Irisin Secretion Research Articles

Hydrogen Sulfide Regulates Irisin and Glucose Metabolism in Myotubes and Muscle of HFD-Fed Diabetic Mice.

Irisin, a novel myokine, is secreted by the muscle following proteolytic cleavage of fibronectin type III domain containing 5 (FNDC5) and is considered a novel regulator of glucose homeostasis. Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) and is involved in glucose homeostasis. We examined the hypothesis that H2S deficiency leads to decreased FNDC5 and irisin secretion, and thereby alters glucose metabolism. High-fat diet-fed mice exhibited elevated blood glucose and significantly reduced levels of CSE, H2S, and PGC-1α, with decreased FNDC5/irisin levels and increased oxidative stress in the muscle compared with those of normal diet-fed mice (control). High glucose or palmitate decreases CSE/PGC-1α/FNDC5 levels and glucose uptake in myotubes. Inhibitors (propargylglycine and aminooxyacetate) of H2S producing enzymes or CSE siRNA significantly decreased levels of H2S and FNDC5 along with PGC-1α; similar H2S-deficient conditions also resulted in decreased GLUT4 and glucose uptake. The levels of H2S, PGC-1α, and FNDC5 and glucose uptake were significantly upregulated after treatment with l-cysteine or an H2S donor. Myoblast differentiation showed upregulation of PGC-1α and FNDC5, which was consistent with the increased expression of CSE/H2S. These findings suggest that the upregulation of H2S levels can have beneficial effects on glucose homeostasis via activation of the PGC-1α/FNDC5/irisin signaling pathway.

Sesamin Activates Skeletal Muscle FNDC5 Expression and Increases Irisin Secretion via the SIRT1 Signaling Pathway.

Sesamin, a major lignin mainly found in sesame (Sesamum indicum) oil and sesame seeds, has been demonstrated to possess lipoclasis-promoting, antiobesity, and antidiabetic effects. Irisin is a newly discovered myokine that has attracted great interest as a key target to prevent/treat obesity and its related metabolic diseases. However, the effect and potential mechanism of sesamin on FNDC5/irisin are still vacant. In this study, we showed that sesamin treatment increased FNDC5/irisin activation and regulated SIRT1, PGC-1α, and p-SMAD3/SMAD3 expression in C2C12 cells. By using specific inhibitors and lentivirus in C2C12 cells, we found that the SIRT1/SMAD3 axis plays an important role in sesamin regulated FNDC5/irisin activation. We also found that sesamin treatment activated FNDC5 expression and regulated the SIRT1/SMAD3 signaling axis in mice's skeletal muscle. What is more, by the high-fat diet induced obese model, we further showed that sesamin improved the high-fat diet induced decrease in irisin production and secretion, which results in an improvement of body weight gain and skeletal muscle dysfunction. Our results suggested that sesamin could activate FNDC5 expression and stimulate irisin secretion through the SIRT1 pathway both in vitro and in vivo, which may provide a new strategy for preventing and improving irisin deficiency related diseases.

Renal protection induced by physical exercise may be mediated by the irisin/AMPK axis in diabetic nephropathy

In patients with diabetes, it has been suggested that physical exercise may reduce albuminuria and the progression of renal disease. However, the molecular mechanism by which physical exercise protects the kidney in diabetes remains poorly understood. The aim of the present study was to determine the contribution of muscle irisin secretion induced by aerobic physical exercise with the subsequent activation of AMPK for kidney protection under diabetic conditions. Aerobic physical exercise in rats protected the kidney in streptozotocin-induced diabetes. It reduced albuminuria, glomerular hypertrophy, and glomerular expression of collagen IV and fibronectin, as well as markers of kidney inflammation, when compared to sedentary diabetic rats. These effects were associated with elevation in muscle FNDC5/irisin and activity of AMPK in the diabetic kidney. However, the beneficial effects of exercise were lost when the diabetic rats were treated with CycloRGDyK, that in the bone it has been described as an irisin receptor blocker. In cultured human tubular (HK-2) cells, treatment with recombinant irisin counteracted the effect of high glucose in a dose-dependent manner. Irisin, per se, also activated AMPK in HK-2 cells. It is concluded that in diabetes, the renal protective effect of exercise may be mediated by the irisin/AMPK pathway.

Pentamethylquercetin Regulates Lipid Metabolism by Modulating Skeletal Muscle-Adipose Tissue Crosstalk in Obese Mice.

Irisin is an exercise-induced hormone that regulates lipid metabolism. The present study investigates whether the anti-obesity effect of the natural flavonoid pentamethylquercetin (PMQ) is related to irisin secretion from skeletal muscle in whole animals and cultured cells. Obese mice induced by monosodium glutamate were administered oral PMQ to determine blood irisin level and in vivo parameters of lipid metabolism, and cultured mouse C2C12 myoblasts and 3T3-L1 preadipocytes were employed to investigate the related molecular identities. PMQ increased circulating irisin and decreased bodyweight, insulin, and lipid levels accompanied with increasing brown-like adipocyte formation in obese mice. The brown adipocyte marker uncoupling protein 1 (UCP-1) and other brown-like adipocyte-specific genes and/or markers were increased in mouse white fat tissue, while PMQ treatment reversed the above changes. PMQ also dose-dependently increased the reduced levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and fibronectin type III domain-containing 5 (FNDC5) signal molecules in obese mice. Interestingly, the irisin level was increased in the culture medium of C2C12 cells treated with PMQ, and the conditioned medium stimulated the brown-like transition of 3T3-L1 preadipocytes with the increased expression of PGC-1α, FNDC5, UCP-1, and other brown-like adipocyte-specific genes. The effects of conditioned culture medium were abolished in C2C12 cells with silenced PGC-1α. On the other hand, PMQ-induced upregulation of PGC-1α and FNDC5 expression was reduced by AMPK inhibitor Compound C in C2C12 cells. Our results demonstrate the novel information that PMQ-induced irisin secretion from skeletal muscle involves the improvement of metabolic dysfunction in obese mice via activating the AMPK/PGC-1α/FNDC5 signal pathway, suggesting that PMQ modulates skeletal muscle-adipose tissue crosstalk and may be a promising drug candidate for treating obesity and obesity-related metabolic diseases.

Investigation of Brain Function-Related Myokine Secretion by Using Contractile 3D-Engineered Muscle.

Brain function-related myokines, such as lactate, irisin, and cathepsin B (CTSB), are upstream factors that control brain-derived neurotrophic factor (BDNF) expression and are secreted from skeletal muscle by exercise. However, whether irisin and CTSB are secreted by muscle contraction remains controversial. Three-dimensional (3D)-engineered muscle (3D-EM) may help determine whether skeletal muscle contraction leads to the secretion of irisin and CTSB, which has never been identified with the addition of drugs in conventional 2D muscle cell cultures. We aimed to investigate the effects of electrical pulse stimulation (EPS)-evoked muscle contraction on irisin and CTSB secretion in 3D-EM. The 3D-EM, which consisted of C2C12 myoblasts and type-1 collagen gel, was allowed to differentiate for 2 weeks and divided into the control and EPS groups. EPS was applied at 13 V, 66 Hz, and 2 msec for 3 h (on: 5 s/off: 5 s). Irisin and CTSB secretion into the culture medium was measured by Western blotting. Irisin secretion was significantly increased following EPS (p < 0.05). However, there was no significant difference in CTSB secretion between the two groups. The present study suggests that irisin may be a contractile muscle-derived myokine, but CTSB is not secreted by EPS-evoked muscle contractile stimulation in 3D-EM.

Applying exercise-mimetic engineered skeletal muscle model to interrogate the adaptive response of irisin to mechanical force

SummaryPhysical exercise induces the secretion of irisin from contractile muscle into circulation; however, the adaptive response of irisin to mechanical stimulus in skeletal muscle in vitro remains numerously unknown. In an effort to investigate whether irisin is inducible in vitro, we developed a bioreactor consisting of a retractable mechanical force controller and a conditional tissue culture system. Upon this model, a distinguished surge of irisin was detected in stretched myotubes as cyclic strain initiated, and the surge was able to be stalled by knocking out FNDC5. Intriguingly, increased irisin secretory is associated with the shifts of MyHC isoforms from anaerobic type to aerobic type in myotubes. We further revealed that PGC-1α1 and PGC-1α4 mRNAs expression, rather than PGC-1α2 and PGC-1α3, contributed to the generation of irisin in myotubes during cyclic strain. Lastly, combined with co-culturing MC3T3 osteoblasts, we demonstrated the bioactivity of generated irisin, promoting the osteogenic differentiation.

Interleukin-6 mediates lipopolysaccharide-inhibited irisin secretion in Nile tilapia (Oreochromis niloticus)

Irisin is a novel immunomodulatory adipomyokine released upon cleavage of the fibronectin type III domain-containing protein 5 (FNDC5). We aimed to examine interleukin-6 (IL-6) role in mediating irisin secretion in immunologically challenged animal and primary head kidney leukocytes cultured from tilapia. Intraperitoneal injection of lipopolysaccharide (LPS) increased plasma IL-6 levels and decreased irisin secretion, suggesting a causal relationship between the induction of IL-6 and irisin. To address this relationship, we further produced recombinant tilapia IL-6 and the anti-tilapia IL-6 polyclonal antiserum. Intraperitoneal injection of recombinant tilapia IL-6 inhibited plasma irisin levels. Consistent with this observation, LPS-induced inhibition of plasma irisin was significantly attenuated by neutralizing circulating IL-6 using an IL-6 antiserum. Besides, IL-6 treatment could inhibit irisin secretion and FNDC5 gene expression in primary cultures of tilapia head kidney leukocytes. In parallel experiments, both LPS and IL-6 blockade of irisin secretion could be reverted by IL-6 receptor antagonism. At the level of the leukocyte, IL-6 treatment also triggered rapid phosphorylation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), whereas IL-6-reduced irisin secretion could be negated by inhibiting the JAK2 and STAT3 signaling pathways. These results, as a whole, provide the first evidence that IL-6 is the mediator of LPS-inhibited irisin secretion via activation of the JAK2/STAT3 signaling pathway.

The Role of Physical Exercise Intesity to Irisin Levels on Overweight and Obese

Highlight:The differences in intensity physical exercise mechanisms associated with increased irisin secretion in overweight and obese subjects were determined.The secretion of irisin in the right intensity blood on obesity can be reduced because the calories were balanced. Abstract:Physical exercise is a non-pharmacological therapy that can secrete various types of myokines to treat obesity problems. One of the myokines that play a role is irisin. Irisin is a polypeptide hormone with 112 amino acid residues that are synthesized in skeletal muscle after the proteolytic precursor cleavage of fibronectin type III domain-containing protein 5 (FNDC5). The release of irisin in the blood circulation will stimulate the browning process in white fat tissue by inducing the expression of uncoupling protein-1 (UCP-1) through signaling p38 mitogen-activated protein kinase (p38-MAPK) to increase energy expenditure, thermogenesis and reduce fat accumulation. This study described the differences in intensity of physical exercise mechanisms associated with the increased irisin secretion in overweight and obese subjects. This study was designed as a literature review that involved studies from research journals in the last 10 years concerning humans from some databases, such as Science Direct, PubMed, and Google Scholar. This study also discussed the relationship between the intensity of physical exercise and the synthesis, secretion, circulation, and regulation of irisin in preventing obesity.

The exercise-instrumental music program and irisin levels in younger non-professional athletes

A passive lifestyle and lack of exercise are triggering factors in increasing metabolic syndrome, whereas metabolic syndrome is associated with increased morbidity and mortality. This study aimed to analyse an exercise-based non-pharmacological approach combined with instrumental music to the plasma levels of irisin. The study employed a randomised pretest-posttest-only group design recruiting 30 male participants. The individuals aged between 19-21 years, body mass index (BMI) 18.5-24.9 kg/m2, normal blood pressure, normal resting heart rate (RHR), VO2max 40-50 ml/kg bodyweight/min, normal haemoglobin (Hb). The subjects were randomly divided into three groups, MIE (n=10, moderate-intensity exercise), MIEM (n=10, moderate-intensity exercise + instrumental music), and HIE (n=10, high-intensity exercise). Blood sampling was collected from pre- and 5 min post-exercise treatment. ELISA method was used to measure the circulating irisin levels. The non-parametric Kruskal-Wallis test, Mann Whitney test and Spearman correlation were chosen to analyse the data. The results showed that there is no significant difference in pre-exercise irisin levels (ng/ml) in MIE (1.58±0.89), MIEM (1.77±3.12), and HIE (1.65±0.88) with a P-value of 0.098. Importantly, the alteration of irisin levels post-exercise program revealed that the level of this peptide (ng/ml) is higher in HIE (7.28±5.11) compared to MIE (1.95±1.85) and MIEM (4.16±3.40) with a P-value of 0.019. The plasma levels of irisin significantly correlate to energy expenditure (r=0.353, P≤0.01), plasma peroxisome proliferator-activated receptor gamma coactivator-1α (r=0.597, P≤0.001), and high-density lipoprotein (r=0.513, P≤0.01). In summary, increased irisin secretion may directly contribute to the gradual alteration of energy expenditure and correlate to physical exercise intensity-related musical treatment.

The Role of Irisin in Exercise-Mediated Bone Health.

Exercise training promotes physical and bone health, and is the first choice of non-drug strategies that help to improve the prognosis and complications of many chronic diseases. Irisin is a newly discovered peptide hormone that modulates energy metabolism and skeletal muscle mass. Here, we discuss the role of irisin in bone metabolism via exercise-induced mechanical forces regulation. In addition, the role of irisin in pathological bone loss and other chronic diseases is also reviewed. Notably, irisin appears to be a key determinant of bone mineral status and thus may serve as a novel biomarker for bone metabolism. Interestingly, the secretion of irisin appears to be mediated by different forms of exercise and pathological conditions such as diabetes, obesity, and inflammation. Understanding the mechanism by which irisin is regulated and how it regulates skeletal metabolism via osteoclast and osteoblast activities will be an important step toward applying new knowledge of irisin to the treatment and prevention of bone diseases such as osteolysis and other chronic disorders.

Exercise‐linked FNDC5/Irisin attenuates macrophage‐mediated renal inflammation in type 1 diabetes in aged mice

Diabetes is associated with chronic low-grade inflammation in the kidney. Both classically and alternately activated macrophages play key roles in diabetic nephropathy by mediating inflammatory processes and anti-inflammatory responses respectively. Physical activity is known to modulate innate immune function, indeed exercise training is reported to reduce low-grade inflammation and improve insulin sensitivity in obese subjects. FNDC5 is a myokine secreted by skeletal muscles during exercise and the cleavage of its extracellular domain yields Irisin. In vitro studies have demonstrated that Irisin exhibits anti-inflammatory properties in adipose tissues and RAW 264.7 cells. The purpose of our study was to investigate the effect of exercise induced FNDC5/Irisin on inflammation and damage of aged kidney in type I diabetes. C57BL/6-Ins2Akita/J (Type 1 diabetes, Akita) and C57BL/6J (Wild type, WT) mice aged 54 - 56 weeks underwent 16-week exercise training of 280 m run on treadmill at speed of 7m/min. for 5 days/week for 2 weeks and increased to 12 m/min. for the remaining 14 weeks. FNDC5/Irisin was upregulated in the kidneys of WT and Akita exercise groups but to a greater magnitude in the WT. Sedentary Akita mice kidneys showed increased macrophage recruitment and M1 macrophages (CCL2, CXCL2, and CD86+/CD40+ cells) and inflammatory cytokine production. In contrast, Akita mice undergoing exercise training increased anti-inflammatory profile and M2 phenotype polarization (CD206+ cells). Exercise induced changes were associated with robust activation of AMPK and MAPK signaling in Akita mice. In comparison to sedentary group, exercise training reduced renal resistive index, improved cortical blood flow and glomerular filtration rate in WT and Akita mice. Taken together, our results suggest that exercise training and Irisin secretion protects the aged kidney from type 1 diabetes induced damage by reducing macrophage-mediated inflammation.

FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin levels via the AMPK/SIRT-1/PGC-α pathway.

Obesity is associated with biological dysfunction in skeletal muscle. As a condition of obesity accompanied by muscle mass loss and physical dysfunction, sarcopenic obesity (SO) has become a novel public health problem. Human fibroblast growth factor 19 (FGF19) plays a therapeutic role in metabolic diseases. However, the protective effects of FGF19 on skeletal muscle in obesity and SO are still not completely understood. Our results showed that FGF19 administration improved muscle loss and grip strength in young and aged mice fed a high‐fat diet (HFD). Increases in muscle atrophy markers (FOXO‐3, Atrogin‐1, MuRF‐1) were abrogated by FGF19 in palmitic acid (PA)‐treated C2C12 myotubes and in the skeletal muscle of HFD‐fed mice. FGF19 not only reduced HFD‐induced body weight gain, excessive lipid accumulation and hyperlipidaemia but also promoted energy expenditure (PGC‐1α, UCP‐1, PPAR‐γ) in brown adipose tissue (BAT). FGF19 treatment restored PA‐ and HFD‐induced hyperglycaemia, impaired glucose tolerance and insulin resistance (IRS‐1, GLUT‐4) and mitigated the PA‐ and HFD‐induced decrease in FNDC‐5/irisin expression. However, these beneficial effects of FGF19 on skeletal muscle were abolished by inhibiting AMPK, SIRT‐1 and PGC‐1α expression. Taken together, this study suggests that FGF19 protects skeletal muscle against obesity‐induced muscle atrophy, metabolic derangement and abnormal irisin secretion partially through the AMPK/SIRT‐1/PGC‐α signalling pathway, which might be a potential therapeutic target for obesity and SO.

Associations of Circulating Irisin with FNDC5 Expression in Fat and Muscle in Type 1 and Type 2 Diabetic Mice.

Irisin is an exercise-induced myokine, suggested to exert beneficial effects on metabolism. However, the studies on the regulation of irisin secretion and the expression of its precursor FNDC5 have shown conflicting data. The discrepancies among previous correlation studies in humans are related to the heterogeneity of the study population. The fact that irisin is not only a myokine but also an adipokine leads to the further complexity of the role of irisin in metabolic regulation. In this study, we examined the regulation of FNDC5 expression and irisin in circulation in both type 1 and type 2 diabetic mice, and their potential relationships with metabolic parameters. In streptozotocin (STZ)-induced type 1 diabetic mice, high-fat diet (HFD)-induced obese mice and db/db mice, the circulating irisin as well as FNDC5 gene expression in subcutaneous fat was downregulated. Muscle FNDC5 expression was only significantly lower in STZ mice, and epididymal fat FNDC5 expression was unaltered. It is interesting to note that plasma irisin levels correlated positively with subcutaneous fat FNDC5 expression, but not epididymal fat or muscle. Moreover, both irisin levels and subcutaneous fat FNDC5 correlated negatively with markers of insulin resistance. These results suggest a regulatory role for subcutaneous fat-derived FNDC5/irisin in metabolic disease.

Ursolic acid induces white adipose tissue beiging in high-fat-diet obese male mice.

Ursolic acid (UA) shows an effect on obesity and related metabolic diseases, but its mechanism of action remains unclear. We found that UA clearly reduced the body weight and adipose tissue mass and improved the glucose tolerance and insulin sensitivity in obese male mice. UA treatment significantly reduced the volume and weights of the epididymal white adipose tissue (eWAT) and inguinal subcutaneous white adipose tissue (igSWAT) of HFD-fed mice, respectively. UA also decreased the expression of genes involved in adipocyte differentiation and lipogenesis in igSWAT. Real-time PCR and immunohistochemistry showed that the expression of beiging-related genes 4-1BB factor (CD137), T-box transcription factor 1 (TBX1), and transmembrane protein 26 (TMEM26) were significantly increased in the UA treatment group. UA treatment significantly reduced the weight of gastrocnemius muscle (GM) and lipid droplets in the GM. UA treatment significantly upregulated the expression of PR domain-containing 16 (PRDM16), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and fibronectin type 3 domain-containing protein 5 (FNDC5) in GM and igSWAT. UA also stimulated irisin secretion in the serum. In conclusion, these results indicate that UA plays an anti-obesogenic role by increasing the secretion of irisin and promoting the beiging of WAT.

Association of Circulating Irisin Levels with Adiposity and Glucose Metabolic Profiles in a Middle-Aged Chinese Population: A Cross-Sectional Study.

ObjectiveThe myokine irisin has been proposed to affect obesity and metabolism disorders. However, data about the association of irisin with obesity and glucose metabolic status in humans remains controversial, and limited data are available concerning the Chinese population. This study aimed to evaluate the association between serum irisin concentrations and obesity, as well as glucose metabolic and cardiovascular factors in the middle-aged physical activity-matched Chinese Han race population.MethodsA total of 740 participants were included in this cross-sectional study, who were divided into a normal weight (NW) group, overweight/obese (OB) group, normal weight type 2 diabetes (DM-NW) group and overweight/obese diabetes (DM-OB) group, and physical activity was evaluated and matched for the four groups. Circulating irisin levels were analyzed and compared among the groups with different adiposity and glucose status. Linear regression analysis was performed to test the relationship between serum irisin and adiposity indices, glucose metabolic and other cardiovascular risk factors.ResultsCirculating irisin levels were significantly correlated with higher levels of direct and indirect adiposity markers, including BMI, waist circumference and fat mass, and other cardiovascular risk factors, such as plasma triglyceride and low-density lipoprotein cholesterol level (p < 0.01). Diabetes patients had lower irisin levels compared to non-diabetes participants, in either normal weight and obese group, resulting in a correlation of irisin with HbA1c, HOMA-IR and HOMA-IS (p < 0.01). Linear regression analysis demonstrated that irisin serum concentrations were independently associated with sex, BMI, HbA1c, HOMA-IR and HOMA-IS (R2 = 0.465).ConclusionThese data indicated that circulating irisin was affected by adiposity and glucose metabolism condition in the middle-aged Chinese population. The increase of irisin under conditions of obesity may indicate its physiological function to improve glucose tolerance which is often impaired in obese subjects, but this compensatory secretion of irisin seems likely to be progressing to a secretion failure once diabetes developed.

Whole-Body Cryotherapy Is an Effective Method of Reducing Abdominal Obesity in Menopausal Women with Metabolic Syndrome.

Abdominal obesity predominates in menopausal women (MW) and contributes to the development of metabolic syndrome (MetS). It is associated with increased mortality related to cardiovascular disease, diabetes and fatty liver disease. The effects of whole-body cryotherapy (WBC) on body composition and the blood concentration of irisin, interleukin-6 (IL-6) and C-reactive proteins (CRP) in MW with MetS and in healthy women (HW), were assessed. The study included 19 women with MetS (61.53 ± 3.99 y, BMI 30.09 ± 4.98 kg/m2) and 18 HW (60.28 ± 3.63 y, BMI 25.50 ± 2.37 kg/m2) who were subjected to 20 WBC treatments at −130 °C for 3 min daily. In both groups, body mass (BM), BMI, abdominal circumference, triceps skinfold, total fat mass and percentage of leg fat significantly decreased after 20 WBC sessions. Additionally, the percentage of total, trunk and android fat in the MetS group were significantly decreased after 20 WBC applications. Waist circumference (WC) and waist-to-height ratio (WHtR) significantly decreased in both groups, and in the HW group, hip circumference and abdominal skinfold also significantly decreased after 10 WBC and 20 WBC treatments. In both groups, the concentration of plasma irisin significantly increased after 1 WBC and 10 WBC exposures, while the concentration of IL-6 significantly increased only in MetS group after 10 WBC and 20 WBC, and were significantly higher than in HW. CRP concentrations were significantly higher in the MetS group than in HW before 1 WBC, after 1 WBC and 10 WBC sessions, but not after 20. In the MetS group, there were significant negative correlations between the change in irisin level and the changes in WC and BM, and between the level of irisin and the change in percentage of total fat, and significant negative correlations between the change in IL-6 level and changes in WC, waist-to-hip ratio and WHtR. Whole-body cryotherapy, assuming the application of 20 treatments in the series, reduces abdominal obesity in menopausal women indirectly through the secretion of irisin and IL-6, and can be used as adjunctive therapy in the treatment of metabolic syndrome. Our conclusion is limited to menopausal women with low–moderate physical activity for whom its level as well as diet were not changed during the treatment.

The effectiveness of military physical exercise on irisin concentrations and oxidative stress among male healthy volunteers.

Background Irisin, a newly discovered hormone, is secreted into the circulation from skeletal muscles in response to physical exercise. The biochemical parameters related to irisin secretion have not been sufficiently investigated yet. The aim of this study was to examine the effectiveness of exercise on the level of irisin and its correlation with biochemical and oxidative stress parameters. Materials and methods In this pre- and post-test observational study, 39 healthy male volunteers from a military training setting were followed up on between September and November 2015. The individuals who were included in this study were between 22 and 27 years old with an average age of 24. Those with inflammatory disorders or chronic diseases such as diabetes mellitus were excluded from the study. The parameters were measured at the baseline, at 4weeks, and at 8weeks of intervention. Results The study found that the systolic and diastolic blood pressures substantially decreased after 8weeks of intervention. The cholesterol-to-HDL ratio and glucose levels were significantly higher at the baseline compared to 8weeks. Total protein and albumin were significantly higher following 4weeks (0.25 and 0.21g/dL) and 8weeks (0.32 and 0.16g/dL), respectively. Meanwhile, total globulin and irisin increased following 8weeks of the intervention by only 0.16g/dL and 0.41μg/mL, respectively. The high sensitivity C-reactive protein (hs-CRP) decreased following 8weeks (-0.81μg/mL). The protein carbonyl (PC) decreased following 4weeks by only 0.34nmol/L. Conclusions This study demonstrated that military training enhanced irisin hormone secretion following 8weeks of military exercise.

Cleavage of FNDC5 and insights into its maturation process

FNDC5 corresponds to an irisin precursor that increases with exercise. Studies suggest that irisin mediates beneficial effects in adipose tissues, skeletal muscle, bone, and brain. However, the cleavage and maturation processes of FNDC5 have not been clearly identified. This study aimed to show that the signal peptide and transmembrane domain of FNDC5 were associated with the secretion of its ectodomain. Localization studies identified the signal peptide that was responsible for endoplasmic reticulum targeting activity of nascent FNDC5 and showed that the FNDC5 ectodomain corresponding to irisin could be transported across the membrane by a transmembrane domain. Analysis of cleavage constructs revealed that the ectodomain of FNDC5 could be cleaved from its signal peptide and transmembrane attachment. Genetic ablation of the signal peptide cleavage site blocked N-glycosylation of FNDC5. Identification of the FNDC5 maturation process should facilitate our understanding of irisin secretion.

Irisin prevents dexamethasone-induced atrophy in C2C12 myotubes

Irisin is a myokine secreted mainly from skeletal muscle that is known for having beneficial metabolic effects via enhancement of energy expenditure and insulin sensitivity. Studies show that irisin also acts as an autocrine/paracrine to promote myogenesis and muscle growth. However, the protective role of irisin against muscular wasting remains unclear. We confirmed that irisin secretion was upregulated by electrical pulse stimulation an in vitro exercise mimetic model. Next, we tested if irisin exerted an anti-atrophic effect on cultured C2C12 myotubes treated with dexamethasone (DEX), a representative inducer of muscular atrophy. Treatment of cultured myotubes with DEX reduced myotube size and increased proteasome activity, which were attenuated by irisin. Also, irisin effectively prevented dephosphorylation of forkhead box O (FoxO) 3α and upregulation of muscle-specific ubiquitin ligases in DEX-treated myotubes. The protective effect of irisin on DEX-mediated myotube atrophy was partially regulated by insulin-like growth factor-1-dependent signaling. These results suggested that irisin may prevent glucocorticoid-induced muscle atrophy by inhibiting FoxO-mediated ubiquitin-proteasome overactivity.

Grape pomace extract supplementation activates FNDC5/irisin in muscle and promotes white adipose browning in rats fed a high-fat diet.

Irisin is a myokine regulated by peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) in the exercising skeletal muscle and released into the bloodstream after cleavage of FNDC5. Circulating irisin can up-regulate UCP-1 expression in white adipose tissue (WAT) promoting the formation of brown-like adipocytes. The aim of this study was to evaluate if supplementation with a grape pomace extract (GPE) could activate the FNDC5/irisin pathway via PGC-1α in rats fed a high fat diet (HFD). For this purpose we characterized the activation of: i. the FNDC5/irisin pathway and AMPK in skeletal muscle and ii. proteins involved in the formation of brown-like cells in epididymal WAT (eWAT). Consumption of the GPE activated the FNDC5/irisin pathway, increased AMPK phosphorylation in skeletal muscle and enhanced irisin plasma levels. In eWAT, the GPE increased the level of proteins involved in WAT browning, i.e. PGC-1α, PPARγ, PRDM16 and UCP-1. The GPE also prevented HFD-induced adipocyte hypertrophy and systemic insulin resistance. Consistently, in L6 myotubes, (-)-epicatechin (EC), a flavonoid abundant in the GPE, prevented palmitate-mediated downregulation of FNDC5/irisin protein expression and secretion, in part via PGC-1α activation. Consumption of the GPE, a winemaking residue rich in bioactive compounds, could be a beneficial strategy to counteract the adverse effects of Western style diets through the promotion of WAT browning.