higher proportion of adrenic acid (β = 0.366, P = 0.008) and docosapentaenoic acid (β = 0.351, P = 0.010) in plasma PL were associated with higher plasma irisin level among overweight/obese children. CONCLUSION:Metabolically unfavourable plasma FA profile was associated with higher plasma irisin level especially in overweight/obese children, suggesting that excess body fat might modulate these relationships.
Irisin exerts dual effects on browning and adipogenesis of human white adipocytes.
Zhang Yuan,Xie Chao,Wang Hai,Foss Robin M,Clare Morgan,George Eva Vertes,Li Shiwu,Katz Adam,Cheng Henrique,Ding Yousong,Tang Dongqi,Reeves Westley H,Yang Li-Jun
American journal of physiology. Endocrinology and metabolism
To better understand the role of irisin in humans, we examined the effects of irisin in human primary adipocytes and fresh human subcutaneous white adipose tissue (scWAT). Human primary adipocytes derived from 28 female donors' fresh scWAT were used to examine the effects of irisin on browning and mitochondrial respiration, and preadipocytes were used to examine the effects of irisin on adipogenesis and osteogenesis. Cultured fragments of scWAT and perirenal brown fat were used for investigating signal transduction pathways that mediate irisin's browning effect by Western blotting to detect phosphorylated forms of p38, ERK, and STAT3 as well as uncoupling protein 1 (UCP1). Individual responses to irisin in scWAT were correlated with basal expression levels of brown/beige genes. Irisin upregulated the expression of browning-associated genes and UCP1 protein in both cultured primary mature adipocytes and fresh adipose tissues. It also significantly increased thermogenesis at 5 nmol/l by elevating cellular energy metabolism (OCR and ECAR). Treating human scWAT with irisin increased UCP1 expression by activating the ERK and p38 MAPK signaling. Blocking either pathway with specific inhibitors abolished irisin-induced UCP1 upregulation. However, our results showed that UCP1 in human perirenal adipose tissue was insensitive to irisin. Basal levels of brown/beige and FNDC5 genes correlated positively with the browning response of scWAT to irisin. In addition, irisin significantly inhibited adipogenic differentiation but promoted osteogenic differentiation. We conclude that irisin promotes "browning" of mature white adipocytes by increasing cellular thermogenesis, whereas it inhibits adipogenesis and promotes osteogenesis during lineage-specific differentiation. Our findings provide a rationale for further exploring the therapeutic use of irisin in obesity and exercise-associated bone formation.
Irisin improves perivascular adipose tissue dysfunction via regulation of the heme oxygenase-1/adiponectin axis in diet-induced obese mice.
Hou Ningning,Liu Yihui,Han Fang,Wang Di,Hou Xiaoshuang,Hou Shuting,Sun Xiaodong
Journal of molecular and cellular cardiology
AIMS:To determine whether irisin could improve perivascular adipose tissue (PVAT) dysfunction via regulation of the heme oxygenase-1 (HO-1)/adiponectin axis in obesity. MATERIALS AND METHODS:C57BL/6 mice were given chow or a high-fat diet (HFD) with or without treatment with irisin. The concentration-dependent responses of the thoracic aorta with or without PVAT (PVAT+ or PVAT-) to phenylephrine were studied in an organ bath. Protein levels of HO-1 and adiponectin were determined by western blot. UCP-1, Cidea, and TNF-α gene expression in PVAT were analyzed by real-time PCR. RESULTS:Treatment of obese mice with irisin improved glucose and lipid metabolism, reduced plasma levels of TNF-α and malondialdehyde, and increased plasma adiponectin levels (P<0.01). The anti-contractile effects of PVAT were attenuated in HFD mice and this attenuation was restored in HFD mice treated with irisin (P<0.05). Incubation of aortas (PVAT+) with the HO-1 inhibitor and adiponectin receptor blocking peptide in irisin-treated HFD mice abolished the beneficial effects of irisin on PVAT function. The same results were also observed in HFD mice treated with irisin ex vivo. Treatment of HFD mice with irisin significantly enhanced protein levels of HO-1 and adiponectin, and reduced superoxide production and TNF-α expression in PVAT. Irisin treatment enhanced brown adipocyte markers UCP-1 and Cidea expression in PVAT from HFD mice. CONCLUSION:Irisin improved the anti-contractile properties of PVAT from the thoracic aorta in diet-induced obese mice. The mechanism for protective effects of irisin appeared to be related to upregulation of the HO-1/adiponectin axis in PVAT and browning of PVAT.
Effects of Body Weight Reduction on Serum Irisin and Metabolic Parameters in Obese Subjects.
Fukushima Yaeko,Kurose Satoshi,Shinno Hiromi,Thi Thu Ha Cao,Takao Nana,Tsutsumi Hiromi,Hasegawa Takaaki,Nakajima Toshiaki,Kimura Yutaka
Diabetes & metabolism journal
BACKGROUND:Irisin is a myokine implicated in lipid and glucose metabolism. The objective of this study is to examine the effect of a body weight reduction on the serum irisin level and physical indicators in obese Japanese patients without diabetes. METHODS:The subjects were 22 patients (male/female, 5/17; age, 46.1±16.0 years; body mass index [BMI], 36.9±5.0 kg/m) who completed a 6-month body weight reduction program at our clinic. The program included diet, exercise therapy and cognitive behavioral therapy. Blood parameters, body composition, exercise tolerance, homeostasis model assessment of insulin resistance (HOMA-IR), and serum irisin were determined before and after intervention, and relationships among changes in these data were examined. RESULTS:There were significant decreases in body weight and BMI after the intervention. Irisin before the intervention was significantly positively correlated with HOMA-IR (=0.434, <0.05). The mean irisin level showed no significant change after the intervention in all participants. However, improvements in % body fat, subcutaneous fat area, triglycerides, and fasting glucose were significantly greater in patients with an increase in irisin compared to those with a decrease in irisin after the intervention. Patients with an increase in irisin also had significantly lower fasting insulin (9.7±4.8 vs. 16.4±8.2, <0.05) and HOMA-IR (2.2±1.1 vs. 3.7±1.6, <0.05) after the intervention, compared to patients with a decrease in irisin. CONCLUSION:Body weight reduction did not alter irisin levels. However, irisin may play important roles in fat and glucose metabolism and insulin resistance, and the effects of body weight reduction on irisin kinetics may be a key for obesity treatment.
Irisin in goldfish (Carassius auratus): Effects of irisin injections on feeding behavior and expression of appetite regulators, uncoupling proteins and lipoprotein lipase, and fasting-induced changes in FNDC5 expression.
Butt Zahndra Diann,Hackett Jessica Dalton,Volkoff Hélène
Irisin is a peptide cleaved from the fibronectin type III domain containing protein 5 (FNDC5) gene that is secreted predominantly by muscle cells but also by other tissues including brain and intestine. In mammals, irisin has been shown to have thermogenic actions via the modulation of uncoupling proteins (UCPs) and to affect feeding and energy homeostasis via actions in brain, adipose tissue, liver, muscle and gastrointestinal tract. To examine the role of irisin on feeding and metabolism in fish, the effects of peripheral (intraperitoneal) injections of irisin on feeding behavior, glucose levels and the mRNA expressions of appetite regulators (cocaine and amphetamine regulated transcript CART, agouti related protein AgRP, orexin), UCPs and lipoprotein lipase LPL and brain factors (brain-derived neurotrophic factor , BDNF and tyrosine hydroxylase TH) were assessed in brain, white muscle and intestine. Irisin injections (100ng/g) induced a decrease in food intake and increases in brain orexin, CART1 and CART2, UCP2, BDNF, muscle UCP2 and intestine LPL mRNA expressions but did not affect blood glucose levels, brain AgRP, TH, UCP1, UCP3 and LPL or muscle UCP1, UCP3 and LPL expressions. A partial goldfish FNDC5 cDNA was isolated and the expressions of FDNC5, UCPs, LPL and BDNF were also compared between fed and fasted fish. Fasting induced decreases FNDC5 mRNA expression in the brain and intestine, but not in muscle. Fasting also induced increases in brain BDNF and LPL expressions and increases in UCP1, UCP2, UCP3 and LPL expressions in muscle. Our result suggest that irisin is an anorexigenic factor in fish and its actions might be in part mediated by appetite-regulating factors such as CART and orexins as well as UCP2 and brain factors such as BDNF.
Association of irisin and oxidative stress with biochemical parameters in patients with metabolic syndrome.
Hassan Israa Issa,Hassan Alan Bapeer,Rajab Heevi Ameen,Saadi Farsat Saeed,Abdulah Deldar Morad,Abdul Majeed Ayoub Abid,Khaleel Bland Bayar,Taher Sherzad Majeed,Ahmed Idris Haji
Hormone molecular biology and clinical investigation
Background Irisin, a hormone-like myokine, is suspected to have a role in metabolic syndrome (MetS) through regulating energy homeostasis and mediating physical activity. In this regard, the role of irisin and malondialdehyde (MDA) along with some other biochemical parameters in the prediction of MetS was examined in the present investigation. Materials and methods In the present case-control study, 36 subjects diagnosed with MetS according to International Diabetes Federation were considered as cases and were matched in age and gender with 31 healthy participants. The difference of biochemical indicators between cases and controls were determined whether by independent t-test or the Mann-Whitney U-test. The predictors of MetS and insulin resistance (IR) were examined through logistic and linear regressions analysis models, respectively. Results Irisin and MDA were not found to be predictors for MetS in logistic regression; p = 0.258 and p = 0.694, respectively. The IR was found to be the only direct predictor of MetS (p = 0.010). Similarly, in linear regression, irisin and MDA were not identified to be predictors for IR; p = 0.801 and p = 0.781, respectively. Conclusions The study did not show that irisin and MDA, directly and indirectly, were predictors of MetS disorder. The IR was only predictor of MetS.
Combined training, FNDC5/irisin levels and metabolic markers in obese men: A randomised controlled trial.
Bonfante Ivan Luiz Padilha,Chacon-Mikahil Mara Patrícia Traina,Brunelli Diego Trevisan,Gáspari Arthur Fernandes,Duft Renata Garbellini,Lopes Wendell Arhur,Bonganha Valéria,Libardi Cleiton Augusto,Cavaglieri Cláudia Regina
European journal of sport science
The effects of training on FNDC5/irisin and its association with fitness and metabolic marker improvements induced by training have been poorly investigated in humans. Thus, the present study assessed the effects of combined training (CT) on FNDC5/irisin levels, metabolic markers and fitness adaptations in obese men. Middle-age obese men (age 49.13 ± 5.75, body mass index (BMI) 30.86 ± 1.63) were randomly distributed in the CT group (n = 12) and control group (CG n = 10). The CT consisted of strength followed by aerobic training, 3 times/week, for 24 weeks. Body composition, physical fitness, plasma FNDC5/irisin, biochemical markers and metabolic scores/index were evaluated. CT maintained FNDC5/irisin levels (µg/mL) (pre: 4.15 ± 0.32, post: 4.21 ± 0.32; p = .96) and improved body composition, metabolic and physical fitness markers. In the CG, decreased FNDC5/irisin (µg/mL) (pre: 4.36 ± 0.23, post: 3.57 ± 0.94; p = .01) and reduced strength (supine exercise/kg) (pre: 71 ± 14.7, post: 60.1 ± 14.05; p < .01) were observed, along with a trend to increase HOMA-IR (pre: 2.63 ± 1.11, post: 3.14 ± 1.27; p = .07) and other indicators of metabolic deterioration. An inverse correlation was found between the change (Δ%) in levels of FNDC5/irisin and Δ% glucose, Δ% total cholesterol, Δ% triglycerides and Δ% waist circumference, in addition to a positive relation with Δ% muscle strength. In conclusion, CT maintained FNDC5/irisin levels and provided metabolic and fitness benefits. The correlation between FNDC5/irisin changes and metabolic parameters, as well as the FNDC5/irisin reduction associated with fitness and metabolic worsening in the CG, suggests a relationship between FNDC5/irisin and a healthy metabolic status in humans.
Adiponectin profile and Irisin expression in Italian obese children: Association with insulin-resistance.
Nigro Ersilia,Scudiero Olga,Ludovica Monaco Maria,Polito Rita,Schettino Pietro,Grandone Anna,Perrone Laura,Miraglia Del Giudice Emanuele,Daniele Aurora
Adiponectin (Acrp30), its high molecular weight (HMW) oligomers, and Irisin are molecules involved in several metabolic processes. To investigate if these cytokines could represent new metabolic markers, we evaluated the expression of Acrp30 and Irisin in serum of obese children from South Italy affected by different degrees of insulin resistance (IR). The anthropometric and metabolic features were evaluated in 27 obese children versus 13 age-matched controls. The expression of Acrp30, its pattern and Irisin were investigated by ELISA, western blotting and fast protein liquid chromatography. The HOMA index was significantly higher in obese children versus controls, and metabolic syndrome was more prevalent in obese children with elevated IR versus those with normal HOMA (38% vs 16%). Total Acrp30 and HMW oligomers were significantly lower in obese than in control children, and the difference was more pronounced in children with HOMA >3.4. In control and obese children, total Acrp30 and HMW oligomers were inversely related to HOMA (r-0.38, p 0.02; r-0.35, p 0.03). Irisin was significantly higher in obese than in control children, and was inversely correlated with Acrp30 and HMW (r-0.32, p 0.04; r-0.39, p 0.01). The inverse correlation of Acpr30 and HMW oligomers with HOMA indicates that Acpr30 is directly involved in IR status. Moreover, the inverse correlation between Irisin and Acrp30 and, more significantly, between Irisin and HMW oligomers suggests that the two cytokines are closely connected. The use of Acrp30, HMW oligomers and Irisin as predictive factors of IR in obese children remains to be further elucidated.
Irisin is weakly associated with usual physical activity in young overweight women
Tenorio Beatriz,Jiménez Teresa,Barrera Gladys,Hirsch Sandra,De la Maza Maria Pia,Troncoso Rodrigo,Farias María Belén,Rodríguez Juan Manuel,Bunout Daniel
PURPOSE:To determine if irisin plasma levels are associated with regular physical activity, body composition and metabolic parameters in women subjected to calorie restriction. SUBJECTS AND METHODS:We studied 42 women aged 34 ± 13 years with a body mass index of 27.7 ± 1.8 kg/m2, who were subjected to a calorie restriction for three months. At baseline and at the end of the study, weight, waist and hip circumference, laboratory parameters, body composition by DEXA, resting and activity energy expenditure by indirect calorimetry and 72 hours actigraphy were measured. Fasting serum irisin was quantified using an ELISA kit. RESULTS:After the intervention period, participants lost 1.5 (0.4-3.4) kg and irisin levels did not change. Irisin baseline levels were positively but weakly correlated with the level of physical activity. This association was lost at the end of the intervention. No association was found between irisin levels and body composition or insulin sensitivity or their changes after calorie restriction. No association between serum irisin levels and PGC-1αexpression in peripheral blood mononuclear cells and serum irisin was observed. CONCLUSIONS:Fasting serum irisin was weakly associated with usual physical activity and did not change after calorie restriction.
Exercise training with dietary restriction enhances circulating irisin level associated with increasing endothelial progenitor cell number in obese adults: an intervention study.
Huang Junhao,Wang Shen,Xu Fengpeng,Wang Dan,Yin Honggang,Lai Qinhao,Liao Jingwen,Hou Xiaohui,Hu Min
OBJECTIVE:Circulating endothelial progenitor cells (EPCs) correlate negatively with obesity. Previous studies have shown that exercise significantly restores circulating EPC levels in obese people; however, the underlying mechanisms have not been elucidated. Recently, irisin has been reported to have a critical role in the regulation of EPCs. This exercise-induced myokine has been demonstrated to play a therapeutic role in obesity. In this study, we hypothesized that the increase in circulating irisin may form a link with increasing EPC levels in obese people after exercise. METHODS:Seventeen obese adults completed an 8-week program of combined exercise and dietary intervention. Clinical characteristics, blood biochemistry, and circulating irisin levels of subjects were measured before and after eight weeks of training. EPC levels were evaluated via flow cytometry, and EPC migratory and adhesive functions were also determined. RESULTS:Circulating irisin levels significantly increased following the 8-week training program ( < 0.05). We furthermore observed an improvement in EPC numbers ( < 0.05), and EPC migratory and adhesive functions ( < 0.001 and < 0.05, respectively) after the intervention. Additionally, we detected a positive correlation between changes in irisin and changes in EPC number ( = 0.52, < 0.05). DISCUSSION:For the first time, a positive correlation between increasing irisin levels and increasing EPC levels has been reported after an 8-week program, consisting of exercise and dietary intervention. This result suggests a novel effect of irisin on the regulation of EPC mobilization, which might contribute to improvement of endothelial function in obese people.
Assessment of Serum Vitamin D and Irisin Levels in Obese Patients.
Gouda Weaam,Mageed Lamiaa,Shaker Yehia,Hamimy W I,Afify Mie
<i>Background:</i> 25-hydroxyvitamin D and irisin have been found to be involved in the pathogenesis of obesity. The aim of the study is to assess the serum levels of 25-hydroxyvitamin D and irisin in obese patients and to determine the association of 25-hydroxyvitamin D and irisin levels with anthropometric parameters. <i>Methods:</i> The study was carried out on 300 obese patients in addition to 156 healthy age and gender matched subjects as a control group. Demographic data were collected from the studied cases. Body mass index, serum levels of insulin, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, 25-hydroxyvitamin D, and irisin were measured. <i>Results:</i> 25-hydroxyvitamin D levels were significantly associated with obesity, the incidence of 25-hydroxyvitamin D deficiency (< 12 ng/mL) was 49.3% in obese patients, especially in females. A positive correlation was noted between 25-hydroxyvitamin D and age TC:HDL ratio. It was negatively correlated with BMI. Serum irisin levels were higher, but not significantly, in obese patients compared to controls. Irisin was positively associated with insulin levels and negatively correlated with total cholesterol. <i>Conclusions:</i> Obesity is associated with 25-hydroxyvitamin D deficiency and high serum levels of irisin. Body mass index and gender are predictors of 25-hydroxyvitamin D status. The positive correlation between serum irisin and insulin indicates that compensatory enhancement of irisin excretion can occur due to insulin resistance.
Association of circulating irisin levels with metabolic and metabolite profiles of Korean adolescents.
Jang Han Byul,Kim Hyo-Jin,Kang Jae Heon,Park Sang Ick,Park Kyung Hee,Lee Hye-Ja
Metabolism: clinical and experimental
CONTEXT:Irisin, a novel exercise-induced myokine, has been suggested to regulate energy metabolism. OBJECTIVE:We studied the relationship between circulating irisin and metabolic and metabolite profiles of Korean adolescents, and investigated the effects of physical activity, obesity, and metabolic syndrome (MetS) on irisin levels. MATERIALS AND METHODS:Data were obtained from the Korean Children-Adolescents Study. Our cross-sectional study included 618 adolescents (370 normal-weight and 248 obese adolescents; 316 boys and 302 girls) aged 12-15years. Body composition was determined using an impedance body composition analyzer and general participant characteristics and lifestyle information were obtained from questionnaires. Serum irisin levels were measured using a commercial kit. RESULTS:Mean body mass index (BMI) was 19.4kg/m in normal-weight adolescents and 31.4kg/m in obese adolescents. Circulating irisin was positively correlated with adiposity indices, including BMI z-score, waist circumference, percent body fat, fat mass, fat-free mass, fat mass to fat-free mass ratio, and lipid and glucose metabolism markers, including total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, glucose, insulin, and homeostasis model assessment-estimated insulin resistance (all p≤0.006). Of these, increased body fat mass [standardized (Std) ß, 0.23; p<0.0001], LDL-C (Std ß, 0.14; p=0.0005) and fasting glucose (Std ß, 0.08; p=0.0383) were the main independent factors associated with higher irisin levels. Moreover, elevated serum irisin was associated with the risk of obesity [odds ratio (OR], 2.2; confidence interval (CI), 1.19-3.87] and MetS (OR, 2.0; CI, 1.15-3.47). Furthermore, irisin and branched-chain amino acids were positively associated (p<4×10 for Bonferroni correction). Additionally, in the normal-weight group, girls had higher irisin levels than boys (p=0.006) and adolescents who engaged in regular physical activity had higher levels of irisin than sedentary adolescents (p=0.0388). The relationship between physical activity and irisin levels was not observed in obese adolescents. CONCLUSIONS:Elevated serum irisin was independently associated with the risk of obesity and positively correlated with unhealthy metabolic parameters and metabolites. Moreover, irisin levels were higher in active versus sedentary adolescents in the normal-weight group, but not in the obese group. Our findings suggest that irisin plays an important role in metabolic disorders and may be affected by physiopathological status.
Irisin is a biomarker for metabolic syndrome in prepubertal children.
Shim Young Suk,Kang Min Jae,Yang Seung,Hwang Il Tae
The aim of the present study was to evaluate the association of irisin with obesity and metabolic syndrome (MetS) in Korean prepubertal children. A total of 96 children and adolescents aged 6 to 10 years (56 males) were included in this study. Subjects were divided into 3 groups: normal weight (n = 54), overweight (n = 16), and obese (n = 26). In the subgroup analyses, overweight/obese children were further divided based on their MetS status (with MetS vs. without MetS). Children with obesity tended to exhibit a lower mean irisin concentration compared to those with normal weight (p = 0.028). Using Pearson's correlation coefficient to compare all the children in the study, there was a significant inverse correlation between irisin and body mass index (BMI) standard deviation scores (SDS) (r = -0.210, p = 0.041), waist circumference SDS (r = -0.203, p = 0.049), and glucose (r = -0.296, p = 0.004). In the subgroup analyses of overweight/obese children, irisin exhibited a significant inverse correlation with glucose (r = -0.507, p = 0.001) and triglycerides (r = -0.331, p = 0.033). Children with MetS exhibited lower irisin concentrations than those without MetS (14.70 ng/mL vs. 22.02 ng/mL, p = 0.001), and these associations were significant after adjusting for age, gender, and BMI SDS (14.51 ng/mL vs. 22.06 ng/mL, p = 0.002). The irisin level of 15.43 ng/mL was determined to be a possible cutoff to distinguish children with metabolic syndrome from overweight/obese children, with a sensitivity of 75% and a specificity of 94% (p < 0.001). Our results suggest that decreased irisin levels may be associated with MetS in prepubertal children and that irisin might be a biomarker for MetS in prepubertal children.
Irisin regulates the expression of BDNF and glycometabolism in diabetic rats.
Huang Lingning,Yan Sunjie,Luo Li,Yang Liyong
Molecular medicine reports
Irisin is a proteolytic product of the fibronectin type III domain‑containing protein 5. The aim of the present study was to verify whether irisin is involved in the pathogenesis of diabetic mild cognitive impairment and elucidate the associated mechanisms. Diabetic rats were divided into four groups: Control, Model, Irisin (overexpression of irisin) and Irisin‑short hairpin (sh)‑RNA (irisin interference). The levels of irisin, brain‑derived neurotrophic factor (BDNF), glycosylated hemoglobin A1c (GHbA1c) and advanced glycated end products (AGEs) in the serum were determined using ELISA. The expression of BDNF in the hippocampal tissue was evaluated by immunohistochemical analysis. Compared with the Control group, the levels of irisin and BDNF were markedly decreased in the Model and Irisin‑shRNA groups, whereas those of GHbA1c and AGEs were markedly increased. However, the levels of irisin and BDNF in the Irisin group were significantly higher than those in the Model group, whereas the levels of GHbA1c and AGEs in the Irisin group were significantly lower. Irisin‑shRNA significantly downregulated the expression of irisin and BDNF, and upregulated the levels of GHbA1c and AGEs, compared with those in the Model group. Rat primary hippocampal nerve cells were isolated and identified by microtubule‑associated protein‑2 labeling. The vitality of primary cells from diabetic rats, evaluated using a methyl thiazolyl tetrazolium assay, was markedly decreased and further reduced following the injection of irisin‑shRNA, however, it was markedly improved following irisin treatment. The mRNA and protein levels of BDNF in the primary cells were evaluated by fluorogenic reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively, following the exposure of cells to different concentrations of glucose: 0 (control), 5.5, 15 and 25 mmol/l for 12, 24 and 48 h. The mRNA and protein expression levels of BDNF in the primary cells following exposure to glucose were significantly lower than those observed in the control. Further exposure to glucose led to a significant decrease in the expression of BDNF. In conclusion, irisin may regulate the expression of BDNF and glycometabolism in diabetic rats.
Plasma irisin is elevated in type 2 diabetes and is associated with increased E-selectin levels.
Rana Karan S,Pararasa Chathyan,Afzal Islam,Nagel David A,Hill Eric J,Bailey Clifford J,Griffiths Helen R,Kyrou Ioannis,Randeva Harpal S,Bellary Srikanth,Brown James E
BACKGROUND:Irisin is a hormone released mainly from skeletal muscle after exercise which increases adipose tissue energy expenditure. Adipocytes can also release irisin after exercise, acting as a local adipokine to induce white adipose tissue to take on a brown adipose tissue-like phenotype, suggesting that irisin and its receptor may represent a novel molecular target for the treatment of obesity and obesity-related diabetes. Previous reports provide conflicting evidence regarding circulating irisin levels in patients with type 2 diabetes (T2DM). METHODS:This study investigated plasma irisin concentrations in 79 T2DM individuals, assessing potential associations with measures of segmental body composition, markers of endothelial dysfunction and peripheral blood mononuclear cell telomere length (TL). RESULTS:Resting, overnight-fasted plasma irisin levels were significantly higher in this group of T2DM patients compared with levels we previously reported in healthy volunteers (p < 0.001). Moreover, plasma irisin displayed a positive correlation with body mass index (p = 0.04), body fat percentage (p = 0.03), HbA1c (p = 0.03) and soluble E-selectin (p < 0.001). A significant negative association was observed between plasma irisin and visceral adiposity (p = 0.006) in T2DM patients. Multiple regression analysis revealed that circulating soluble E-selectin levels could be predicted by plasma irisin (p = 0.004). Additionally, cultured human umbilical vein endothelial cells (HUVEC) exposed to 200 ng/ml irisin for 4 h showed a significant fourfold increase in E-selectin and 2.5-fold increase in ICAM-1 gene expression (p = 0.001 and p = 0.015 respectively), and there was a 1.8-fold increase in soluble E-selectin in conditioned media (p < 0.05). CONCLUSION:These data suggest that elevated plasma irisin in T2DM is associated with indices of adiposity, and that irisin may be involved in pro-atherogenic endothelial disturbances that accompany obesity and T2DM. Accordingly, irisin may constitute a potentially novel therapeutic opportunity in the field of obesity and cardiovascular diabetology.
The Effects of Exercise Regimens on Irisin Levels in Obese Rats Model: Comparing High-Intensity Intermittent with Continuous Moderate-Intensity Training.
Tine Kartinah Neng,Rosalyn Sianipar Imelda,Nafi'ah ,Rabia
BioMed research international
Background:Recently, high-intensity intermittent training (HIIT) appears to have the same beneficial effects or even superior to those of continuous moderate-intensity training (CMIT) on body fat mass reduction. Exercise may induce myokine secretion such as irisin, which plays a role as a mediator of beiging process, and thus might contribute as treatment of obesity. However, the effects of those exercise formulas on irisin level changes as beiging agent are not known. In addition, metabolic states may affect the irisin responses to those exercise formulas. Therefore, this study was aimed to determine the different effects of exercises using HIIT and CMIT on circulating and tissue irisin levels in normal and abnormal metabolic conditions (obese). Methods:Sixteen male Sprague-Dawley rats (8 weeks of age) were randomized to 4 groups according to training regimens (HIIT and CMIT) and metabolic conditions (normal and abnormal/obese). The groups are (1) HIIT on normal metabolic (n=4), (2) CMIT on normal metabolic (n=4), (3) HIIT on abnormal metabolic (n=4), and (4) CMIT on abnormal metabolic (n=4). Abnormal metabolic condition was induced with high fat diet (19% fat) for 8 weeks in obese rats. Irisin levels in serum, skeletal muscle, and white adipose tissue were evaluated by ELISA. Results:Serum irisin levels were shown significantly higher in normal metabolic compared to abnormal metabolic condition (P<0.001). The effect of interaction between metabolic condition and exercise formula was found (P<0.01) on adipose irisin levels. The effect of HIIT was shown significantly more effective on adipose irisin levels, compared with CMIT in abnormal metabolic conditions. However, no significant differences of skeletal muscle irisin levels were found in both normal and abnormal metabolic subjects (P>0.05). Regarding exercise formula, no different effects were found between HIIT and CMIT on skeletal muscle irisin levels in both metabolic conditions (P>0.05). The similar findings were observed in serum irisin levels (P>0.05). Conclusions:The exercise effects in abnormal metabolic condition might be more adaptable in maintaining the irisin levels in skeletal muscle and induce the irisin uptake from circulation into adipose tissue. In addition, HIIT might be more involved to induce irisin uptake into adipose tissue; thus it might have the significant role in beiging process. However, further research about how the HIIT formula affects the regulation mechanisms of irisin uptake into adipose tissue is still warranted.
Obesity and its Association with Irisin Level Among Individuals with FNDC5/Irisin Gene Variants RS16835198 and RS726344.
Abdu Allah Azza M,Hammoudah Sahar Af,Abd El Gayed Eman Masoud,El-Attar Lama Mohamed,Shehab-Eldin Walid A
Protein and peptide letters
BACKGROUND:Irisin; a novel myokine/adipokine; encoded by FNDC5 gene have been suggested to play an important role in energy metabolism and obesity. However, the genetic variations at this locus and their effects on different metabolic parameters is still poorly understood. AIM:This study aimed to investigate the role of FNDC5/irisin gene polymorphisms (RS16835198 and RS726344) in obese individuals and their genotype phenotype correlation with circulating serum irisin level and other biochemical parameters like glucose, lipid metabolism and liver enzymes. METHODS:The study included 200 subjects divided into two groups: obese group (110 subject) and control non obese group (90 subject). All selected individuals were subjected to a comprehensive questionnaire, clinical assessment and laboratory investigations including fasting blood glucose (FBS), serum insulin, lipid profile (Total Cholesterol (TC), Triglycerides (TG), Low Density Lipoprotein (LDLc), High Density Lipoprotein (HDLc), liver enzymes (ALT, AST, GGT), Serum irisin level and HOMA-IR was calculated. DNA extraction and FNDC5 allelic discrimination analysis for FNDC5 SNPs, rs16835198and rs726344 using the TaqMan SNP genotyping assays by Real time PCR. RESULTS:In obese group; serum irisin was significantly lower (0.55 ± 0.2) than control group (1.7 ± 0.3) P value < 0.001. Regarding genotype and allele frequency, T allele of rs16835198 polymorphism is associated with high BMI, high total cholesterol, TG and LDL-C, low level of serum HDL-C, high FBS, low serum insulin, low HOMA-IR and low serum level of irisin. While G allele of rs726344 is significantly associated with high BMI, FBS, low serum insulin and HOMA-IR, High total cholesterol, TG, LDL-C, low level of HDL-C and low serum irisin. CONCLUSION:Our data suggest that FNDC5 SNPs, rs16835198and rs726344 are associated with obesity in Egyptian population. GG genotype and G allele of rs726344 variant and TT genotype and T allele of rs16835198 variant may increase the susceptibility to obesity and there were a genotype phenotype correlation with circulating serum irisin and several metabolic parameters.
Supervised Short-term High-intensity Training on Plasma Irisin Concentrations in Type 2 Diabetic Patients.
Dünnwald Tobias,Melmer Andreas,Gatterer Hannes,Salzmann Karin,Ebenbichler Christoph,Burtscher Martin,Schobersberger Wolfgang,Grander Wilhelm
International journal of sports medicine
Irisin is a myokine involved in adipocyte transformation. Its main beneficial effects arise from increased energy expenditure. Irisin production is particularly stimulated by physical exercise. The present study investigates the changes of plasma irisin in type 2 diabetic patients performing 2 different training modalities. Fourteen type 2 diabetic patients underwent 4 week of supervised high-intensity interval training (HIT; n=8) or continuous moderate-intensity training (CMT; n=6), with equivalent total amounts of work required. Plasma samples were collected in the resting state atbaseline and one day after the exercise intervention to analyse resting plasma irisin, blood lipids, blood glucose, hsCRP, Adiponectin, Leptin and TNF-α concentrations. In addition, body composition and VO were determined Resting plasma irisin increased after HIT (p=0.049) and correlated significantly with plasma fasting glucose at follow-up (r=0.763; p=0.006). CMT did not significantly change the amount of plasma irisin, although follow-up values of plasma irisin correlated negatively with fat-free mass (r=-0.827, p=0.002) and with fasting plasma glucose (r = - 0.934, p=0.006). Plasma irisin was found to increase with higher training intensity, confirming the assumption that exercise intensity, in addition to the type of exercise, may play an important role in the stimulation of the irisin response.
High irisin levels in overweight/obese children and its positive correlation with metabolic profile, blood pressure, and endothelial progenitor cells.
De Meneck F,Victorino de Souza L,Oliveira V,do Franco M C
Nutrition, metabolism, and cardiovascular diseases : NMCD
BACKGROUND AND AIMS:Irisin is involved in the compensatory mechanisms for metabolic regulation and appears to be associated with glucose homeostasis and lipid profile. However, it's possible implications on obesity-associated cardiometabolic complications have not been completely elucidated. This study aimed to investigate the association between irisin level and anthropometric data, metabolic parameters, blood pressure, and endothelial progenitor cells (EPCs) level among children with overweight/obesity. METHODS AND RESULTS:This study included 24 children with overweight/obesity (9 girls and 15 boys) and 63 children with normal weight (25 girls and 38 boys). The anthropometric data, blood pressure, blood biochemistry, EPCs and irisin levels were evaluated. Children with overweight/obesity had significantly higher circulating irisin and EPCs levels than those with normal weight (P < 0.001). Additionally, we found that irisin level was positively correlated with BMI (rho = 0.407), waist circumference (rho = 0.449), triglycerides (rho = .334), glucose (rho = 0.226), insulin (rho = 0.533), HOMA (rho = 0.545), and negatively correlated with HDL cholesterol level (rho = -0.218). Importantly, we also found that irisin levels were significantly correlated with systolic (rho = 0.420), diastolic (rho = 0.331) blood pressure and circulating EPCs level (rho = 0.391). CONCLUSION:Our study provides evidence that overweight/obese children had elevated circulating levels of both irisin and EPCs and address the gap in the literature with regard to the understanding of the implications of irisin on obesity-related cardiometabolic complications among these children and also highlight the possible involvement of irisin regulation on insulin resistance and endothelial function in childhood overweight and obesity.
Expression, purification and biological characterisation of recombinant human irisin (12.5 kDa).
Panati Kalpana,Narala Venkata Ramireddy,Narasimha Vydyanath R,Derangula Madhavi,Arva Tatireddigari Venkat R R,Yeguvapalli Suneetha
Journal, genetic engineering & biotechnology
Fibronectin type III domain containing 5 (FNDC5) is a transmembrane protein. Upon cleavage, it yields a peptide called irisin that is supposedly bind to an unknown receptor and facilitates browning of white adipose tissue (WAT). Increased levels of irisin are associated with increased levels of energy expenditure markers PGC-1α, UCP-1, besides abundance of beige adipocytes in WAT. Though varied sizes of irisin were reported in humans and rodents it is not yet clear about the actual size of the irisin produced physiologically. Hence, we cloned and expressed human irisin (32-143 aa of FNDC5) in based on the proposed cleavage site that yields 12.5 kDa peptide to study its antigenicity and other biological functions . We purified recombinant human irisin (rh-irisin) to 95% homogeneity with simple purification method with a yield of 25 mg/g wet cell pellet. rh-irisin has been detected by commercially available antibodies from different sources with similar antigenicity. Biological activity of the rh-irisin was confirmed by using 3T3-L1 pre-adipocyte differentiation by Oil red O staining. Further, rh-irisin treatment on pre-adipocytes showed increased expression of markers associated with energy expenditure. As it is involved in energy expenditure process, it could be considered as potential therapeutic option for various metabolic diseases.
Association of Circulating Irisin Concentrations with Weight Loss after Roux-en-Y Gastric Bypass Surgery.
Lee Yeon Ji,Heo Yoonseok,Choi Ji-Ho,Park Sunghyouk,Kim Kyoung Kon,Shin Dong Wun,Kang Ju-Hee
International journal of environmental research and public health
Irisin is a myokine with potential anti-obesity properties that has been suggested to increase energy expenditure in obese patients. However, there is limited clinical information on the biology of irisin in humans, especially in morbidly obese patients undergoing bariatric surgery. We aimed to assess the association of circulating irisin concentrations with weight loss in obese patients undergoing bariatric surgery. This was a pilot, single-centre, longitudinal observational study. We recruited 25 morbidly obese subjects who underwent Roux-en-Y gastric bypass surgery (RYGBP), and blood samples from 12 patients were taken to measure serum irisin concentrations before, and one and nine months after surgery. Their clinical characteristics were measured for one year. The preoperative serum irisin concentration (mean 1.01 ± 0.23 μg/mL, range 0.73⁻1.49) changed bidirectionally one month after RYGBP. The mean concentration at nine months was 1.11 ± 0.15 μg/mL (range 0.92⁻1.35). Eight patients had elevated irisin levels compared with their preoperative values, but four did not. Elevations of irisin levels nine months, but not one month, after surgery, were associated with lower preoperative levels ( = 0.016) and worse weight reduction rates ( = 0.006 for the percentage excess weight loss and = 0.032 for changes in body mass index). The preoperative serum irisin concentrations were significantly correlated with the percentage of excess weight loss for one year (R² = 0.612; = 0.04) in our study. Our results suggest that preoperative circulating irisin concentrations may be at least in part associated with a weight loss effect of bariatric surgery in morbidly obese patients. Further large-scale clinical studies are needed to ratify these findings.
Increased irisin versus reduced fibroblast growth factor1 (FGF1) in relation to adiposity, atherogenicity and hematological indices in metabolic syndrome patients with and without prediabetes.
Saber Govand Yaseen,Kasabri Violet,Saleh Mohammad Issa,Suyagh Maysa,Halaseh Lana,Jaber Ruba,Abu-Hassan Hana,Alalawi Sundos
Hormone molecular biology and clinical investigation
Background Irisin and fibroblast growth factor 1 (FGF1) are intricately involved in metabolic syndrome (MetS) and prediabetes (preDM) pathophysiology. This study aimed to compare and correlate irisin and FGF1 plasma levels, adiposity, atherogenicity and hematological indices in 29 normoglycemic MetS and 30 newly diagnosed drug naive prediabetic (PreDM) MetS patients vs. 29 lean and normoglycemic controls. Materials and methods Irisin and FGF1 plasma levels were measured using colorimetric assays. Intergroup comparisons were conducted by analysis of variance (ANOVA). Spearman's rank correlation was also examined. Results The mean circulating irisin levels (ng/mL) were significantly higher in the normoglycemic (but not prediabetic) MetS group (p < 0.01), while the mean circulating FGF1 levels (pg/mL) were markedly lower in the prediabetic (but not normoglycemic) MetS group (p < 0.05). Of note unlike FGF1, irisin in the MetS (both normoglycemic and prediabetic;N=59) groups correlated significantly and positively with each of waist circumference (WC), hip circumference (HC), body mass index (BMI), body adiposity index (BAI) and high-density lipoprotein-cholesterol (HDL-C) but not the non-HDL-C. Distinctively MetS-irisin negatively associated with the non-HDL-C/HDL-C ratio, total cholesterol (TC)/HDL-C ratio and the low-density lipoprotein-cholesterol (LDL-C)/HDL-C ratio, but positively with the red cell distribution width (RDW). In the same pool of 59 MetS reruits; Neither biomarker had a relationship with the visceral adiposity index (VAI), the lipid accumulation product (LAP), the conicity index (CI), the waist-hip ratio (WHR), the waist-to-height ratio (WHtR), the blood ratios or the atherogenicity index of plasma (AIP). Conclusions As any potential molecular crosstalk of irisin and FGF1 in MetS or its related dysregularities cannot be ruled out; Conversely the utility of irisin and FGF1 as surrogate prognostic biomarkers and putative pharmacotherapeutic targets in the predtion/prevention/management of diabetes and MetS is strongly suggested.
Irisin levels in LMNA-associated partial lipodystrophies.
Bensmaïne F,Benomar K,Espiard S,Vahe C,Le Mapihan K,Lion G,Lemdani M,Chazard E,Ernst O,Vigouroux C,Pigny P,Vantyghem M-C
Diabetes & metabolism
AIM:The adipo-myokine irisin regulates energy expenditure and fat metabolism. LMNA-associated familial partial lipodystrophy (FPLD2) comprises insulin resistance, muscle hypertrophy and lipoatrophy. The aim of this study was to investigate whether irisin could be a biomarker of FPLD2. PATIENTS AND METHODS:This case control study included 19 FPLD2 subjects, 13 obese non-diabetic (OND) patients and 19 healthy controls (HC) of normal weight (median BMI: 26, 39 and 22 kg/m, respectively). Serum irisin and leptin levels, body composition (DXA/MRI) and metabolic/inflammatory parameters were compared in these three groups. RESULTS:BMI and MRI intra-abdominal fat significantly differed among these three groups, whereas DXA total fat mass and leptin levels were higher in the OND group, but did not differ between HC and FPLD2. Lipodystrophy patients had higher intra-abdominal/total abdominal fat ratios than the other two groups. Irisin levels were higher in FPLD2 and OND patients than in HC (medians: 944, 934 and 804 ng/mL, respectively). However, irisin/leptin ratios and lean body mass percentages were strikingly higher, and lean mass indices lower, in FPLD2 and HC than in the OND (median irisin/leptin ratios: 137, 166 and 21, respectively). In the entire study group, irisin levels positively correlated with BMI, lean body mass and index, intra-abdominal/total abdominal fat ratio, triglyceride, cholesterol, insulin, glucose and HbA levels. Also, intra-abdominal/total abdominal fat ratio and lean body mass better differentiated the three groups only in female patients. CONCLUSION:Circulating irisin is similarly increased in FPLD2 and OND patients, who are characterized by higher lean body mass regardless of their clearly different fat mass. However, irisin/leptin ratios, strikingly higher in FPLD2 than in OND patients, could help to make the diagnosis and prompt genetic testing in clinically atypical cases.
Relationship between circulating irisin levels and overweight/obesity: A meta-analysis.
Jia Jue,Yu Fan,Wei Wei-Ping,Yang Ping,Zhang Ren,Sheng Yue,Shi Yong-Qin
World journal of clinical cases
BACKGROUND:Currently, the findings about irisin as a novel myokine related to obesity are inconsistent in overweight/obese people. To our knowledge, no systematic analysis has been conducted to evaluate the relationship between irisin levels and overweight/obesity. AIM:To evaluate the association between circulating irisin levels and overweight/obesity. METHODS:The Cochrane Library, MEDLINE, SCOPUS, and the ISI Web of Science were searched to retrieve all of the studies associated with circulating irisin levels and overweight/obesity. Standard mean difference values and 95% confidence intervals (CI) were estimated and pooled using meta-analysis methodology. RESULTS:A total of 18 studies were included in our meta-analysis containing 1005 cases and 1242 controls. Our analysis showed that the circulating irisin level in overweight/obese people was higher than that in overall healthy controls (random effects MD = 0.63; 95%CI: 0.22-1.05; = 0.003). In the subgroup analysis by ethnicity, the irisin level was higher in overweight/obesity people than that in controls in Africa (random effects MD = 3.41; 95%CI: 1.23-5.59; < 0.05) but not in European, Asian, or American populations. In addition, in a subgroup analysis by age, the results showed that obese children exhibited a higher irisin level than controls (random effects MD = 0.86; 95%CI: 0.28-1.43; < 0.05). CONCLUSION:This meta-analysis provides evidence that circulating irisin is higher in obese individuals compared to healthy controls and it is important to identify the relationship between circulating irisin levels and overweight/obesity in predicting overweight/obesity.
Study on the relationship between the levels of irisin in umbilical cord blood and neonatal growth in China.
Zheng Shoujuan,Guo Wenwen,Wang Xia
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
OBJECTIVE:The results of the study on the relationship between obesity and cord blood irisin were far apart. The aim of this study was to explore the relationship between cord blood irisin levels and neonatal growth in China. METHODS:A cross-sectional study of 400 neonates and their mothers was conducted in the obstetrics department of Shandong provincial hospital in China. Neonates were divided into a fetal macrosomia group and a normal birth weight group based on customized birth-weight standards and divided into non-high-ponderal index group and high ponderal index group based on ponderal index. Levels of irisin in umbilical cord blood were measured by enzyme-linked immunosorbent assay. RESULTS:Irisin concentrations in the fetal macrosomia group were significantly higher than in the normal birth weight group (p = .032). Irisin levels in the high ponderal index group were significantly higher compared with the non-high-ponderal index group (p = .032). After adjustment for confounding variables, logistic regression analysis identified macrosomia affected factors include weight gained during pregnancy (OR = 1.15, p = .028), infant's sex (OR = 9.73, p = .001) and found that affected factors of high ponderal index include weight gained during pregnancy (OR = 1.08, p = .025), maternal age (OR = 1.10, p = .018). Compared with the reference category (<108.62 ng/ml), infants with a cord blood irisin level above 241.44 ng/ml had significantly elevated risk of macrosomia (OR = 8.57, p = .010) and had significantly elevated risk of high birth ponderal index (PI) (OR = 3.15, p = .002). A nonlinear relationship was observed between irisin levels and fetal macrosomia. The higher the concentration of irisin, the greater the risk of fetal macrosomia. CONCLUSIONS:We found that as the cord blood irisin increased, the risk of having fetal macrosomia was greater. Weight gained during pregnancy and high cord blood irisin levels were independent predictors of fetal adiposity.
Irisin Exerts Inhibitory Effect on Adipogenesis Through Regulation of Wnt Signaling.
Ma Eun Bi,Sahar Namood E,Jeong Moonsup,Huh Joo Young
Frontiers in physiology
Irisin is an exercise-induced myokine known to induce adipocyte browning through induction of uncoupling protein 1. Recent studies have reported that irisin is also an adipokine. However, there is limiting evidence on the role of endogenous irisin from adipocytes. In this study we aim to elucidate the expression and secretion pattern of irisin during adipocyte differentiation and the role of endogenous and exogenous irisin on the adipogenic process. As such, recombinant irisin, plasmid expressing FNDC5 and small interfering RNA were utilized. Our results show that the gene expression of irisin precursor FNDC5 and irisin secretion increases at the early stage of adipogenesis. Both recombinant irisin treated cells and FNDC5-overexpressed cells resulted in inhibition of adipogenesis evidenced by downregulated C/EBPα, PPARγ, and FABP4 expression and reduced lipid accumulation. Further data showed that the inhibitory effect of irisin on adipogenesis is mediated though potentiation of Wnt expression, which is known to determine the fate of mesenchymal stem cells and regulate adipogenesis. Conversely, FNDC5 knockdown cells showed downregulated Wnt expression, but failed to further induce adipogenesis. This study suggests that both exogenous and endogenous irisin is able to inhibit adipogenesis and that activation of Wnt and subsequent repression of transcription factors is partly involved in this process. This provides a novel insight on the local effect of irisin on adipocytes and additional benefit to protect against obesity-related metabolic disorders.
Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis.
Li Hong,Shen Jing,Wu Tong,Kuang Jiangying,Liu Qinhui,Cheng Shihai,Pu Shiyun,Chen Lei,Li Rui,Li Yanping,Zou Min,Zhang Zhiyong,Jiang Wei,Qu Aijuan,He Jinhan
Frontiers in pharmacology
Objective:The aim of this study was to investigate whether the nuclear receptor farnesoid X receptor (FXR) could regulate FNDC5/Irisin expression and the role of Irisin in hyperlipidemia and atherosclerosis in ApoE-/- mice. Methods and Results:We treated primary human hepatocytes, HepG2 cells, and Rhesus macaques with FXR agonist (CDCA, GW4064, and ivermectin). FNDC5 expression was highly induced by CDCA and GW4064 in hepatocytes, HepG2 cells, and the circulating level of Irisin increased in Rhesus macaques. Luciferase reporter and CHIP assays were used to determine whether FXR could regulate FNDC5 promoter activity. Irisin-ApoE-/- and ApoE-/- mice were used to study the metabolic function of Irisin in dyslipidemia and atherosclerosis. Irisin-ApoE-/- mice showed improved hyperlipidemia and alleviated atherosclerosis as compared with ApoE-/- mice. Irisin upregulated the expression of Abcg5/Abcg8 in liver and intestine, which increased the transport of biliary cholesterol and fecal cholesterol output. Conclusion:Activation of FXR induces FNDC5 mRNA expression in human and increased the circulating level of Irisin in Rhesus macaques. FNDC5/Irisin is a direct transcriptional target of FXR. Irisin may be a novel therapeutic strategy for dyslipidemia and atherosclerosis.
Myokine-adipokine cross-talk: potential mechanisms for the association between plasma irisin and adipokines and cardiometabolic risk factors in Mexican children with obesity and the metabolic syndrome.
Gonzalez-Gil Adrian M,Peschard-Franco Mariana,Castillo Elena C,Gutierrez-DelBosque Gustavo,Treviño Victor,Silva-Platas Christian,Perez-Villarreal Luisa,Garcia-Rivas Gerardo,Elizondo-Montemayor Leticia
Diabetology & metabolic syndrome
Background:Adipokines and the myokine irisin, involved in mechanisms associated with obesity and metabolic syndrome (MS), are understudied in the pediatric population. Objective:To investigate the relationship between irisin, and leptin, resistin, adiponectin, adipsin, anthropometric and cardiovascular risk factors in Mexican children. Methods:A cross-sample of 126 Mexican children aged 6-12 years old were classified as normal weight (n = 46), obese (n = 40), and MS (n = 40) according to CDC's and Cook's age-modified criteria for obesity and MS. Anthropometric parameters and blood pressure were determined and percentiles calculated for age and gender. Irisin, leptin, adiponectin, adipsin, resistin, triglycerides, glucose, high-density lipoprotein cholesterol (HDL-c) levels, and physical activity were determined. Statistical tests for differences between groups, correlation, and multiple regression analyses were performed. Results:Irisin plasma levels were significantly lower in the obese (6.08 [4.68-6.65]) and MS groups (6.46 [5.74-7.02]) compared with the normal-weight group (8.05 [7.24-8.94]) (p < 0.001). Irisin levels were not influenced by age or gender, but significant dispersion was observed in obese girls (95% CI median [2.29-6.30]). Leptin, resistin, and adipsin levels were significantly increased in the obese and MS groups. Lean-fat ratio was significantly higher in the NW group. Irisin correlated negatively with leptin (- 0.310), resistin (- 0.389), adipsin (- 0.362), BMI% (-0.472), WC% (- 0.453), BMI z-score (- 0.496), fat free mass (- 0.257), fat percentage (- 0.532), fat mass (- 0.515), triglycerides (- 0.291), the number of cardiometabolic risk factors (- 0.443) (p < 0.001); positively with lean-fat ratio (0.489) and HDL-c (0.328) (p < 0.001) and none with physical activity (< 0.001). Following stepwise multiple linear regression analysis, the lean-fat ratio was the only determinant of irisin levels (B = 1.168, p < 0.001). Conclusions:Lean-fat ratio, more than the absolute amount of muscle or fat mass, as well as potential myokine-adipokine cross-talk mechanisms may explain the lower irisin levels in children with obesity and MS, through blunted compensatory responses interfering with tissue-dependent irisin secretion, contributing to a continuous deleterious effect cycle.
The Effect of Pubertal Stage on the Concentrations of the Novel Adipomyokine, Irisin, in Male Adolescents
Taş Demet,Akman Öden Alkım,Akgül Sinem,Metin Ziya E.,Pınar Aslı,Kanbur Nuray
Journal of clinical research in pediatric endocrinology
Objective:Irisin is a recently discovered protein and is defined as an adipomyokine. The relation of irisin with carbohydrate metabolism and other hormone parameters have been investigated. However, studies evaluating the relationship between irisin and puberty are limited and inconclusive. The aim was to evaluate serum concentrations of irisin during different pubertal stages in male adolescents. Methods:The study included normal weight pubertal male adolescents between the ages of 13-14 who had entered puberty. Fasting serum irisin concentrations were evaluated, and bioelectrical impedance analysis was used to measure body fat ratio (BFR) and fat-free mass (FFM). BFR was also calculated by caliper measurement of subcutaneous fat at the triceps. Results:Sixty-eight adolescents were enrolled. The number of adolescents in pubertal stage 2, 3, 4 and 5 were n=17 (25%), n=13 (19.1%), n=21 (30.1%) and n=17 (25%), respectively. The median values of the irisin are 8.80, 8.20, 9.15 and 7.24 ng/mL according to the 2-5 pubertal stages, respectively. The levels of circulating irisin did not differ according to the pubertal stage. Additionally, there was no significant relationship between irisin levels and body fat percentage or FFM. Conclusion:Irisin levels do not differ after the onset of puberty or with progressing pubertal maturation. This study strengthens the evidence that there is no change in irisin concentration as puberty progresses. This may have important implications when using this adipomyokine in the future for diagnosis or treatment of obesity-related diseases.
Irisin as a mediator between obesity and vascular inflammation in Chinese children and adolescents.
Yin Chunyan,Hu Wei,Wang Ming,Lv Weicheng,Jia Tian,Xiao Yanfeng
Nutrition, metabolism, and cardiovascular diseases : NMCD
BACKGROUND AND AIM:This study aims to characterize the role of Irisin in obesity and early onset metabolic and vascular sequelae in Chinese children. Furthermore, we aim to examine whether Irisin mediate endothelial cells dysfunction and vascular inflammation which eventually leads to obesity. METHODS AND RESULTS:We quantified plasma Irisin levels using enzyme-linked immunosorbent assay (ELISA) among 85 lean and 120 obese children, and assessed the association of Irisin levels with anthropometric, metabolic, cardiovascular and inflammatory parameters of obese children comparing with lean children. We further characterized the markers for endothelial cells and inflammation between obese and lean children to assess potential correlations. In addition, a potential direct effect of Irisin on the expression of endothelial adhesion molecules was assessed in human coronary artery endothelial cells. Irisin levels from obese children was significantly lower than lean children, and this reduced Irisin levels is correlated with certain physical parameters of studied children. Moreover, we identified significant inverse associations between inflammation markers of endothelial activation with Irisin levels in obese children. Multiple regression analyses confirm Irisin serves as a strong predictor of SDS-SBP, Ang-2, ICAM-1, E-selectin and hsCRP levels, independent of SDS-BMI. Lifestyle intervention results in a significant improvement of these cardiovascular and inflammatory parameters, and these were accompanied by a significant improvement of Irisin levels and weight loss. Finally, in the mediation effect model, our data showed that Irisin changes act as partial mediators of the relationship between SDS-BMI changes and changes in inflammatory and endothelial parameters for ICAM-1, E-selectin and hsCRP after controlling for covariates. Likewise, on the cellular level, Irisin inhibition hsCPR, ICAM-1 and E-selectin expression in endothelial cells, whereas Ang-2, VCAM-1 and eNOS expression were unaffected. CONCLUSIONS:Our study showed that Irisin levels change may indicate the early stages of cardiovascular disease in obese children.
Recombinant irisin induces weight loss in high fat DIO mice through increase in energy consumption and thermogenesis.
Niranjan Sanjay B,Belwalkar Shraddha Vijay,Tambe Suhas,Venkataraman Krishnan,Mookhtiar Kasim A
Biochemical and biophysical research communications
OBJECTIVE:Irisin is known to be an important metabolic regulator of glucose and lipid metabolism. The aims of the present study are to assess the role of mouse Irisin in obesity and energy metabolism and its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) mice model. METHODS:DIO mice were treated with recombinant murine Irisin or vehicle, and parameters such as body weight, feed intake, glucose, and lipid levels, obesity, energy consumption, and insulin sensitivity were assessed. mRNA and protein levels of UCP1 and different thermogenesis biomarker were evaluated by quantitative real-time PCR and Western blot, respectively, in tissues and major metabolic organs. RESULTS:Irisin decreased body weight and whole-body fat mass in DIO mice in a dose dependent manner due to marked increases in total energy expenditure. It also lowered blood glucose, insulin, and lipid levels and possibly reversed hepatic steatosis. Irisin improved hepatic and peripheral insulin sensitivity in DIO mice along with body weight reduction and adiposity. Gene expression of UCP1 in different organs (adipose tissue and major organs, i.e., liver, kidney, heart, brain, and spleen) have suggested the role of irisin is global. Gene expression profile of different biomarkers in spleen suggest a profound role of Irisin in inflammation. Liver tissue have also shown significant increase of UCP1 expression in dose dependent manner which suggest a role of irisin in liver.