[A novel myokin: Irisin]. Luo Li-Jie,Zhang Jing Sheng li ke xue jin zhan [Progress in physiology]
    Irisin in humans: recent advances and questions for future research. Boström Pontus A,Fernández-Real José Manuel,Mantzoros Christos Metabolism: clinical and experimental 10.1016/j.metabol.2013.11.009
    [Irisin--a new mediator of energy homeostasis]. Pukajło Katarzyna,Kolackov Katarzyna,Łaczmański Łukasz,Daroszewski Jacek Postepy higieny i medycyny doswiadczalnej (Online) Skeletal muscles as an active hormonal compartment in the response of physical activity secrete substances named myokines capable of modulating metabolic processes. Myokines take part in communication between muscles and other tissues. Irisin (Ir) - a newly discovered adipomyokine - is cleaved and secreted to the circulation from a fibronectin type III domain containing protein 5 (FNDC5). The mechanism of Ir action has not been described precisely, and receptors for the molecule are not defined yet, but it has been proposed to promote browning of white adipose tissue into beige fat cells. To date we have distinguished two types of adipose tissue in mammals - white, which not only functions as a store of energy but also can play a pro-inflammatory role (secreting adipokines), and brown adipose tissue. Brown adipose tissue has a high mitochondrial content and can dissipate chemical energy in the form of heat (nonshivering termogenesis). It plays a natural antiobesity role and protects against obesity-related diseases. The development of beige adipose tissue, which in its structure and function is similar to brown adipose tissue, and the possibility to modify its amount through some external factors, are nowadays among the most important targets of research on fat cell biology. 10.5604/17322693.1141097
    Laser-scanning cytometry can quantify human adipocyte browning and proves effectiveness of irisin. Kristóf Endre,Doan-Xuan Quang-Minh,Bai Péter,Bacso Zsolt,Fésüs László Scientific reports Laser-scanning cytometry is presented as a tool allowing population scale analysis of ex vivo human brown adipogenic differentiation. It combines texture analysis and detection of Ucp1 protein content in single brown adipocytes of mixed cell populations with gene expression pattern and functional characteristics of browning. Using this method we could validate mouse data in human samples demonstrating the effectiveness of irisin to induce "beige" differentiation of subcutaneous white adipocytes. 10.1038/srep12540
    Irisin: A true, circulating hormone. Polyzos Stergios A,Mathew Hannah,Mantzoros Christos S Metabolism: clinical and experimental 10.1016/j.metabol.2015.09.001
    FNDC5/irisin is not only a myokine but also an adipokine. Roca-Rivada Arturo,Castelao Cecilia,Senin Lucía L,Landrove María O,Baltar Javier,Belén Crujeiras Ana,Seoane Luisa María,Casanueva Felipe F,Pardo María PloS one 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. 10.1371/journal.pone.0060563
    Circulating irisin detection: Does it really work? Sanchis-Gomar Fabian,Alis Rafael,Lippi Giuseppe Trends in endocrinology and metabolism: TEM The recent discovery of irisin has generated considerable interest in the scientific community. However, many studies on the biochemistry and biology of this intriguing hormone yielded controversial results in humans, which were mostly attributable to a number of drawbacks in the methods used for its detection and measurement. 10.1016/j.tem.2015.05.004
    Irisin, two years later. Novelle Marta G,Contreras Cristina,Romero-Picó Amparo,López Miguel,Diéguez Carlos International journal of endocrinology In January 2012, Boström and colleagues identified a new muscle tissue secreted peptide, which they named irisin, to highlight its role as a messenger that comes from skeletal muscle to other parts of the body. Irisin is a cleaved and secreted fragment of FNDC5 (also known as FRCP2 and PeP), a member of fibronectin type III repeat containing gene family. Major interest in this protein arose because of its great therapeutic potential in diabetes and perhaps also therapy for obesity. Here we review the most important aspects of irisin's action and discuss its involvement in energy and metabolic homeostasis and whether the beneficial effects of exercise in these disease states could be mediated by this protein. In addition the effects of irisin at the central nervous system (CNS) are highlighted. It is concluded that although current and upcoming research on irisin is very promising it is still necessary to deepen in several aspects in order to clarify its full potential as a meaningful drug target in human disease states. 10.1155/2013/746281
    Irisin and Myonectin Regulation in the Insulin Resistant Muscle: Implications to Adipose Tissue: Muscle Crosstalk. Gamas Luis,Matafome Paulo,Seiça Raquel Journal of diabetes research Myokines are peptides produced and secreted by the skeletal muscle, with autocrine, paracrine, and endocrine actions. Many of them are overexpressed during physical exercise and appear to contribute to the benefits of exercise to metabolic homeostasis. Irisin, resulting from the cleavage of the membrane protein FNDC5, was shown to induce adipocyte browning, with increased lipid oxidation and thermogenesis. Myonectin was only recently discovered and initial studies revealed a role in fatty acid uptake and oxidation in adipose tissue and liver. However, the mechanisms of their regulation by exercise are not entirely established. Impaired secretion and action of myokines, such as irisin and myonectin, may have a role in the establishment of insulin resistance. On the other hand, several studies have shown that insulin resistance in the skeletal muscle may change myokines expression and secretion. This may have consequences on lipid and glucose metabolism in adipose tissue and lead to a vicious cycle between impaired myokines production and insulin resistance. This review summarizes the current knowledge about the influence of skeletal muscle insulin resistance on the secretion of irisin and myonectin, as well as its impact on adipose tissue metabolism. 10.1155/2015/359159
    Common genetic variation in the human FNDC5 locus, encoding the novel muscle-derived 'browning' factor irisin, determines insulin sensitivity. Staiger Harald,Böhm Anja,Scheler Mika,Berti Lucia,Machann Jürgen,Schick Fritz,Machicao Fausto,Fritsche Andreas,Stefan Norbert,Weigert Cora,Krook Anna,Häring Hans-Ulrich,de Angelis Martin Hrabě PloS one AIMS/HYPOTHESIS: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. 10.1371/journal.pone.0061903
    Irisin as an exercise-stimulated hormone binding crosstalk between organs. Liu J European review for medical and pharmacological sciences Irisin is a newly discovered 112 amino acid residues' glycosylated protein hormone that was firstly found up-regulated by exercise-induced peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and then play an important role in circulation so as to target other organs. It conducts many downstream events including osteoblast differentiation, nerve cell and β-cell regeneration and so on. In clinical research, non-inflammation and inflammation related diseases correlated with basal level of irisin and they benefited from exercise-induced irisin endocrinology.
    Irisin/FNDC5--An updated review. Panati K,Suneetha Y,Narala V R European review for medical and pharmacological sciences OBJECTIVE:The irisin, recently identified novel molecule, has been shown to be secreted from fibronectin type III domain containing 5 (FNDC5) of skeletal muscle by an unknown protease. It has been proposed that this molecule plays an important role in converting the white adipose tissue to brown adipose tissue and regulating the energy expenditure. Apart from this, its expression and role in various other conditions such as inflammation, hippocampal neurogenesis, aging and other metabolic conditions have been reported. However, due to conflicting results, several issues have been raised regarding its expression, cleavage, circulating levels, detection, excretion, designation, etc. MATERIALS AND METHODS:Complete literature survey was performed using PubMed database search to gather available information regarding FNDC5/irisin. RESULTS AND CONCLUSIONS:The present review discussed on the discovery of irisin, its possible role in physiological and pathological conditions and controversies. It also discussed the current challenges and future perspectives.
    Differentiating SGBS adipocytes respond to PPARγ stimulation, irisin and BMP7 by functional browning and beige characteristics. Klusóczki Ágnes,Veréb Zoltán,Vámos Attila,Fischer-Posovszky Pamela,Wabitsch Martin,Bacso Zsolt,Fésüs László,Kristóf Endre Scientific reports Brown and beige adipocytes are enriched in mitochondria with uncoupling protein-1 (UCP1) to generate heat instead of ATP contributing to healthy energy balance. There are few human cellular models to reveal regulatory networks in adipocyte browning and key targets for enhancing thermogenesis in obesity. The Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte line has been a useful tool to study human adipocyte biology. Here we report that SGBS cells, which are comparable to subcutaneous adipose-derived stem cells, carry an FTO risk allele. Upon sustained PPARγ stimulation or irisin (a myokine released in response to exercise) treatment, SGBS cells differentiated into beige adipocytes exhibiting multilocular lipid droplets, high UCP1 content with induction of typical browning genes (Cidea, Elovl3) and the beige marker Tbx1. The autocrine mediator BMP7 led to moderate browning with the upregulation of the classical brown marker Zic1 instead of Tbx1. Thermogenesis potential resulted from PPARγ stimulation, irisin and BMP7 can be activated in UCP1-dependent and the beige specific, creatine phosphate cycle mediated way. The beige phenotype, maintained under long-term (28 days) conditions, was partially reversed by withdrawal of PPARγ ligand. Thus, SGBS cells can serve as a cellular model for both white and sustainable beige adipocyte differentiation and function. 10.1038/s41598-019-42256-0
    [Irisin: a messenger from the gods?]. Moreno María,Moreno-Navarrete José María,Fernández-Real José Manuel Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis Due to the need to understand the basis of the metabolic benefits of exercise, irisin was discovered a few years ago. This cytokine, secreted by skeletal muscle due to exercise, should have positive effects on energetic metabolism. In particular, it could act as a messenger on white adipose tissue, modifying its phenotype into the beige adipocyte, and increasing its thermogenic capacity. Since it was described, there have been numerous studies led to depict its function, with the aim of determining if irisin could become a therapeutic target in the context of diseases associated with a caloric excess, such as obesity and diabetes. In this review, the irisin discovery is summarized, along with its in vitro and in vivo effects described up until now. 10.1016/j.arteri.2013.11.002
    Three new players in energy regulation: preptin, adropin and irisin. Aydin Suleyman Peptides Homeostasis of energy is regulated by genetic factors, food intake, and energy expenditure. When energy input is greater than expenditure, the balance is positive, which can lead to weight gain and obesity. When the balance is negative, weight is lost. Regulation of this homeostasis is multi-factorial, involving many orexigenic (appetite-stimulating) and anorexigenic (appetite-suppressing) peptide hormones. Peripheral tissues are now known to be involved in weight regulation and research on its endocrine characteristics proceeds apace. Preptin with 34 amino acids (MW 3948 Da), adropin with 43 amino acids and a molecular weight of (4999 Da), and irisin with 112 amino acids (12587 Da), are three newly discovered peptides critical for regulating energy metabolism. Preptin is synthesized primarily in pancreatic beta cells, and adropin mainly in the liver and brain, and many peripheral tissues. Irisin, however, is synthesized principally in the heart muscle, along with peripheral tissues, including salivary glands, kidney and liver. The prime functions of preptin and adropin include regulating carbohydrate, lipid and protein metabolisms by moderating glucose-mediated insulin release. Irisin is an anti-obesitic and anti-diabetic hormone regulating adipose tissue metabolism and glucose homeostasis by converting white to brown adipose tissue. This review offers a historical account of these discovery and function of these peptides, including their structure, and physiological and biochemical properties. Their roles in energy regulation will be discussed. Their measurement in biological fluids will be considered, which will lead to further discussion of their possible clinical value. 10.1016/j.peptides.2014.03.021
    Inconsistency in circulating irisin levels: what is really happening? Sanchis-Gomar F,Alis R,Pareja-Galeano H,Romagnoli M,Perez-Quilis C Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme The discovery of irisin as a novel and promising peptidic hormone for the treatment of obesity and diabetes has recently been reported. As a result, great hopes have been raised based on this finding, hypothesizing that irisin might provide additional benefits, not only for obesity and diabetes, but also for a wide range of pathological conditions requiring therapeutical and clinical attention. However, controversial results and conclusions on circulating irisin concentrations and correlations with other variables, including its role in metabolism, have recently been reported. Although laboratory assessment of irisin by ELISA is easily available and may provide interesting information for therapeutics and clinical practice, the heterogeneous and often discrepant results published so far, raise serious concerns about its measurement, indicating that it may still not be ready for use or whether irisin really exists. We highlight here some aspects on these discrepancies and contradictions, and put forward their implications. 10.1055/s-0033-1363283
    Irisin: a new molecular marker and target in metabolic disorder. Chen Jia-qi,Huang Yue-ye,Gusdon Aaron M,Qu Shen Lipids in health and disease Irisin is a newly discovered exercise-mediated myokine which regulates energy metabolism and has been the subject of much recent research. Irisin plays an important role in metabolic diseases making it a potential new target to combat obesity and its associated disorders, such as T2DM. However, the results of several recent studies investigating the effects of irisin have been controversial. The present review will introduce the discovery of irisin, the role of irisin in metabolic disorders, possible mechanisms, and unanswered questions for future research. 10.1186/1476-511X-14-2
    Evidence against a beneficial effect of irisin in humans. Raschke Silja,Elsen Manuela,Gassenhuber Hans,Sommerfeld Mark,Schwahn Uwe,Brockmann Barbara,Jung Raphael,Wisløff Ulrik,Tjønna Arnt E,Raastad Truls,Hallén Jostein,Norheim Frode,Drevon Christian A,Romacho Tania,Eckardt Kristin,Eckel Juergen PloS one Brown adipose tissue has gained interest as a potential target to treat obesity and metabolic diseases. Irisin is a newly identified hormone secreted from skeletal muscle enhancing browning of white fat cells, which improves systemic metabolism by increasing energy expenditure in mice. The discovery of irisin raised expectations of its therapeutic potential to treat metabolic diseases. However, the effect of irisin in humans is unclear. Analyses of genomic DNA, mRNA and expressed sequence tags revealed that FNDC5, the gene encoding the precursor of irisin, is present in rodents and most primates, but shows in humans a mutation in the conserved start codon ATG to ATA. HEK293 cells transfected with a human FNDC5 construct with ATA as start codon resulted in only 1% full-length protein compared to human FNDC5 with ATG. Additionally, in vitro contraction of primary human myotubes by electrical pulse stimulation induced a significant increase in PGC1α mRNA expression. However, FNDC5 mRNA level was not altered. FNDC5 mRNA expression in muscle biopsies from two different human exercise studies was not changed by endurance or strength training. Preadipocytes isolated from human subcutaneous adipose tissue exhibited differentiation to brite human adipocytes when incubated with bone morphogenetic protein (BMP) 7, but neither recombinant FNDC5 nor irisin were effective. In conclusion, our findings suggest that it is rather unlikely that the beneficial effect of irisin observed in mice can be translated to humans. 10.1371/journal.pone.0073680
    Irisin: what promise does it hold? Elbelt Ulf,Hofmann Tobias,Stengel Andreas Current opinion in clinical nutrition and metabolic care PURPOSE OF REVIEW:The recently identified myokine, irisin has raised great expectations as a potential target in the conservative treatment of obesity. This review focuses on studies exploring the effects of irisin in humans. RECENT FINDINGS:Peroxisome proliferator-activated receptor γ coactivator-1 α expression in skeletal muscles is induced by exercise followed by expression of the membrane protein fibronectin type III domain containing 5. After cleavage from fibronectin type III domain containing 5, irisin is secreted into blood increasing thermogenesis by browning of subcutaneous white/beige adipose tissue. Although clear-cut data have been reported in rodents, the thermogenic effect of irisin in humans remains controversial. The initially reported exercise-dependent increase of irisin in humans could not be confirmed in most studies. However, a robust finding in human studies is the association of irisin with BMI. SUMMARY:The discovery of irisin provides more insight into exercise-induced browning of adipose tissue, and therefore leads to a better understanding of mechanisms underlying body weight regulation and further down the road possibly may lead to treatment strategies of diseases with greatly altered body weight such as obesity or anorexia nervosa. 10.1097/MCO.0b013e328363bc65
    The structure of irisin reveals a novel intersubunit β-sheet fibronectin type III (FNIII) dimer: implications for receptor activation. Schumacher Maria A,Chinnam Nagababu,Ohashi Tomoo,Shah Riddhi Sanjay,Erickson Harold P The Journal of biological chemistry 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 have 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 Å 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 β-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. 10.1074/jbc.M113.516641
    A comprehensive immunohistochemical examination of the distribution of the fat-burning protein irisin in biological tissues. Aydin Suleyman,Kuloglu Tuncay,Aydin Suna,Kalayci Mehmet,Yilmaz Musa,Cakmak Tolga,Albayrak Serdal,Gungor Sami,Colakoglu Neriman,Ozercan Ibrahim Hanifi Peptides Irisin was first identified in skeletal muscle cells, but its precise location has not yet been demonstrated, and there is limited information about irisin protein in other human and rat tissues. The present immunohistochemical study was undertaken to screen skeletal muscle and other tissues for irisin immunoreactivity. İrisin staining was found in the brain (neurons and neuroglia), cardiac and skeletal muscle (fibers) and skin (sebaceous glands) tissues in male rats. In both human adult and fetal skeletal muscle, the most intense immunohistochemical staining was in the perimysium and endomysium, in the peripheral nerve (epineurium) and axon and nerve sheaths spreading among the cells, in the sarcoplasma and subendomysium. Irisin was also demonstrated in the testis (seminiferous tubules, some spermatogenic cells in fetal and Leydig cells in fetal and adult testis, ductus epididymis in fetal human epididymis); pancreas (islets of Langerhans, serous acini cells, intralobular and intralobular ducts cells); liver (hepatocytes; Kupffer cells and sinusoidal endothelial cells); spleen (subcapsular region and periarterial lymphatic sheets); the stomach (gastric parietal cells, tunica muscularis cells). We conclude that the fat-burning protein irisin locally produced in peripheral and central tissues could act as a gatekeeper of metabolic energy regulation in those tissues, since this myokine converts white into brown adipose tissue, enhancing energy expenditure. 10.1016/j.peptides.2014.09.014
    Browning of white fat: does irisin play a role in humans? Elsen Manuela,Raschke Silja,Eckel Jürgen The Journal of endocrinology The discovery of irisin as an exercise-regulated myokine inducing browning of WAT has gained interest as a potential new strategy to combat obesity and its associated disorders, such as type 2 diabetes. However, there are inconsistencies regarding the relevance of irisin in humans. The regulation of FNDC5 mRNA expression by exercise and contraction could not be reproduced by a number of human studies using several exercise protocols and in vitro approaches. Furthermore, the nature of FNDC5 fragments and the presence of irisin in humans are questionable and probably contribute to conflicting data obtained with commercially available ELISA kits. Most importantly, the information regarding the concentration of circulating irisin in humans is not clear, as different studies using different kits measure irisin levels in a wide range. Data about the role of irisin in states of human obesity and metabolic diseases are conflicting and, in some cases, changes in irisin levels have been observed; they were only moderate in 10-20%. Independent of the presence and regulation of FNDC5/irisin in humans, the application of recombinant irisin could still represent a therapeutic strategy to fight obesity. However, the current data obtained from human cell models reveal that FNDC5/irisin has no effect on browning of the major WAT depots in humans and is likely to selectively target a small subpopulation of adipocytes, which are located in classical BAT regions, such as the supraclavicular adipose tissue. Thus, other candidates, such as BMP7 or CNPs, seem to be more prominent candidates as inducers of browning in humans. 10.1530/JOE-14-0189
    Characterization of the metabolic effects of irisin on skeletal muscle in vitro. Vaughan R A,Gannon N P,Barberena M A,Garcia-Smith R,Bisoffi M,Mermier C M,Conn C A,Trujillo K A Diabetes, obesity & metabolism AIMS:This work explored the effects of irisin on metabolism, gene expression and mitochondrial content in cultured myocytes. METHODS:C2C12 myocytes were treated with various concentrations of irisin for various durations. Glycolysis and oxidative metabolism were quantified by measurement of extracellular acidification and oxygen consumption, respectively. Metabolic gene expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and mitochondrial content was assessed by flow cytometry and confocal microscopy. RESULTS:Cells treated with irisin exhibited significantly increased oxidative metabolism. Irisin treatment also significantly increased mitochondrial uncoupling at various doses and durations. Lastly, treatment with irisin also significantly elevated metabolic gene expression including peroxisome proliferator-activated receptor γ coactivator-1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), irisin, glucose transporter 4 (GLUT4) and mitochondrial uncoupling protein 3 (UCP3) leading to increased mitochondrial biogenesis. CONCLUSIONS:Our observations are the first to document increased metabolism in myocytes through irisin-mediated induction of mitochondrial biogenesis and uncoupling with corresponding gene expression. These observations support the need for further investigation into the therapeutic and pharmacological effects of irisin, as well as development of irisin-based therapy. 10.1111/dom.12268
    Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans. Huh J Y,Dincer F,Mesfum E,Mantzoros C S International journal of obesity (2005) BACKGROUND:Irisin is a recently identified exercise-induced myokine suggested to induce browning of white adipocytes. Deficiency of myostatin, and thus stimulation of muscle growth, has also been reported to induce irisin and its precursor FNDC5 expression in muscle and drive the browning of white adipocytes in mice, implying that irisin may be related to muscle growth in addition to its beneficial effects in adipocytes. In humans, the effect of irisin in muscle hypertrophy as well as adipocyte metabolism has not been fully investigated. METHODS:Primary cultured human myocytes/adipocytes and 3T3-L1 cells were used to examine irisin-regulated gene/protein expression. Lipid accumulation, ATP content, glycolysis, lipolysis and metabolite profile were measured in control and irisin-treated (10 and 50 nM) adipocytes. RESULTS:In human myocytes, FNDC5 mRNA and irisin secretion were increased during myogenic differentiation, along with PGC1α and myogenin expression. Irisin treatment significantly increased insulin-like growth factor 1 and decreased myostatin gene expression through ERK pathway. PGC1α4, a newly discovered PGC1α isoform specifically related to muscle hypertrophy, was also upregulated. In human adipocytes, irisin induced uncoupling protein 1 and consequently increased adipocyte energy expenditure, expression of metabolic enzymes and metabolite intermediates, resulting in inhibition of lipid accumulation. Irisin and FNDC5 treatment also reduced preadipocyte differentiation, suggesting an additional mechanism in suppressing fat mass. CONCLUSIONS:These results suggest that irisin/FNDC5 has a pleiotropic role in muscle and improvement of adipocyte metabolism in humans. 10.1038/ijo.2014.42
    Cardiac, skeletal muscle and serum irisin responses to with or without water exercise in young and old male rats: cardiac muscle produces more irisin than skeletal muscle. Aydin Suna,Kuloglu Tuncay,Aydin Suleyman,Eren Mehmet Nesimi,Celik Ahmet,Yilmaz Musa,Kalayci Mehmet,Sahin İbrahim,Gungor Orhan,Gurel Ali,Ogeturk Murat,Dabak Ozlem Peptides 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 from 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 from connective tissues around skeletal muscle, especially nerve sheaths located within it. Skeletal muscle is probably not a main irisin source. 10.1016/j.peptides.2013.11.024
    Central and peripheral irisin differentially regulate blood pressure. Zhang Weizhen,Chang Lin,Zhang Chao,Zhang Ruthann,Li Ziru,Chai Biaoxin,Li Jiyao,Chen Eugene,Mulholland Michael Cardiovascular drugs and therapy 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. 10.1007/s10557-015-6580-y
    Irisin Is Regulated by CAR in Liver and Is a Mediator of Hepatic Glucose and Lipid Metabolism. Mo Li,Shen Jing,Liu Qinhui,Zhang Yuwei,Kuang Jiangying,Pu Shiyun,Cheng Shihai,Zou Min,Jiang Wei,Jiang Changtao,Qu Aijuan,He Jinhan Molecular endocrinology (Baltimore, Md.) Irisin, a hormone proteolytically processed from fibronectin type III domain-containing protein 5 (FNDC5), has been reported to induce the browning of sc adipocytes by increasing the level of uncoupling protein 1. In this study, we showed that activation of the nuclear receptor constitutive androstane receptor induced FNDC5 mRNA expression in the liver and increased the circulating level of irisin in mice. FNDC5/irisin is a direct transcriptional target of constitutive androstane receptor. Hepatic-released irisin functioned as a paracrine/autocrine factor that inhibited lipogenesis and gluconeogenesis via the Adenosine 5'-monophosphate (AMP)-activated protein kinase pathway. Adenovirus-overexpressed irisin improved hepatic steatosis and insulin resistance in genetic-induced obese mice. Irisin transgenic mice were also protected against high-fat diet-induced obesity and insulin resistance. In conclusion, our results reveal a novel pathway in regulating FNDC5/irisin expression and identify a physiological role for this hepatic hormone in glucose and lipid homeostasis. 10.1210/me.2015-1292
    Irisin, a Novel Myokine, Regulates Glucose Uptake in Skeletal Muscle Cells via AMPK. Lee Hye Jeong,Lee Jung Ok,Kim Nami,Kim Joong Kwan,Kim Hyung Ip,Lee Yong Woo,Kim Su Jin,Choi Jong-Il,Oh Yoonji,Kim Jeong Hyun,Suyeon-Hwang ,Park Sun Hwa,Kim Hyeon Soo Molecular endocrinology (Baltimore, Md.) 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, a ROS scavenger, blocked irisin-induced AMPK phosphorylation. Moreover, irisin activated p38 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 glucose transporter type 4 to the plasma membrane and that this effect was suppressed in cells pretreated with a p38 MAPK inhibitor or p38 MAPK small interfering RNA. In primary cultured myoblast cells, irisin increased the concentration of intracellular calcium. STO-609, a calcium/calmodulin-dependent protein kinase kinase 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. 10.1210/me.2014-1353
    SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) during exercise. Tiano Joseph P,Springer Danielle A,Rane Sushil G The Journal of biological chemistry Beige adipose cells are a distinct and inducible type of thermogenic fat cell that express the mitochondrial uncoupling protein-1 and thus represent a powerful target for treating obesity. Mice lacking the TGF-β effector protein SMAD3 are protected against diet-induced obesity because of browning of their white adipose tissue (WAT), leading to increased whole body energy expenditure. However, the role SMAD3 plays in WAT browning is not clearly understood. Irisin is an exercise-induced skeletal muscle hormone that induces WAT browning similar to that observed in SMAD3-deficient mice. Together, these observations suggested that SMAD3 may negatively regulate irisin production and/or secretion from skeletal muscle. To address this question, we used wild-type and SMAD3 knock-out (Smad3(-/-)) mice subjected to an exercise regime and C2C12 myotubes treated with TGF-β, a TGF-β receptor 1 pharmacological inhibitor, adenovirus expressing constitutively active SMAD3, or siRNA against SMAD3. We find that in Smad3(-/-) mice, exercise increases serum irisin and skeletal muscle FNDC5 (irisin precursor) and its upstream activator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) to a greater extent than in wild-type mice. In C2C12 myotubes, TGF-β suppresses FNDC5 and PGC-1α mRNA and protein levels via SMAD3 and promotes SMAD3 binding to the FNDC5 and PGC-1α promoters. These data establish that SMAD3 suppresses FNDC5 and PGC-1α in skeletal muscle cells. These findings shed light on the poorly understood regulation of irisin/FNDC5 by demonstrating a novel association between irisin and SMAD3 signaling in skeletal muscle. 10.1074/jbc.M114.617399
    Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review. Chen Ning,Li Qingxue,Liu Jun,Jia Shaohui Diabetes/metabolism research and reviews Irisin, as a new hormone-like myokine, is discovered in the presence of exercise-induced peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α). Which substance plays an important role in energy metabolism in each organ in the body and the regulation of metabolic diseases such as obesity and diabetes. The finding of irisin can contribute to the exploration of the novel and effective therapeutic targets or therapeutic strategies of these metabolic diseases or metabolism-associated health issues. To date, little is known regarding the functions and regulatory mechanisms of irisin with respect to metabolic diseases or metabolism-associated health issues. In this narrative review article, we systematically introduce its structural characteristics, production and distribution in tissues and organs, and the regulation and corresponding mechanisms for metabolic diseases or metabolism-associated health issues of irisin. Meanwhile, its future prospects and the development of irisin-related products for the promotion of human health have also been proposed, which will benefit future research and application of irisin. Copyright © 2015 John Wiley & Sons, Ltd. 10.1002/dmrr.2660
    Effects and Molecular Mechanism of GST-Irisin on Lipolysis and Autocrine Function in 3T3-L1 Adipocytes. Gao Shanshan,Li Fangmin,Li Huimin,Huang Yibing,Liu Yu,Chen Yuxin PloS one Irisin, which was recently identified as a myokine and an adipokine, transforms white adipose tissue to brown adipose tissue and has increasingly caught the attention of the medical and scientific community. However, the signaling pathway of irisin and the molecular mechanisms responsible for the lipolysis effect remain unclear. In this study, we established an efficient system for the expression and purification of GST-irisin in Escherichia coli. The biological activity of GST-irisin was verified using the cell counting kit-8 assay and by detecting the mRNA expression of uncoupling protein 1. Our data showed that GST-irisin regulates mRNA levels of lipolysis-related genes such as adipose triglyceride lipase and hormone-sensitive lipase and proteins such as the fatty acid-binding protein 4, leading to increased secretion of glycerol and decreased lipid accumulation in 3T3-L1 adipocytes. In addition, exogenous GST-irisin can increase its autocrine function in vitro by regulating the expression of fibronectin type III domain-containing protein 5. GST-irisin could regulate glucose uptake in 3T3-L1 adipocytes. Hence, we believe that recombinant GST-irisin could promote lipolysis and its secretion in vitro and can potentially prevent obesity and related metabolic diseases. 10.1371/journal.pone.0147480
    Effects of central irisin administration on the uncoupling proteins in rat brain. Erden Yavuz,Tekin Suat,Sandal Suleyman,Onalan Ebru Etem,Tektemur Ahmet,Kirbag Sevda Neuroscience letters Irisin is a thermogenic peptide that enables the development of brown adipose tissue from white adipose tissue by activating the UCP1. This study has been designed to determine the effects of the irisin on UCPs. Sprague Dawley female rats were used in the study. 1, 3 and 10μM concentrations of irisin were injected intracerebroventricularly to the rats, and the control group was received only vehicle. The animals were killed at the 16, 24, and 48h time intervals and their brains were taken out. The hypothalamus, pituitary gland, hippocampus, cerebellum, striatum and cortex areas were separated and the UCP2, UCP3, UCP4 and UCP5 mRNA levels were determined. Just before the animals were killed, their body temperatures were recorded. It was observed that after application of the high dose irisin, UCP5 mRNA level in the all brain areas increased (p<0.05); it was also observed that the three doses decreased the UCP4 expression in all brain areas (except the pituitary gland; p<0.05). The UCP2 and UCP3 mRNA expressions showed significantly increase in cerebellum and striatum (p<0.05). The UCP2 mRNA expression decreased in hypothalamus, pituitary gland, hippocampus and cortex areas (p<0.05). It was also observed that the body temperatures of the rats increased depending on the irisin injection and this increase was the most considerable at the 24h (p<0.05). The results of this study suggest that the UCP2-5 is expressed in different areas of the brain, and the irisin affects this expression, and may have effective roles in some brain functions. 10.1016/j.neulet.2016.02.046
    -Glycosylation is required for FDNC5 stabilization and irisin secretion. Nie Yongwei,Liu Dongjun The Biochemical journal Irisin, a myokine derived from the extracellular domain of FNDC5, has been shown to mediate thermogenesis of white adipose tissue. Biochemical data have shown that -glycosylation of FNDC5 is unlikely to affect ligand or receptor activation of irisin. The -glycosylation of FNDC5 remains poorly understood. In the present study, we analysed -glycosylation sites of FNDC5 and found that two potential -glycosylation sites (Asn and Asn) could indeed be occupied by -glycan. Furthermore we showed that the lack of -glycosylation decreases the secretion of irisin, which is relevant to the instability of FNDC5 and the deficiency of cleavage of the signal peptide. We also found that the expression level of -glycosylated FNDC5 was elevated after myoblast differentiation. These findings show that the secretion of irisin is modulated by -glycosylation, which in turn enhances our understanding of the secretion of glycosylated irisin. 10.1042/BCJ20170241
    Crosstalk Between Muscle and Bone Via the Muscle-Myokine Irisin. Colaianni G,Mongelli T,Colucci S,Cinti S,Grano Maria Current osteoporosis reports Several lines of evidence have recently established that skeletal muscle is an endocrine organ producing and releasing myokines acting in a paracrine or endocrine fashion. Among these, the newly identified myokine Irisin, produced by skeletal muscle after physical exercise, was originally described as molecule able to promote energy expenditure in white adipose tissue. Recently, it has been shown that the myokine Irisin affects skeletal metabolism in vivo. Thus, mice treated with a micro-dose of r-Irisin displayed improved cortical bone mass, geometry and strength, resembling the effect of physical activity in developing an efficient load-bearing skeleton. Further studies highlighted the autocrine effect of Irisin on skeletal muscle, and research performed in humans has definitively established that Irisin is a circulating hormone-like myokine, increased by physical activity. Albeit there are still few, since Irisin has been very recently discovered, herein are summarized the most relevant research findings published on this topic. 10.1007/s11914-016-0313-4
    Immunohistochemical localization of irisin in skin, eye, and thyroid and pineal glands of the crested porcupine (Hystrix cristata). Gençer Tarakçı B,Girgin A,Timurkaan S,Yalçın M H,Gür F M,Karan M Biotechnic & histochemistry : official publication of the Biological Stain Commission Irisin was first identified in muscle cells. We detected irisin immunoreactivity in various organs of the crested porcupine (Hystrix cristata). In the epidermis, irisin immunoreactivity was localized mainly in stratum basale, stratum spinosum and stratum granulosum layers; immunoreactivity was not observed in the stratum corneum. In the dermis, irisin was found in the external and internal root sheath, cortex and medulla of hair follicles, and in sebaceous glands. Irisin immunoreactivity was found in the neural retina and skeletal muscle fibers associated with the eye. The pineal and thyroid glands also exhibited irisin immunoreactivity. 10.1080/10520295.2016.1183820
    Immunohistochemical localization of irisin in mole rats (Spalax leucodon). Gür F M,Timurkaan S,Yalcin M H,Girgin A,Gençer Tarakçı B Biotechnic & histochemistry : official publication of the Biological Stain Commission Irisin was first identified in skeletal muscle cells. It is an exercise protein that is secreted into the circulation; it causes conversion of white adipose tissue to brown adipose tissue. We investigated irisin immunoreactivity in mole rat (Spalax leucodon) tissues. We examined cerebellum, pituitary, heart, liver, pancreas, spleen, uterus, kidney and striated muscle in female adult mole rats. Tissues were processed, embedded in paraffin, sectioned at 5 μm and stained immunohistochemically for irisin. Irisin immunostaining was detected in the cytoplasm of stained cells; the cytoplasm of Purkinje cells was unstained. We found that irisin may be synthesized in many tissues. The function of locally synthesized irisin currently is unknown. 10.1080/10520295.2017.1303194
    Irisin and Fibronectin Type III Domain-Containing 5 Responses to Exercise in Different Environmental Conditions. Bubak Matthew P,Heesch Matthew W S,Shute Robert J,Dinan Nicholas E,Laursen Terence L,LA Salle D Taylor,Slivka Dustin R International journal of exercise science Fibronectin type III domain-containing 5 (FNDC5) is a skeletal muscle membrane-bound precursor to the myokine irisin. Irisin is involved in stimulating adipose tissue to become more metabolically active in order to produce heat. The purpose of this study was to determine the effects of exercise in a hot (33 °C), cold (7 °C), and room temperature (RT, 20 °C) environment on the skeletal muscle gene expression of FNDC5 and the plasma concentrations of irisin. Twelve recreationally trained males completed three separate, 1 h cycling bouts at 60% of W in a hot, cold, and RT environment followed by three hours of recovery at room temperature. Blood samples were taken from the antecubital vein and muscle biopsies were taken from the pre-, post-, and 3 h post-exercise. Plasma concentrations of irisin did not change from pre- (9.23 ± 2.68 pg·mL) to post-exercise (9.6 ± 0.2 pg·mL, p = 0.068), but did decrease from post-exercise to 3 h post-exercise (8.9 ± 0.5 pg·mL, p = 0.047) regardless of temperature. However, when plasma volume shifts were considered, no differences were found in irisin (p = 0.086). There were no significant differences between trials for irisin plasma concentrations (p > 0.05). No significant differences in FNDC5 were observed between the hot, cold, or RT or pre-, post-, or 3 h post-exercise time points (p > 0.05). These data indicate that the temperature in which exercise takes place does not influence FNDC5 transcription or circulating irisin in a human model.
    Identification of irisin immunoreactivity in porcupine (Hystrix cristata) adrenal glands and kidneys. Timurkaan Sema,Gür Fatih M,Gençer Tarakçı Berrin,Yalçın Mehmet H,Girgin Mustafa Anatomia, histologia, embryologia Irisin, a novel peptide, was initially been shown to be expressed explicitly in the muscle tissues. We studied the presence of irisin immunoreactivity in porcupine adrenal glands and kidneys. Immunocytochemistry showed that irisin was localised both in the adrenal cortex and adrenal medulla. In organs, irisin immunoreactivity was found in the tubular and collecting system of the nephron. The functional role of irisin in the adrenal gland and kidney has not been precisely yet. However, irisin might have a paracrine and autocrine function as do other locally produced peptides. 10.1111/ahe.12371
    Identification of immunohistochemical localization of irisin in the dwarf hamster (Phodopus roborovskii) tissues. Gür F M,Timurkaan S,Gençer Tarakçi B,Yalçin M H,Özkan Z E,Baygeldi S B,Yilmaz S,Eröksüz H Anatomia, histologia, embryologia Irisin is mainly secreted by heart and skeletal muscle cells. It is an exercise-induced protein that converts white adipose tissue to brown. Increased irisin expression was lead to weight loss and improved glucose tolerance. We investigated irisin immunoreactivity in various tissues of the dwarf hamsters (Phodopus roborovskii). Tissues were processed, embedded in paraffin, sectioned at 5 μm and stained immunohistochemically for irisin. In the retina, irisin was found almost all layers, except outer nuclear layer. Also, irisin immunoreactivity was observed in the skin, cornea, striated muscle, parotid gland, tongue, oesophagus, stomach and small intestine. The findings from this study support the notion that skeletal muscle is not the primary source of irisin. 10.1111/ahe.12345