Exercise provides many health benefits, including improved metabolism, cardiovascular health, and cognition. We have shown previously that FNDC5, a type I transmembrane protein, and its circulating form, irisin, convey some of these benefits in mice. However, recent reports questioned the existence of circulating human irisin both because human FNDC5 has a non-canonical ATA translation start and because of claims that many human irisin antibodies used in commercial ELISA kits lack required specificity. In this paper we have identified and quantitated human irisin in plasma using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. This precise state-of-the-art method shows that human irisin is mainly translated from its non-canonical start codon and circulates at ∼ 3.6 ng/ml in sedentary individuals; this level is increased to ∼ 4.3 ng/ml in individuals undergoing aerobic interval training. These data unequivocally demonstrate that human irisin exists, circulates, and is regulated by exercise.
Jedrychowski MP, Wrann CD, Paulo JA, et al. Cell Metab. 2015;22(4):734-740.
As a link between exercise and metabolism, irisin is assumed to be involved in increased total body energy expenditure, reduced body weight, and increased insulin sensitivity. Although our recent evidence supported the contribution of irisin to vascular endothelial cell (ECs) proliferation and apoptosis, further research of irisin involvement in the angiogenesis of ECs was not conclusive. In the current study, it was found that irisinpromoted Human Umbilical Vein Endothelial Cell (HUVEC) angiogenesis via increasing migration and tube formation, and attenuated chemically-induced intersegmental vessel (ISV) angiogenic impairment in transgenic TG (fli1: GFP) zebrafish. It was further demonstrated that expression of matrix metalloproteinase (MMP) 2 and 9 were also up-regulated in endothelial cells. We also found that irisin activated extracellular signal-related kinase (ERK) signaling pathways. Inhibition of ERK signaling by using U0126 decreased the pro-migration and pro-angiogenic effect of irisin on HUVEC. Also, U0126 inhibited the elevated expression of MMP-2 and MMP-9 when they were treated with irisin. In summary, these findings provided direct evidence that irisin may play a pivotal role in maintaining endothelium homeostasis by promoting endothelial cell angiogenesis via the ERK signaling pathway.
Objective: Betatrophin has recently been introduced as a novel adipokine/hepatokine, which promotes pancreatic β cell proliferation and improves glucose tolerance in several mouse models of insulin resistance. However, regulation of betatrophin in gestational diabetes mellitus (GDM), as well as its association with markers of obesity, such as glucose and lipid metabolism, inflammation, and renal function, have not been elucidated.
Design and methods: Circulating betatrophin was quantified in 74 women with GDM and 74 healthy and gestational age-matched controls by ELISA. In a subset of the study population comprising of 85 patients (41 previous controls, 44 previous women with GDM), postpartum betatrophin levels were measured in a follow-up study.
Results: Median (interquartile range) serum betatrophin levels were higher in women with GDM (1.79 (0.53) ?g/l) as compared to non-diabetic pregnant controls (1.58 (0.44) ?g/l) (P=0.002). In multivariate analysis, GDM status was an independent and positive predictor of circulating betatrophin (P=0.001). Furthermore, betatrophin levels were significantly higher during gestation (1.70 (0.53) ?g/l) as compared to postpartum levels (1.55 (0.66) ?g/l) (P=0.028). Moreover, postpartum irisin remained a positive and independent predictor of postpartum betatrophin concentrations.
Conclusions: Women with GDM have significantly higher betatrophin levels as compared to healthy pregnant controls and GDM status positively predicts circulating betatrophin. Furthermore, postpartum levels are significantly lower as compared to betatrophin concentrations during pregnancy. Moreover, irisin is a significant predictor of postpartum betatrophin levels.
This publication used an Irisin kit from Phoenix Pharmaceuticals.
Irisin is a newly identified myokine. Several studies have reported irisin concentrations in patients with gestational diabetes mellitus (GDM), but because of smaller sample sizes, the data from previous reports showed a wide range in serum/plasma irisin. Therefore, the present investigation is designed to summarize a precise confidence interval of circulating irisin in participants with GDM from a cross-sectional study in Chinese population and a meta-analysis for validation. Serum irisin was tested in patients with GDM and healthy controls (newly diagnosed cases: 61 and matched controls: 61) in the cross-sectional study. The two groups of participants were matched with > for age and pregnancy duration. Furthermore, we did a comprehensive meta-analysis to confirm whether serum/plasma irisin differs between participants with GDM and controls. Articles reported “circulating irisin and GDM” in Medline, PubMed, and EMBase were obtained, with the key word “myokine” or “irisin”. The comparison was analyzed by Review Manager 5.2. In the cross-sectional investigation, serum irisin showed a significant lower level in the GDM patients, compared with that in the control group. In the meta-analysis study, the summarized results of the present 5 studies in which 632 participants were included indicated that there was a lower level irisin of -58.68 ng/ml [95% confidence interval (CI)](-113.42, -3.93, P=0.04) in GDM patients than in the control group. The present cross-sectional investigation and meta-analysis is the first to show significant lower circulating irisin in subjects with GDM.
This publication used an Irisin kit from Phoenix Pharmaceuticals.
Vascular complications are the major causes of death in patients with diabetes, and endothelial dysfunction is the earliest event in vascular complications of diabetes. It has been reported that plasma irisin level is significantly reduced in patients with type 2 diabetic patients. The present study aimed to investigate whether irisin improved endothelial function in type 2 diabetes as well as the underlying mechanisms. The type 2 diabetes model was established by feeding C57BL/6 mice with high-fat diet. The type 2 diabetic mice exhibited reduced serum irisin level and impaired endothelial function. Irisin treatment (0.5mg/kg/d) for two weeks improved vascular function based on the evaluation of endothelium-dependent vasorelaxation and p-VASP levels. To investigate the direct endothelial protective effects of irisin, diabetic aortic segments were incubated with irisin(1?g/ml) ex vivo. Exposure to irisin improved endothelium-dependent vasorelaxation of diabetic aortas. Mechanically, the diabetic aortic segments exhibited increased oxidative/nitrative stresses. Irisin reduced the diabetes-induced oxidative/nitrative stresses evidenced by reducing overproduction of superoxide and peroxynitrite, and down-regulation of iNOS and gp91phox. To further investigate the protective effects of irisin on endothelial cells and the underlying mechanisms, human umbilical vein endothelial cells (HUVECs) cultured in high-glucose/high-fat (HG/HF) medium were pre-incubated with irisin. Irisin (1?g/ml) reduced the oxidative/nitrative stresses and apoptosis induced by HG/HF in HUVECs probably via inhibiting activation of PKC-?/NADPH oxidase and NF-?B/iNOS pathways. Taken together, irisin alleviates endothelial dysfunction in type 2 diabetes partially via reducing oxidative/nitrative stresses through inhibiting signaling pathways implicating PKC-?/NADPH oxidase and NF-?B/iNOS, suggesting that irisin may be a promising molecule for the treatment of vascular complications of diabetes.
Irisin is a newly identified hormone induced in muscle and adipose tissues by physical activity. This protein and its encoding gene have been identified in the brain; in addition, the precursor for irisin, FNDC5, can cross the blood-brain barrier. The fact that irisin is secreted during exercise together with the lower resting heart rate in athletes prompted us to investigate the effect of irisin on cardiac-projecting vagal neurons of nucleus ambiguus, a key regulatory site of heart rate. In vitro experiments in cultured nucleus ambiguus neurons indicate that irisin activates these neurons, inducing an increase in cytosolic Ca(2+) concentration and neuronal depolarization. In vivo microinjection of irisin into the nucleus ambiguuspromotes bradycardia in conscious rats. Our study is the first to report the effects of irisin on the neurons controlling the cardiac vagal tone and to link a myokine to a cardioprotective role, by modulating central cardiovascular regulation.
This publication used an Irisin recombinant protein from Phoenix Pharmaceuticals.
INTRODUCTION: Irisin is a newly identified 112 amino acid hormone, derived as a product of fibronectin type III domain containing 5 (FNDC5), which is highly related to metabolic activity in skeletal muscle and brown fat. The effects of irisin on cardiovascular functions are unknown.
PURPOSE: To explore the effects of central and peripheral irisin on cardiovascular functions.
METHODS: Irisin was either administrated into 3rd ventricle of rats or intravenously, and its effects on blood pressure and cardiac contractibility measured.
RESULTS: Administration of recombinant human irisin into the 3rd brain ventricle of rats activated neurons in the paraventricular nuclei of the hypothalamus. Central administration of irisin increased blood pressure and cardiac contractibility. Exogenous irisin reversed atenolol-induced inhibition of cardiac contractibility. In contrast, peripheral administration of irisin reduced blood pressure in both control and spontaneously hypertensive rats. Irisin dilated mesenteric artery rings through ATP-sensitive potassium channels.
CONCLUSION: Our studies indicate that central and peripheral irisin may differentially regulate cardiovascular activities.
This publication used an Irisin recombinant protein from Phoenix Pharmaceuticals.
Irisin is a novel myokine produced by skeletal muscle. However, its metabolic role is poorly understood. In the present study, irisin induced glucose uptake in differentiated skeletal muscle cells. It increased AMP-activated protein kinase (AMPK) phosphorylation and the inhibition of AMPK blocked glucose uptake. It also increased reactive oxygen species (ROS) generation. N-acetyl-cysteine (NAC), a ROS scavenger, blocked irisin-induced AMPK phosphorylation. Moreover, irisin activated p38 mitogen-activated protein kinase (MAPK) in an AMPK-dependent manner. The inhibition and knockdown of p38 MAPK blocked irisin-induced glucose uptake. A colorimetric absorbance assay showed that irisin stimulated the translocation of GLUT4 to the plasma membrane, and that this effect was suppressed in cells pre-treated with a p38 MAPK inhibitor or p38 MAPK siRNA. In primary cultured myoblast cells, irisin increased the concentration of intracellular calcium. STO-609, a calcium/calmodulin-dependent protein kinase kinase (CaMKK) inhibitor, blocked irisin-induced AMPK phosphorylation, implying that calcium is involved in irisin-mediated signaling. Our results suggest that irisin plays an important role in glucose metabolism via the ROS-mediated AMPK pathway in skeletal muscle cells.
This publication used an Irisin recombinant protein from Phoenix Pharmaceuticals.
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 [[Formula: see text]O2peak] for 45 min, 3 days/week). Before and after the intervention, we evaluated serum irisin level, [Formula: see text]O2peak, and body composition. The increase in [Formula: see text]O2peak 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.
Irisin is a newly discovered factor that is secreted by skeletal muscle and plays an important role in the homeostasis and metabolism of energy balance. This study used irisin radiolabeled with 125I and small-animal SPECT/CT imaging to investigate the metabolic elimination and distribution ofirisin in vivo. Irisin was labeled with 125I using the Iodogen method. Small-animal SPECT/CT imaging was performed on C57/B16 mice at 15, 30, 60, 120, and 240?min after receiving a tail vein injection, and the radioactive distribution in the organs of mice was determined at 15, 60, and 120?min. Small-animal SPECT/CT imaging revealed the highest level of radioactivity in the gallbladder followed by the liver and kidney. Radioactivity decreased gradually with time in all organs. The radioactive distribution in the mice organs also showed that the highest %ID/g was in the gallbladder followed by the kidney and liver, and decreased gradually with time. The radioactivity in the gastric system reached its highest level at 60?min. Finally, our study showed the metabolic clearance of 125I-irisin is achieved primarily through the hepatobiliary and renal system and provided the basis for the clinical application of irisin.
Context: Polycystic ovary syndrome (PCOS) is an insulin resistance (IR) state, like obesity and type 2 diabetes mellitus (T2DM). Although previous studies have suggested a correlation between irisin and the metabolic parameters associated with obesity and T2DM, the results have been inconsistent.
Objective: Our objective was to 1) determine circulating irisin levels in women with PCOS and control subjects, 2) examine the relationship of irisin and conventional markers of insulin resistance, and 3) examine irisin changes with interventions modulating IR in PCOS women.
Patients and Design: This study was comprised of a series of cross-sectional and interventional studies of 178 PCOS and 123 healthy women from the general population and outpatients of the Internal Medicine Department at the Second Affiliated Hospital, Chongqing Medical University, China. 47 women with PCOS were randomly assigned to 6 months of oral metformin (850 mg bid). OGTT and EHC were performed to assess glucose tolerance and insulin sensitivity. Outcome measures were IR (AUC Insulin and M values) on an OGTT and EHC, irisin levels, and metabolic markers.
Results: Circulating irisin was significantly higher in both overweight/obese (BMI?25 kg/ m2) and PCOS women (P<0.01). Circulating irisin levels correlated with BMI, WHR, FAT%, TG, TC, LDL-C, AUC Insulin, HOMA2-IR, M values and FAI. During EHC, short-term hyperinsulinemia exhibited an inhibitory effect on irisin levels. After 6 months of metformin treatment, there was a significant decrease in circulating irisin in PCOS women following improved IR.
Conclusions: These data suggest that irisin may be a useful marker of IR in PCOS women.
BACKGROUND: although there is evidence of correlation between irisin and osteoporotic fractures, previous studies have not elucidated the relationship between irisin and either lean or fat mass. The main aim of this study is to investigate the relationship between irisin and body composition in postmenopausal women with osteoporosis and the impact of irisin levels on fragility vertebral fractures.
METHODS: In this cross-sectional study, 36 overweight subjects affected by at least one vertebral osteoporotic fracture confirmed by a X-ray vertebral morphometry and 36 overweight non-osteoporotic subjects were enrolled. Serum irisin levels were measured using an irisin competitive ELISA. We evaluated lumbar spine and hip BMD and body composition using dual energy X-ray absorptiometry. To measure and monitor daily physical activity, each subject wore an armband for approximately 72 hours.
RESULTS: No significant correlations were found between irisin and BMD at any site and between irisin with either lean or fat mass. Serum levels ofirisin were not correlated with the daily physical activity. Serum irisin levels were lower in subjects with previous osteoporotic fractures than in controls (p= 0.032) and the difference in irisin levels remained significant after adjustment for creatinine (p=0.037), vitamin D (p=0.046), lean mass (p=0.02), lumbar BMD (p=0.023) and femoral BMD (p=0.032).
CONCLUSION: our data confirm an inverse correlation between irisin levels and vertebral fragility fractures but no significant correlation was found with BMD or lean mass. Irisin may play a protective role on bone health independent of BMD but further studies are needed to clarify the relationship between irisin and bone metabolism. This article is protected by copyright. All rights reserved.
Irisin is a newly discovered myokine that links exercise with metabolic homeostasis. It is involved in modest weight loss and improves glucose intolerance. However, the direct effects and mechanisms of irisin on vascular endothelial cells (ECs) are not fully understood. In the current study, we demonstrated that irisin promoted Human Umbilical Vein Endothelial Cell (HUVEC) proliferation. It was further demonstrated that this pro-proliferation effect was mediated by irisin-induced activation of extracellular signal-related kinase (ERK) signaling pathways. Inhibition of ERK signaling with U0126 decreased the pro-proliferation effect of irisin on HUVECs. It was also demonstrated that irisin reduced high glucose-induced apoptosis by up-regulating Bcl-2 expression and down-regulating Bax, Caspase-9 and Caspase-3 expression. In summary, these results suggested that irisin plays a novel role in sustaining endothelial homeostasis by promoting HUVEC proliferation via the ERK signaling pathway and protects the cell from high glucose-induced apoptosis by regulating Bcl-2,Bax and Caspase expression.
Ursolic acid (UA), a type of pentacyclic triterpenoid carboxylic acid purified from natural plants, can promote skeletal muscle development. We measured the effect of resistance training (RT) with/without UA on skeletal muscle development and related factors in men. Sixteen healthy male participants (age, 29.37±5.14 years; body mass index=27.13±2.16 kg/m2) were randomly assigned to RT (n=7) or RT with UA (RT+UA, n=9) groups. Both groups completed 8 weeks of intervention consisting of 5 sets of 26 exercises, with 10?15 repetitions at 60-80% of 1 repetition maximum and a 60?90-s rest interval between sets, performed 6 times/week. UA or placebo was orally ingested as 1 capsule 3 times/day for 8 weeks. The following factors were measured pre-and post-intervention: body composition, insulin, insulin-like growth factor-1 (IGF-1), irisin, and skeletal muscle strength. Body fat percentage was significantly decreased (p£¼0.001) in the RT+UA group, despite body weight, body mass index, lean body mass, glucose, and insulin levels remaining unchanged. IGF-1 and irisin were significantly increased compared with baseline levels in the RT+UA group (p£¼0.05). Maximal right and left extension (p£¼0.01), right flexion (p£¼0.05), and left flexion (p£¼0.001) were significantly increased compared with baseline levels in the RT+UA group. These findings suggest that UA-induced elevation of serum irisin may be useful as an agent for the enhancement of skeletal muscle strength during RT.
This study investigated the regulation of thermogenic capacity in classical BAT and SC WAT, and how it affects whole-body energy expenditure in sedentary (Sed) and endurance-trained (Ex) rats fed ad libitum either low-fat (LF) or high-fat (HF) diets. Analysis of tissue mass, PGC-1? and UCP-1 content, presence of multilocular adipocytes, and palmitate oxidation revealed that HF diet increased the thermogenic capacity of the interscapular and aortic brown adipose tissues, while exercise markedly suppressed it. Conversely, exercise induced browning of the subcutaneous inguinal (SC Ing) WAT. This effect was attenuated by HF diet. Endurance training neither affected skeletal muscle FNDC5 content nor circulatingirisin, but it increased FNDC5 content in SC Ing WAT. This suggests that locally produced FNDC5 rather than circulating irisin mediated the exercise-induced browning effect on this fat tissue. Importantly, despite reducing the thermogenic capacity of classical BAT, exercise increased whole-body energy expenditure during the dark cycle. Therefore, browning of SC WAT, likely exerted a compensatory effect and raised whole-body energy expenditure in endurance-trained rats. Based on these novel findings, we propose that exercise-induced browning of the SC WAT provides an alternative mechanism that reduces thermogenic capacity in core areas and increases it in peripheral body regions. This could allow the organism to adjust its metabolic rate to accommodate diet-induced thermogenesis while simultaneously coping with the stress of chronically increased heat production through exercise.
BACKGROUND: Skeletal muscles produce irisin. Growing controversy exists on the association between this myokine and chronic disease risk. On the basis of the potential protective effects that irisin could exert on both vascular function and skeletal muscle mass, we hypothesized that an elevated level of this molecule may contribute to successful aging.
METHODS: Serum irisin levels were measured using enzyme-linked immunosorbent assay in disease-free centenarians, young healthy controls, and patients with precocious acute myocardial infarction.
RESULTS: We found the highest levels of serum irisin in disease-free centenarians (35.3 ± 5.5 ng/mL) compared with young healthy controls (20.7 ± 6.3 ng/mL) and especially with young patients with acute myocardial infarction (15.1 ± 5.4 ng/mL).
CONCLUSIONS: Our study demonstrates that healthy centenarians are characterized by increased serum irisin levels, whereas levels of this molecule were found to be significantly lower in young patients with myocardial infarction. Our findings may prompt further research into the role played by irisin not only in vascular disorders but also in life span modulation.
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.
Background: Peripheral action of irisin improves glucose homeostasis and increases energy expenditure, with no data on a central role of irisin in metabolism. These studies sought to examine (1) presence of irisin in human cerebrospinal fluid (CSF) and banked human hypothalamic tissue, (2) serum irisin in maternal subjects across varying adiposities with or without gestational diabetes (GDM), and (3) their respective neonate offspring.
Methods: CSF, serum and neonatal cord serum were collected from 91 pregnant women with and without GDM attending for an elective Caesarean section (BMI: 37.7±7.6 Kg/m2; age: 32±8.3 years). Irisin was assessed by ELISA and correlated with biochemical and anthropometric dxata. Irisin expression was examined in human hypothalamus by immunohistochemical staining.
Results: Serum irisin in pregnant women was significantly lower in non-obese compared to obese and GDM subjects, after adjusting for BMI, lipids and glucose. Irisin was present in neonatal cord serum (237±8ng/ml) and maternal CSF (32±1.5ng/ml). CSF irisin correlated positively with serum irisin levels from non-obese and obese pregnant women (p<0.01), with CSF irisin significantly raised in GDM subjects (p<0.05). Irisin was present in human hypothalamic sections in the paraventricular neurons, co-localized with neuropeptideY.
Conclusions: Irisin was detectable in CSF and in paraventricular neurons. Maternal serum irisin was lower in non-obese pregnant women after adjusting for BMI and a number of metabolic parameters. These studies indicate that irisin may have a central role in metabolism in addition to the known peripheral role. Further studies investigating the central action of irisin in human metabolic disease are required.
OBJECTIVE: Irisin has recently been introduced as a novel an exercise-inducible myokine which improves glucose metabolism in mice. However, regulation of circulating irisin in gestational diabetes mellitus (GDM) and in the peripartal period has not been assessed so far.
METHODS: Circulating irisin was quantified in 74 GDM patients and in 74 healthy, pregnant, gestational age-matched controls. In a subset of these patients (44 GDM, 41 controls), postpartum follow-up data were also available. In a second study population of 40 healthy women with singleton pregnancies undergoing elective Cesarean section, irisin was assessed in maternal serum before and within 24h after delivery, as well as in umbilical cord blood and in placental tissue.
RESULTS: In the first study population, median [interquartile range] irisin levels were significantly higher in GDM patients as compared to controls after delivery (previous GDM: 446.3 [146.9]?g/l; controls: 378.0 [111.4]?g/l) but not during pregnancy (GDM: 482.1 [132.1]?g/l; controls: 466.6 [178.0]?g/l). Interestingly, fasting insulin (FI) was independently and positively associated with serum irisin in multivariate analysis during pregnancy. In agreement with these findings, relative changes (ratio) of FI independently and positively predicted relative changes of irisin (ratio) in the second study population.
CONCLUSIONS: The myokine irisin is independently associated with FI in pregnancy. The physiological significance of these findings needs to be assessed in future experiments.
This publication used an Irisin kit from Phoenix Pharmaceuticals.
Irisin converts white adipose tissue (WAT) into brown adipose tissue (BAT), as regulated by energy expenditure. The relationship between irisin concentrations after exercise in rats compared humans after exercise remains controversial. We therefore: 1) measured irisin expression in cardiac and skeletal muscle, liver, kidney, peripheral nerve sheath and skin tissues, as also serum irisin level in 10 week-old rats without exercise, and 2) measured tissue supernatant irisin levels in cardiac and skeletal muscle, and in response to exercise in young and old rats to establishing which tissues produced most irisin. Young (12 months) and old rats (24 months) with or without 10min exercise (water floating) and healthy 10 week-old Sprague-Dawley rats without exercise were used. Irisin was absent in sections of skeletal muscle of unexercised rats, the only part being stained being the perimysium. In contrast, cardiac muscle tissue, peripheral myelin sheath, liver, kidneys, and skin dermis and hypodermis were strongly immunoreactivity. No irisin was seen in skeletal muscle of unexercised young and old rats, but a slight amount was detected after exercise. Strong immunoreactivity occurred in cardiac muscle of young and old rats with or without exercise, notably in pericardial connective tissue. Serum irisin increased after exercise, being higher in younger than older rats. Irisin in tissue supernatants (cardiac and skeletal muscle) was high with or without exercise. High supernatant irisin could come with connective tissues around skeletal muscle, especially nerve sheaths located within it. Skeletal muscle is probably not an irisin source.
Irisin was identified as a myokine secreted by contracting skeletal muscle, possibly mediating some of exercise health benefits via "browning" of white adipose tissue. However, a controversy exists concerning irisin origin, regulation&function in humans. Thus, we have explored Fndc5/irisin in 2 clinical studies: (i) a cross-sectional study (effects of type-2-diabetes (T2D) in drug-naïve men); (ii) an intervention study (exercise effects in sedentary, overweight/obese individuals). Methods. Glucose tolerance and insulin sensitivity were assessed. VO2max and muscle strength were measured before and after training. Body composition (MRI), muscle&liver fat content (1H-MRS) and in vivo muscle metabolism (32P-MRS) were determined. Skeletal muscle and subcutaneous abdominal adipose tissue samples were taken in the fasted state, during euglycemic hyperinsulinemia (adipose tissue) and before/after exercise training (muscle). Results. Muscle Fndc5 mRNA was increased in prediabetes but not T2D. Fndc5/irisin in adipose tissue/plasma were reduced in T2D by 40% and 50%, respectively. Opposite to that, T2D-derived myotubes expressed/secreted the highest levels of Fndc5/irisin. Neither hyperinsulinemia (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 glycemia. Glucose and palmitate decreased Fndc5 mRNA in myotubes in vitro. Conclusions. Distinct patterns of Fndc5/irisin in muscle, adipose tissue nad 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.
Fig.1 of example #1 . Plasma irisin concentration (A) and Fndc5 gene expression in skeletal muscle (C) and subcutaneous adipose tissue (E) in individuals with obesity, prediabetes and type 2 diabetes. Data are shown as means ±SEM. *p<0.05. ** p<0.01. *** p<0.005
Figure 3 of example #1. Fndc5/irisin Subset of the differentiated human primary muscles originating from lean, obese, prediabetes and tupe 2 diabetic individuals. (A) Fndc5 mRNA in differentiated human primary muscle cells number of samples from experiment 2. (B) Irisin in the conditioned media from human primary muscle cells. Data are shown as means ± SEM. *p<0.05.
Subset of the 21 plasma samples from the study were measured with a more recently developed recombinant irisin EIA kit (#EK-067-29). This assay provided authors with identical results, but revealed that previously measured plasma concentrations might be underestimated by approximately 25 fold.
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 Metabolic Syndrome (MetS) patients 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 of plasma irisin levels and the depletion of important lipid metabolism biomarkers was observed in patients with MetS undergoing an energy restricted program.
AIMS: Chronic kidney disease (CKD) secondary to type 2 diabetes mellitus (T2DM) is associated with multifaceted energy dysmetabolism. We aim to study the relationship between renal function, body composition and irisin, the recently identified myokine which is involved in energy regulation, in T2DM.
METHODS: Circulating irisin and body composition were measured in 365 T2DM subjects across a wide range of renal function.
RESULTS: Circulating irisin was significantly decreased in T2DM with renal insufficiency (77.4 ¡À 13.7ng/ml in T2DM with eGFR ~60ml/min/1.73m2 versus 72.5 ± 14.9ng/ml in those with eGFR<60ml/min/1.73m2, p=0.001) and the reduction in irisin was most pronounced in stage 5 CKD patients. In T2DM with preserved renal function, irisin was correlated with age (r=-0.242, p=0.001) and pulse pressure (r=-0.188, p=0.002). Among those with renal insufficiency, irisin was correlated with BMI (r=0.171, p=0.022), fat mass (r=0.191, p=0.013), percentage of fat mass (r=0.210, p=0.007) and eGFR (r=0.171, p=0.020). Multivariate linear regression models revealed that variations in circulating irisin were mainly attributable to eGFR and age in T2DM with and without renal impairment, respectively.
CONCLUSION: Our observations suggest that the level of circulating irisin may be associated with renal function in T2DM. The role of reduced irisin in energy dysmetabolism in diabetic patients with renal insufficiency deserves further investigation.
Irisin was recently identified as a putative myokine that is induced by exercise. Studies suggest that it is produced by cleavage of the FNDC5 (fibronectin domain-containing protein 5) receptor; irisin corresponds to the extracellular receptor ectodomain. Data suggesting that irisin stimulates white to brown fat conversion has led to the hypothesis that it does so by binding an unknown receptor, thus functioning as a myokine. As brown fat promotes energy dissipation, myokines that elicit the transformation of white to brown fat have potentially profound benefits in the treatment of obesity and metabolic disorders. Understanding the molecular basis for such exercise-induced phenomena is thus, of considerable interest. Moreover, FNDC5-like receptors are highly conserved and have been shown to be critical for neuronal development. However, the structural and molecular mechanisms utilized by these proteins are currently unknown. Here we describe the crystal structure and biochemical characterization of the FNDC5 ectodomain, corresponding to the irisin myokine. The 2.28 Angstrom structure shows that irisin consists of an N-terminal fibronectin III(FNIII)-like domain attached to a flexible C-terminal tail. Strikingly, the FNIII-like domain forms a continuous intersubunit ?-sheet dimer, previously unobserved for any FNIII protein. Biochemical data confirm that irisin is a dimer and that dimerization is unaffected by glycosylation. This finding suggests a possible mechanism for receptor activation by the irisin domain as a preformed myokine dimer ligand or as a paracrine or autocrine dimerization module on FNDC5-like receptors.
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\'\' statewhich 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 bodyweight and improved glucose homeostasis. We further showed that irisin upregulated UCP-1 (a regulator of thermogenic capability of brown fat) expression. This effect was possibly mediated by irisin induced phosphorylation of p38 MAPK and ERK signaling pathway. 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 beta 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 p38 MAPK and ERK pathway.
The purpose of this study was to ascertain (1) whether human saliva contains irisin and whether its level correlates with serum irisin concentration, (2) whether salivary glands, eccrine glands and sebaceous glands in human skin produce irisin, (3) how the changes in saliva and serum irisin concentrations after the Turkish bath at 47±3°C compare with the changes caused by moderate exercise in obese and normal weight subjects. Seven obese male subjects and seven normal weight subjects were enrolled for Turkish bath. Seven obese male subjects and seven normal weight subjects were also enrolled for moderate outdoor exercise, and thirteen male normal weight subjects neither exercised nor showered at the Turkish bath. From each participant, 1.5ml of saliva and 5ml blood were collected simultaneously before and after the moderate exercise and Turkish bath. Salivary glands and eccrine and sebaceous glands in the skin were screened immunohistochemically for irisin while serum and saliva irisin were measured with an ELISA. Submandibular glands, eccrine glands and sebaceous glands in the human skin showed strong irisin immunoreactivity. Human saliva contained irisin and its level was significantly higher than the serum levels in both obese and normal weight subjects. However, irisin concentrations were more markedly increased in both saliva and serum samples from subjects who had showered at a Turkish bath than in obese subjects who had exercised or in normal weight subjects. Human submandibular glands, eccrine sweat glands and sebaceous glands synthesize irisin.
OBJECTIVE: Skeletal muscle is considered to be an endocrine organ that secretes a number of myokines including follistatin, myostatin, activin A and the newly identified irisin. Irisin\'s biology and function exhibits similarities with the functions of the follistatin-myostatin-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 follistatin, myostatin and activin A axis.
MATERIAL-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 Body Mass Index (BMI) 23.18± 3.75 kg/m². 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/m². Blood samples were obtained after an overnight fast. Eight out of the fourteen 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, follistatin, myostatin and activin A.
RESULTS: We report that FNDC5 mRNA in muscle is positively correlated with follistatin mRNA expression in morbidly obese subjects (rho=0.93, p<0.001). We also found that circulating irisin is positively correlated with follistatin circulating levels among lean subjects (rho=0.17, p=0.05) while this association was suggestive among the obese (rho=0.56, p=0.07).
CONCLUSION: The newly identified myokine irisin may be positively associated with follistatin at both the mRNA and circulating protein level.
Irisin, a newly discovered, PGC-1α dependent myokine, has recently been shown to increase in circulation in response to sprint exercise. This study examined the effect of prolonged exercise on irisin concentrations in young men (n=7) as well as in young women (n=5) during different stages of the menstrual cycle. Seven young men completed 90 min of treadmill exercise at 60% of VO2max and a resting control trial. Five women completed the same exercise protocol in two different trials: during the early follicular phase and mid-luteal phase of the menstrual cycle. Blood samples were collected and analyzed for irisin concentrations immediately before exercise, at 54 and 90 min of exercise, and at 20 min of recovery (R20). Findings revealed that by 54 min of a 90 min treadmill exercise protocol at 60% of VO2max, irisin concentrations significantly increased 20.4% in young men and 20.3% as well as 24.6% in young women during the early follicular and mid-luteal phases of the menstrual cycle, respectively. However, by 90 min of exercise as well as R20, irisin concentrations were no longer elevated. Stage of the menstrual cycle did not affect responses in young women. Findings indicate that prolonged aerobic exercise produces a transient increase in irisin concentrations during the first hour of exercise for both genders and suggest that this form of moderate exercise may be helpful in improving fat metabolism.
Context: Irisin, a recently identified hormone, has been proposed to regulate energy homeostasis and obesity in mice. Whether irisin levels are associated with risk of the metabolic syndrome (MetS), cardiometabolic variables, and cardiovascular disease (CVD) risk in humans remains unknown.
Objective: To assess the associations between baseline serum irisin levels and MetS, cardiometabolic variables, and CVD risk.
Design, Setting, and Subjects: Comparative cross-sectional evaluation of baseline circulating levels of the novel hormone irisin, and the established adipokine adiponectin with MetS, cardiometabolic variables, and CVD risk in a sample of 151 subjects.
Results:Baseline irisin levels were significantly higher in subjects with MetS compared to subjects without MetS. Irisin was associated negatively with adiponectin (r= -0.4, p<0.001) and positively with BMI (r=0.22, p=0.008), systolic (r=0.17, p=0.04), diastolic blood pressure (r=0.27, p=0.001), fasting glucose (r=0.25, p=0.002), triglycerides (r=0.25, p=0.003), and HOMA-IR (r=0.33, p<0.001). After adjustment for potential confounders, including BMI, subjects in the highest tertile of irisin levels were more likely to have MetS (OR 9.44, 95%CI 2.66-33.44), elevated fasting blood glucose (OR 5.80, 95%CI 1.72-19.60), high triglycerides (OR 3.89, 95%CI 1.16-13.03), and low HDL-cholesterol (OR 3.30, 95%CI 1.18-9.20). Irisin was independently associated with HOMA-IR and general Framingham risk profile in multiple linear regression analyses after adjustment for confounders. Adiponectin demonstrated the expected associations with outcomes.
Conclusions: Irisin is associated with increased risk of MetS, cardiometabolic variables, and CVD in humans, indicating either increased secretion by adipose/muscle tissue and/or a compensatory increase of irisin to overcome an underlying irisin resistance in these subjects.
This publication used a Irisin kit from Phoenix Pharmaceuticals
Patients with chronic kidney disease have abnormal energy expenditure and metabolism. The mechanisms underlying altered energy expenditure in uremia are unknown and remain to be elucidated. Irisin is a peroxisome proliferator-activated receptor c coactivator 1-a–dependent myokine, and it increases energy expenditure in the absence of changes in food intake or activity. We hypothesize that chronic kidney disease patients have altered irisin levels. We measured resting irisin levels in 38 patients with stage 5 chronic kidney disease and in 19 age- and sex-matched normal subjects. Plasma irisin levels were significantly decreased in chronic kidney disease patients (58.59%; 95% CI 47.9%–69.2%, p,0.0001). The decrease in irisin levels was inversely correlated with the levels of blood urea nitrogen and creatinine. Further association analysis revealed that irisin level is independently associated with high-density lipoprotein cholesterol level. Our results suggest that chronic kidney disease patients have lower than normal irisin levels at rest. Furthermore, irisin may play a major role in affecting high-density lipoprotein cholesterol levels and abnormal energy expenditure in chronic kidney disease patients.
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 PGC1? 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). PGC1? 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 PGC1? 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.
This publication used an Irisin kit from Phoenix Pharmaceuticals.
Irisin is a recently identified myokine secreted from the muscle in response to exercise. In the rats and mice, immunohistochemical studies with an antiserum against irisin peptide fragment (42-112), revealed that irisin-immunoreactivity (irIRN) was detected in three types of cells; namely, skeletal muscle cells, cardiomyocytes, and Purkinje cells of the cerebellum. Tissue sections processed with irisin antiserum pre-absorbed with the irisin peptide(42-112) (1 ug/ml) showed no immunoreactivity. Cerebellar Purkinje cells were also immunolabeled with an antiserum against fibronectin type II domain containing 5 (FNDC5), the precursor protein of irisin. Double-labeling of cerebellar sections with irisin antiserum and glutamate decarboxylase (GAD) antibody showed that nearly all irIRN Purkinje cells were GAD-positive. Injection of the fluorescence tracer Fluorogold into the vestibular nucleus of the rat medulla retrogradely labeled a population of Purkinje cells, some of which were also irIRN. Our results provide the first evidence of expression of irIRN in the rodent skeletal and cardiac muscle, and in the brain where it is present in GAD-positive Purkinje cells of the cerebellum. Our findings together with reports by others led us to hypothesize a novel neural pathway, which originates from cerebellum Purkinje cells, via several intermediary synapses in the medulla and spinal cord, and regulates adipocyte metabolism.
This publication used a Irisin and FNDC5 antibody from Phoenix Pharmaceuticals.
AIMSHYPOTHESIS: Recently, the novel myokine irisin was described to drive adipose tissue \'browning\', to increase energy expenditure, and to improve obesity and insulin resistance in high fat-fed mice. Here, we assessed whether common single nucleotide polymorphisms (SNPs) in the FNDC5 locus, encoding the irisin precursor, contribute to human prediabetic phenotypes (overweight, glucose intolerance, insulin resistance, impaired insulin release).
METHODS: A population of 1,976 individuals was characterized by oral glucose tolerance tests and genotyped for FNDC5 tagging SNPs. Subgroups underwent hyperinsulinaemic-euglycaemic clamps, magnetic resonance imaging/spectroscopy, and intravenous glucose tolerance tests. From 37 young and 14 elderly participants recruited in two different centres, muscle biopsies were obtained for the preparation of human myotube cultures.
RESULTS: After appropriate adjustment and Bonferroni correction for the number of tested variants, SNPs rs16835198 and rs726344 were associated with in vivo measures of insulin sensitivity. Via interrogation of publicly available data from the Meta-Analyses of Glucose and Insulin-related traits Consortium, rs726344\'s effect on insulin sensitivity was replicated. Moreover, novel data from human myotubes revealed a negative association between FNDC5 expression and appropriately adjusted in vivo measures of insulin sensitivity in young donors. This finding was replicated in myotubes from elderly men.
CONCLUSIONS & INTERPRETATION: This study provides evidence that the FNDC5 gene, encoding the novel myokine irisin, determines insulin sensitivity in humans. Our gene expression data point to an unexpected insulin-desensitizing effect of irisin.
AIMS: Irisin is a novel myokine secreted in response to PPAR-? co-activator-1? (PGC-1?) activation. Earlier studies suggested that PGC-1α expression and activity were lower in myocytes in type 2 diabetes mellitus (T2DM). Therefore, we hypothesize that circulating irisin levels are lower in T2DM patients.
METHODS: In this observational study, we recruited 96 T2DM subjects and 60 non-diabetic control subjects. Among T2DM subjects, 38% were on insulin treatment, 78% were taking statins and 72% were taking renin-angiotensin system antagonists. Circulating irisin was quantified by ELISA and its association with markers of metabolic phenotype was analyzed by Pearson bivariate correlation and multiple linear regression.
RESULTS: Circulating irisin was significantly lower in individuals with T2DM compared with non-diabetic controls (T2DM 204±72ng/ml vs. non-diabetic control 257±24ng/ml, p<0.0001). In non-diabetic subjects, circulating irisin was correlated with age (r=0.398, p<0.01), BMI (r=0.387, p<0.01), total cholesterol (r=0.341, p<0.01), total triglycerides (r=0.299, p<0.05), fasting blood glucose (r=0.430, p<0.01) and diastolic blood pressure (r=0.306, p<0.05). Multiple linear regression model revealed that BMI (?=0.407, p=0.012) and FBG (?=0.315, p=0.034) were associated with irisin in non-diabetic subjects after adjusting for multiple co-variates. However, similar analysis in T2DM subjects didn\'t reveal significant association between circulating irisin and major markers of metabolic phenotype.
CONCLUSIONS: Circulating irisin is lower in T2DM compared with non-diabetic controls. Plasma irisin levels appear to be associated with important metabolic factors in non-diabetic subjects but not in individuals with type 2 diabetes.
Exercise provides clear beneficial effects for the prevention of numerous diseases. However, many of the molecular events responsible for the curative and protective role of exercise remain elusive. The recent discovery of FNDC5/irisin protein that is liberated by muscle tissue in response to exercise might be an important finding with regard to this unsolved mechanism. The most striking aspect of this myokine is its alleged capacity to drive brown-fat development of white fat and thermogenesis. However, the nature and secretion form of this new protein is controversial. The present study reveals that rat skeletal muscle secretes a 25 kDa form of FNDC5, while the 12 kDa/irisin theoretical peptide was not detected. More importantly, this study is the first to reveal that white adipose tissue (WAT) also secretes FNDC5; hence, it may also behave as an adipokine. Our data using rat adipose tissue explants secretomes proves that visceral adipose tissue (VAT), and especially subcutaneous adipose tissue (SAT), express and secrete FNDC5. We also show that short-term periods of endurance exercise training induced FNDC5 secretion by SAT and VAT. Moreover, we observed that WAT significantly reduced FNDC5 secretion in fasting animals. Interestingly, WAT of obese animals over-secreted this hormone, which might suggest a type of resistance. Because 72% of circulating FNDC5/irisin was previously attributed to muscle secretion, our findings suggest a muscle-adipose tissue crosstalk through a regulatory feedback mechanism.
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 8week 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 6months after bariatric surgery. Circulating irisin levels were significantly upregulated 30min 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.
Background—Exercise induced increase in peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (FNDC5) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and since PGC-1? and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF. Methods and Results—Systolic HF (LVEF ≤40%) patients underwent cardiopulmonary exercise testing (CPX) to evaluate aerobic performance. High vs. low aerobic performance was assessed using oxygen consumption [peak VO2 (>14mlO2•kg-1•min-1 vs. ≥14 mlO2•kg-1•min-1)] and ventilatory efficiency [VE/VCO2 slope (<34 vs. ≥34)]. Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression. Twenty-four patients were studied. FNDC5 (5.7±3.5 vs. 3.1±1.2, p<.05) and PGC-1α (9.9±5.9 vs. 4.5±1.9, p<.01) gene expression was greater in the high peak VO2 group; correlation between FNDC5 and PGC-1? was significant (r=0.56, p<.05) only in the high peak VO2 group. Similarly, FNDC5 and PGC-1α gene expression was greater in the high performance group based on lower VE/VCO2 slopes (5.8±3.6 vs. 3.3±1.4, p<.05 and 9.7±6 vs. 5.3±3.4, p<.05); FNDC5 also correlated with PGC-1α (r=0.55, p<.05) only in the low VE/VCO2 slope group. Conclusions—This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients.
Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional co-activator PPAR-gamma co-activator-1 a (PGC1-a). Here we show in mouse that PGC1-a expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown-fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in the blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be therapeutic for human metabolic disease and other disorders that are improved with exercise.
The identification of several peroxisomal proteins in the past decade has deepened our understanding of the biology of peroxisomes and their involvement in human disorders. We report the cloning and expression pattern during the mouse development of a cDNA encoding a novel protein, named PeP, and show that its product is imported specifically to the peroxisome matrix in a variety of cell types. We also demonstrate that PeP is imported to the organelle through the PEX5 receptor pathway, which indicates that the C-terminal tripeptide SKI behaves as a type 1 peroxisomal targeting signal (PTS1). PeP expression is tightly regulated, as shown by Northern and in situ hybridization experiments. Thus during embryonic development in the mouse, PeP mRNA is detected almost exclusively in the skeletal muscle, whereas in adult mice, strong expression is also found in the heart and brain. In addition, PeP mRNA accumulation is induced after myoblast differentiation in vitro, when myotube formation is promoted. Sequence analysis reveals that PeP has no significant homology to any known protein, except for a short stretch of amino acids containing the fingerprint of the fibronectin type III superfamily, a domain present in proteins often related to molecular and cellular recognition and binding processes. Thus our data suggest a connection between the function of PeP and murine cell differentiation and development.
Nonshivering cold exposure increases FGF21, which may be a brown adipokine.
• Irisin and/or FGF21 upregulates brown-fat-like program in human adipocytes
• Exercise may be a shivering mimic exemplifying muscle-fat thermogenic crosstalk.
Figure from: Cell Metabolism, Volume 19, Issue 2, 302-309.