DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE Diabetes Metab Res Rev 2016; 32: 51–59. Published online 25 June 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2660
Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review
Ning Chen1* Qingxue Li2,3 Jun Liu1 Shaohui Jia1 1
College of Health Science, Hubei Provincial Collaborative Innovation Center for Exercise and Health Promotion, Wuhan Sports University, Wuhan, China
2
Graduate School, Wuhan Sports University, Wuhan, China
3
College of Sports Science and Technology, Wuhan Sports University, Wuhan, China *Correspondence to: Ning Chen, Professor in Biochemistry and Molecular Exercise Physiology, College of Health Science, Hubei Provincial Collaborative Innovation Center for Exercise and Health Promotion, Wuhan Sports University, Wuhan 430079, China. E-mail: [email protected]
Received: 20 February 2015 Accepted: 23 April 2015
Copyright © 2015 John Wiley & Sons, Ltd.
Summary Irisin, as a new hormone-like myokine, is discovered in the presence of exerciseinduced 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. Keywords
irisin; myokine; exercise; metabolic disease; obesity; diabetes
Introduction In the high-speed development age, because of the fast rhythm or too much pressure of work and life as well as the change of lifestyle, more and more people spend less time on physical activity or regular exercise, thus resulting in the change of body compositions and high incidence of metabolic diseases such as diabetes, obesity and lipid metabolic syndrome [1,2]. Based on previous reports, physical inactivity could reduce the average life span of people for approximately 5–10 years when compared with that of people with regular physical activity or exercise [3]. It is well known that physical activity or regular exercise is an economical and environment-friendly style for accomplishing health promotion; however, its exact molecular mechanisms are still unclear, which cannot effectively provide scientific guidance for the intervention of diseases sometimes or the rational development of exercise-mimic drugs for some chronic diseases [4,5]. The research group of Spiegelman from Harvard University first discovered and reported a small peptide generated in muscle tissue in the presence of exercise-induced upregulation of peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) [6]. Once this small peptide as one of the myokines generates in muscle, it will secrete into blood stream and
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transport to adipose tissue or other tissues or organs for executing the regulation of energy metabolism, promoting the browning of white adipocytes, improving the activity of insulin and reducing the resistance of insulin, and optimizing the body compositions [7]. Because of its physiological regulation of exercise-induced irisin for health promotion and many diseases, exercise or corresponding strategies for inducing irisin or irisin-related products have gained tremendous attention for the prevention, intervention, or even treatment of metabolic diseases such as obesity and diabetes [8]. Although some investigations involved in energy metabolism, browning of white adipocytes, and insulin sensitivity or resistance in the presence of irisin in recent 2 years since it is discovered, the underlying mechanisms and corresponding signal pathways for these regulations are still unclear. It is highly desired to conduct further studies on irisin so that it will be better to facilitate human health promotion and disease prevention, intervention and treatment. In order to provide a systematic reference for further exploration of irisin, we have summarized and updated its structural characteristics, production and distribution in tissues and organs, and regulation and corresponding mechanisms for metabolic diseases or metabolismassociated health issues in this narrative review article.
Production and distribution of irisin It is well known that physical activity or exercise is a green and environment-friendly lifestyle for promoting human health and preventing and treating metabolic and cardiovascular diseases as well as improving the cognitive capacity of the brain [9–11]. All of these functions are highly correlated with the mitochondrial quality and bioenergetics of skeletal muscle or other tissues during exercise. Since the discovery of exercise-induced irisin, the attentions and studies on irisin have revealed an increasing explosion. The acute or long-term exercise training can obviously upregulate the expression of PGC-1α in skeletal muscle or cardiac muscle, which can promote the generation of its downstream fibronectin domain-containing protein 5 (FNDC5) and the proteolytic cleavage of FNDC5 to result in the production of irisin as a hormone-like myokine [12]. Although the first investigation has reported the generation of irisin in skeletal muscle and its release in blood circulation to regulate the functions of other tissues or organs, the ultimate location and distribution of irisin for its wide range of powerful physiological characteristics and roles are still unknown [6,13–17]. Currently, the distribution and corresponding levels of irisin in different target tissues or organs in human have revealed its physiological functions for promoting health Copyright © 2015 John Wiley & Sons, Ltd.
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or executing the regulation of metabolic diseases. Nowadays, irisin has been reported to be distributed in skeletal muscle, cardiac muscle, adipose tissue, liver, brain, bone, pancreas, kidney and ovary at various levels [18–20]. Most strikingly, the increased expression of PGC-1α can often benefit a lot of tissues besides muscle. However, the corresponding mechanisms are still unclear. Some scholars speculate that the expression of PGC-1α can stimulate the release of some special factors in skeletal muscle, which will be also benefit for other tissues [21]. In contrast, other investigations have reported that the male mice with the age of 13 weeks after a voluntary wheelrunning for 30 days reveals a high expression of irisin in cardiac muscle, brain, spinal cord and oxidative muscle such as soleus muscle, while lung, liver, spleen, kidney, interscapular brown adipose tissue (BAT) and inguinal white adipose tissue (WAT) exhibit a relatively low expression of irisin, suggesting that the generation and accumulation of irisin is highly correlated with the higher PGC-1α levels in oxidative muscle than that in glycolytic or mixed muscles such as gastrocnemius or quadriceps muscle. Therefore, the secretion of exerciseinduced irisin may be independent of the upregulation of PGC-1α, and these studies need to be further explored and validated. Previous studies have also demonstrated that circulating irisin is positively correlated with biceps circumference, body mass index, glucose, endogenous intestinal peptide (inhibiting the secretion of insulin) and insulinlike growth factor-1. On the other hand, irisin level is negatively correlated with age, and insulin, triglyceride and adiponectin levels, suggesting that irisin may be involved in compensatory mechanisms for metabolic regulation [22]. Based on our current knowledge, irisin is not only a myokine, but also an adipokine, with autocrine and paracrine functions [23]. The adipose tissues from different anatomic regions could reveal the various secretion styles and levels. For example, compared with visceral adipose tissue, subcutaneous adipose tissue has the lesser secretion of FNDC5/irisin. In addition, the expression of irisin in human WAT is only 5% of the expression level of irisin in skeletal muscle [12]. Similarly, physical activity or exercise can improve the cognitive function of brain at each age stage [24]. Moreover, physical activity or exercise not only can enhance cardiovascular and immune functions but also can improve neurotrophic factor pathway that is critical to cognitive capability [25–27]. Therefore, regular exercise training or physical activity plays an important role in the modulation of immune and anti-inflammation functions, which can enhance the cognitive capability of older people or individuals with neuropathy. Recent studies have demonstrated that the secretion and release of exercise-induced myokines in muscle can regulate the synthesis of brainDiabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
Irisin as a Metabolic Regulator
derived neurotrophic factor (BDNF) in the dentate gyrus of hippocampus tissue [14]. Similarly, the mRNA expression of FNDC5 is extensively distributed in brain tissues including midbrain, pons, cerebellum and olfactory bulb, as well as hippocampus tissues, which may be positively correlated with the improvement of cognitive capability after regular physical activity or exercise [28].
Structural characterization of irisin Irisin, as a hormone-like polypeptide including 112 amino acid residues, is generally synthesized in muscle tissue after the proteolytic cleavage of its precursor, FNDC5. Its molecular weight is approximately 12 kDa [29]. FNDC5 is generated by a type I membrane protein undergoing proteolytic cleavage, which results in the release of N-terminal part of the protein into extracellular space [30]. FNDC5 is composed of three parts including a signal peptide, two fibronectin domains and a hydrophobic C-terminal domain. FNDC5 itself is a glycoprotein with glycosylation sites of 39K and 84A [31]. The X-ray crystallographic structure has demonstrated that irisin has an Nterminal fibronectin type III-like domain for forming a continuous intersubunit beta-sheet dimer and a flexible C-terminal tail. Biochemical data have confirmed that irisin is prone to dimerization without the influence from glycosylation. This finding suggests a possible mechanism for receptor activation by irisin domain as a preferred myokine dimer ligand or as a paracrine or autocrine dimerization module on FNDC5-like receptors. Irisin is released from muscle tissue in response to exercise. It is the secretion portion of FNDC5 protein and is able to promote the beige of WAT and prevent or inhibit many metabolic diseases in both human and mice [32].
Physiological functions Irisin-induced browning of white adipocytes Generally, adipose tissue includes two parts such as WAT, which functions as the dominant site for the storage of lipid, and BAT, which functions as the thermogenesis through uncoupled respiration [33]. Increasing documentation has demonstrated the physiological, metabolic and regulatory characteristics of WAT and BAT [34–39]. Adipocytes from WAT are the characteristics of unilocular lipid droplets, few mitochondria and relatively low metabolic rate; on the other hand, adipocytes from BAT are the characteristics of multilocular lipid droplets, plentiful mitochondria and relatively high metabolic rate [39]. Copyright © 2015 John Wiley & Sons, Ltd.
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Meanwhile, the large amount of uncoupling protein 1 (UCP1) generation results in the relatively high metabolic rate in BAT, while its expression can be negligible in WAT [39]. Because brown adipocytes in WAT of BALB/c mice have been detected after cold acclimatization, the browning of adipocytes in WAT has gained extensive investigations because of the attractive therapeutic potential for obesity and metabolic disease in the presence of enrichment and activation of BAT [40]. Subsequently, brown adipocytes have also been observed in multiple WAT fat pads of rats [41]. Later, some investigations have demonstrated that the stimulation of beta-adrenergic agents [41–43] or peroxisome proliferator-activated receptor gamma agonists can result in the pharmacological accumulation of UCP1 in WAT and the enrichment of BAT [44–46]. Recent evidence has demonstrated that the brown adipocytes in WAT are rich in UCP1 as the sub-population of white adipocytes and can be defined as the brown-in-white (brite) or beige adipocytes [33,44]. In the presence of treatment using peroxisome proliferator-activated receptor gamma agonists such as rosiglitazone, beige/brite adipocytes in co-culture experiments can be induced to differentiate into adipocytes with thermogenic potential in the absence of classical brown adipocyte-specific markers such as Zic2, Lhx8, Meox3 and PRDM16 [44]. In addition, these beige/brite adipocytes are also characterized as having the white adipocyte-specific marker Hoxc9 while lacking the white adipocyte-specific marker tcf21 [44]. Based on these observations, beige/brite adipocytes can be classified as a distinct subtype of white adipocytes with potential capacity for higher metabolic rate [44]. According to the first time demonstration, the beige/brite adipocytes can be emerged from non-myf-5 progenitor cells rather than brown adipocytes derived from myf-5 positive progenitor cells [33]. The exact regulation for the browning of white adipocytes in response to environmental, hormonal and metabolic stimuli is quite remarkable. In addition, the development and regulatory control of beige/brite adipocytes have recently been proposed [37,47]. Similar to BAT, the enrichment and activation of beige/brite adipocytes represent an attractive therapeutic strategy to combat obesity and metabolic diseases. The recent discovery of irisin and its potential to induce the browning of white adipocytes has gained much attention over the last 2 years [6]. Many investigations have demonstrated that irisin can enhance the browning of white adipocytes in mice [6,33], especially in white adipocytes with the high expression of CD137 [33]. However, recent evidence has a series of doubts associated with the physiological functions of irisin in human [48,49]. In 2012, the existence of beige/brite adipocytes has been confirmed in WAT depots in mice [33], and the beige/brite adipocytes in Diabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
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humans are distinct from classical brown adipocytes in mice as the specialized depots [37,47]. Currently, endurance exercise training combined with resistance exercise training has been reported to result in approximately twofold enhancement of circulating irisin level in older adults, thus exhibiting positively proportional to the increased mRNA expression of FNDC5 in skeletal muscle [6]. However, according to Timmons’s report, neither endurance training nor resistance training can improve the expression of FNDC5 mRNA in skeletal muscle of healthy adults. On the other hand, the elevated expression of FNDC5 is detected in a subset of exercise-trained older adults when compared with that of their sedentary counterparts, not in younger adults [49]. Raschke et al. have also conducted the experiments to evaluate the expression of FNDC5 using an in vitro model of endurance training (electrical pulse stimulation) in human myotubes and sedentary men subjected to aerobic interval training and strength training; similarly, the elevated expression of FNDC5 is not observed [48]. Moreover, a recently published randomized clinical trial composed of 102 middleaged participants (30–60 years) has also demonstrated that neither endurance training nor resistance training can increase circulating irisin levels after 26 weeks of training when compared with the controls [50]. An important observation that irisin may be prone to the degradation during the storage period can be achieved from this study [50]. Therefore, the dynamic change of circulating irisin levels in the absence of time-matched controls should be carefully considered. Similarly, another study has revealed the contradictory results in the elevated expression of PGC-1α and FNDC5, as well as the circulating irisin level in skeletal muscle during a bout of acute endurance exercise, chronic endurance exercise or chronic endurance coupled with resistance exercise [51]. In addition, although exercise training for 12 weeks could result in a significantly increased expression of FNDC5 in skeletal muscle, its little effect on the expression of genes such as UCP1, PRDM16, TBX1, TMEM26 or CD137 associated with the browning of WAT in subcutaneous WAT is observed [12]. Taken together, these results raise significant concerns regarding the muscle-specific effects of exercise training on the stimulation of irisin in human. Therefore, it is highly necessary for further conducting extensive exploration to confirm whether the achieved results in mice can be easily translated to human. In addition, it is highly desired for exploring the possibility, potential or location of the synthesis, secretion and distribution of irisin in human. Human exercise cohorts with the analysis of FNDC5 mRNA expression in skeletal muscle after different modes of exercise [52] show that sprints or treadmill exercise or cycling at 70% VO2max for dozens of minutes and endurance or strength or resistance training for several weeks can induce circulating irisin level directly after exercise. Copyright © 2015 John Wiley & Sons, Ltd.
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Contracting skeletal muscles are able to communicate to other organs via humoral factors, which are released into the blood circulation in the presence of different exercise training modes [53]. Such factors like irisin may directly or indirectly affect the functions of other organs including adipose tissue, liver, brain, bone, pancreas, kidney, cardiovascular system and immune system. Clinical research has confirmed that both non-inflammatory and inflammatory diseases are correlated with the basal level of irisin, which will be benefited from exercise-induced irisin, and reveal a cross-interaction between physical activity and these chronic diseases.
Improvement of insulin sensitivity The discovery of irisin has brought the prospect for obesity, diabetes and other metabolic diseases. The irisin-induced browning of white adipocytes can be accomplished through the overexpression of UCP1 and regulated through the activation of p38 mitogen activated protein kinase (p38 MAPK) and extracellular regulated protein kinase. When compared with the individuals without diabetes, the patients with diabetes reveal a lower level of circulating irisin [54,55]; in contrast, the mice transfected with recombinant irisin exhibit the obviously improved glucose resistance. Irisin mainly acts on WAT and functions as the improved energy consumption, which can reduce high-fat-dietinduced insulin resistance [56–58]. The investigation from Lopez-Legarre has demonstrated that 96 ultra-weight patients and metabolic syndrome patients subjected to 8-week treatment of low-energy diets reveal an obvious decrease in body weight and high basal irisin level. The high irisin level is highly correlated with the reduced glucose and insulin concentration as well as the decrease in the consumption of carbohydrates, thus suggesting that irisin is involved in the regulation of glucose metabolism of high-fat-dietinduced obesity individuals [59]. Kurdiova has found a higher level of FNDC5 mRNA in muscle before diabetes; however, once there is an occurrence of type II diabetes, the levels of FNDC5 mRNA in adipose tissue and plasma reveal the reduction by 40% and 50%, respectively [60]. Circulating irisin level is positively correlated with muscle mass, strength and metabolism and negatively correlated with fast blood glucose. Under the condition of cell culture in vitro, glucose and palmitic acids result in the reduction of FNDC5 mRNA expression. Moreno-Navarrete has found that in subcutaneous and visceral adipose tissue, the expression of FNDC5 gene is significantly reduced and is negatively correlated with obesity, and leptin, tumor necrosis factor-alpha and fat-specific protein 27 (brown gene inhibitor) on the contrary are positively correlated with BAT markers, insulin signal pathways, mitochondria and macrophage markers. Similarly, the negative correlation of Diabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
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circulating irisin levels is associated with obesity and insulin resistance [56]. In addition, many previous studies suggest that body weight loss and insulin sensitivity improvement are closely related to FNDC5 in skeletal muscle and serum irisin levels [54–56,61]. In 2013, a new hormone, insulin-regenerating hormone (betatrophin), is found and identified and can specifically accelerate the generation of mouse beta cells and increase the number of mouse beta cells. The regeneration of beta cells in human body will put forward a new avenue for the treatment of diabetes [62]. Based on these studies, a new hypothesis of signalling pathway, p38-PGC-1α-irisinbetatrophin beta cell signal pathway, is proposed. In this signal pathway, under the condition of muscle stimulation, the expression of PGC-1α reveals an obvious increase, thus correspondingly stimulating the expression and cleavage of FNDC5 to generate irisin, activating the expression of UCP1 in the presence of irisin, accelerating the browning of WAT, increasing energy consumption and promoting the regeneration of insulin, as well as completing the rebuilding of beta cells. The level of circulating irisin can improve glucose tolerance and reduce insulin resistance, which can initiate a novel strategy for the treatment of diabetes [57].
Regulation of bone metabolism Bone is the lever of skeletal muscle. The interaction between bone and skeletal muscle plays an important role in the movement of the body. In addition, the interaction between both tissues can be stimulated by secreted factors including insulin-like growth factor-1, fibroblast growth factor-2 and myostatin from skeletal muscle and prostaglandin E2 and Wnt3a from bone [63]. During the investigation of bone metabolism and differentiation, the enhanced expression of irisin is observed in myoblasts from the mice subjected to voluntary wheel-running training when compared the mice without exercise training. Similarly, exercise training can induce the differentiation of osteoblasts and improve the expression of alkaline phosphatase and type I collagen in osteoblasts in an irisin-dependent manner, thereby confirming that irisin reveals a direct involvement in bone metabolism to accelerate the transformation of matured osteoblasts from bone marrow stromal cells [64]. In addition, under post-menopausal women with low bone density, the level of circulating irisin is highly correlated with osteoporotic fracture but not related to bone mass. Denosumab and teriparatide used for treating osteoporosis have no obvious effect on irisin concentration [65]. Recent studies have also pointed out that irisin level is negatively correlated with the fracture because of osteoporosis, but no significant relationship between bone density and lean body mass, suggesting that irisin may be involved in the protection of bone health in a mineral density-independent Copyright © 2015 John Wiley & Sons, Ltd.
manner [66]. Therefore, the relationship between bone metabolism and irisin still needs to be further explored.
Enhancement of cognitive capacity Metabolic syndrome including obesity, hypertension, dyslipidemia and insulin resistance has common pathological and physiological characteristics, which also has extensively adverse effects on cognitive function of brain due to the metabolic dysfunction of nerve cells [67,68]. A large number of studies show that physical activity can effectively improve the cognitive function of the brain at each age stage, especially for the elderly who are the most susceptible to degenerative nerve disorder [69–71]. Physical activity not only can improve the function of cardiovascular and immune systems but also can improve the neurotrophic factor pathway because the structure and function of the nervous system are vital to human cognitive capability [25–27]. Recent studies suggest that the release of muscle cytokines during muscle movement will affect the synthesis of BDNF in hippocampal dentate gyrus, as a novel substance is considered as an important regulating factor for therapeutic implication [13,14]. Erickson has systematically investigated the correlation among physical activity, hippocampal volume and cognitive capability [19] and found that physical activity has direct correlation with cognitive capability due to the exerciseinduced increase in hippocampal volume, which has confirmed that physical activity can lead to the change in anatomic structure and physiological functions of the brain. Pajonk has conducted the studies using the patients with schizophrenia and found that physical activity can improve the hippocampus volume and spatial memory of patients [72]. During testing of healthy individuals, physical activity with higher level could result in the increased hippocampal volume, accelerated cerebellum blood flow and improved spatial memory [73]. Most of the current studies suggest that the excellent effect of exercise on cognitive function can mainly be realized through the improvement of neurotrophic factor [74,75]. BDNF is usually synthesized in vascular endothelial cells, T-cells, B-cells, monocytes and skeletal muscle. Once BDNF is released, it can pass through blood–brain barrier. BDNF is widely expressed in brain and can conveniently cross blood–brain barrier to accomplish the significant impact on the structure and function of hippocampus dentate gyrus, which is confirmed by the widespread expression of its receptor, TrkB, and reveals negative feedback on the regulation of FNDC5 synthesis. The striatum and cortex of PGC-1α-deficient mice show a sponge-like neurodegenerative change, and the symptoms of Parkinson’s disease and Huntington disease [76,77], which means that PGC-1α plays an important role in maintaining the function of the nervous system. Because PGC-1α Diabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
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has the function of mitochondrial biogenesis, it may have the protective role in neuron. PGC-1α, as a transcription factor, without binding capability to DNA, can be associated with oestrogen receptor binding (oestrogen receptorrelated receptor, ERRα). Exercise can upregulate the expression of ERRα in brain [78]. Overexpression of PGC-1α leads to the increased expression of ERRα. The abnormity of ERRα/PGC-1α usually leads to the decreased expression of FNDC5; thus, the knockdown of ERRα can block the PGC-1α-induced FNDC5 gene expression [79]. In the rodent brain, FNDC5 mRNA exists mainly in midbrain, pons, cerebellum and olfactory bulb, and less expression of FNDC5 mRNA is observed in hippocampus [28]. Peripheral circulating irisin in skeletal muscle and myocardial cells has immune reaction. In the central nervous system, immune response to irisin exists only in the cerebellum and vestibular nucleus of medulla oblongata. In fact, immunoreaction of FNDC5 is only found in Purkinje neurons in the brain [80]. Therefore, FNDC5 mRNA translation process and mechanism still need to be further explored. Recent studies have found that FNDC5 is involved in the construction of dendritic spines [81]. Meanwhile, muscle movement can induce the expression of FNDC5 gene to improve the level of circulating irisin, and endurance training induces the expression of FNDC5 gene in hippocampus [14]. The exact function of FNDC5 remains to be further validated; however, one
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of the previous studies has found that FNDC5 can promote the expression of BDNF gene in cerebral cortex cells significantly. The intravenous injection of FNDC5 in mice leads to a significant enhancement of BDNF gene expression. On the contrary, the mice subjected to BDNF treatment reveals the decreased expression of FNDC5 in hippocampal neurons. The expression of FNDC5 gene in the liver leads to an increase in BDNF mRNA level in hippocampus, which reveals a positive correlation [14]. The knockout of FNDC5 gene in embryonic stem cells could result in the lower level of both neural progenitor cell differentiation and neural differentiation, indicating that FNDC5 is required for neutral differentiation of mouse embryonic stem cells [82]. Another report has demonstrated that irisin at physiological dose (5–10 nmol/L) has no obvious effect on the proliferation of mouse H19-7 hippocampal neurons; on the other hand, irisin at pharmacological concentration (50–100 nmol/L) can result in the enhancement of proliferation capability when compared with the control group. Hippocampus is a major region affected by Alzheimer’s disease, and the exercise-induced nerve regeneration can reduce the damage resulted from Alzheimer’s, Parkinson’s and other neurodegenerative diseases. Irisin may play a connecting role in exercise and brain health, which provides a new approach for the treatment of neurodegenerative diseases.
Figure 1. The regulation of exercise-induced irisin on metabolic diseases or metabolism-associated health issues. ‘×’ indicates the inhibition or blockage of signal pathways or diseases. PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1-alpha; FNDC5, fibronectin domain-containing protein 5; UCP1, uncoupling protein 1; ROS, reactive oxygen species Copyright © 2015 John Wiley & Sons, Ltd.
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Future remarks Obesity has become a worldwide epidemic disease, and many diseases related to obesity also reveal a gradual rising, including insulin resistance, metabolic syndrome, type II diabetes, hypertension, chronic kidney disease, cardiovascular disease, heart failure, cancer and nervous system diseases or health issues. Because irisin has gained tremendous insight in the field of life science, its potential therapeutic value in metabolic diseases or metabolismassociated health issues offers the prospects for the treatment of obesity, type II diabetes and other metabolic diseases, and the regulation of exercise-induced irisin on metabolic diseases or metabolism-related health issues is summarized in Figure 1. Although some conclusions have been achieved in rodent models, the molecular mechanisms of irisin in human still have many debates. Therefore, further studies are highly necessary. For example, the identification and functions of irisin receptors, characteristics and signal transduction pathway of irisin need to be further explored; irisin-like hormones may exist, and their functions should be explored; the interaction or cross-talk of irisin and other cytokines or other signal pathways including exercise-induced autophagy pathway is still unclear. Irisin can be activated, secreted and transported to a target on multiple tissues or organs for executing its corresponding physiological functions such as regulating WAT browning, improving energy consumption,
improving glucose utilization, reducing insulin resistance and synergistically treating metabolic diseases or metabolism-associated health issues such as obesity, diabetes and cognitive diseases. Therefore, irisin may be exploited as functional foods, drugs or a novel target for the treatment of metabolic diseases or metabolismassociated health issues; meanwhile, the strategies for modulating the upstream signal pathways of irisin may be also a creative thought for the control or intervention of human metabolic diseases or metabolism-associated health issues, so as to accomplish prevention of metabolic disease or metabolism-associated health issues and improvement of life quality. All of these strategies will be particularly important for the people with limited physical activity or regular exercise because of disability.
Acknowledgements This work is financially supported by Chutian Scholar Program awarded to N. C. from the Education Department of Hubei Province and Innovative Start-up Foundation to N. C. from Wuhan Sports University.
Conflict of interest The authors have no conflicts of interest.
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50. Hecksteden A, Wegmann M, Steffen A, et al. Irisin and exercise training in humans—results from a randomized controlled training trial. BMC Med 2013; 11: 235. 51. Pekkala S, Wiklund PK, Hulmi JJ, et al. Are skeletal muscle FNDC5 gene expression and irisin release regulated by exercise and related to health? J Physiol 2013; 591(Pt 21): 5393–5400. 52. Elsen M, Raschke S, Eckel J. Browning of white fat: does irisin play a role in humans? J Endocrinol 2014; 222(1): R25–38. 53. Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012; 8(8): 457–465. 54. Choi YK, Kim MK, Bae KH, et al. Serum irisin levels in new-onset type 2 diabetes. Diabetes Res Clin Pract 2013; 100 (1): 96–101. 55. Hojlund K, Bostrom P. Irisin in obesity and type 2 diabetes. J Diabetes Complications 2013; 27(4): 303–304. 56. Moreno-Navarrete JM, Ortega F, Serrano M, et al. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab 2013; 98(4): E769–778. 57. Sanchis-Gomar F, Perez-Quilis C. The p38-PGC-1alpha-irisin-betatrophin axis: exploring new pathways in insulin resistance. Adipocyte 2014; 3(1): 67–68. 58. Sesti G, Andreozzi F, Fiorentino TV, et al. High circulating irisin levels are associated with insulin resistance and vascular atherosclerosis in a cohort of nondiabetic adult subjects. Acta Diabetol 2014; 51(5): 705–713. 59. Lopez-Legarrea P, de la Iglesia R, Crujeiras AB, et al. Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects. Nutr Diabetes 2014; 4: e110. 60. Kurdiova T, Balaz M, Vician M, et al. Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue: in vivo and in vitro studies. J Physiol 2014; 592(Pt 5): 1091–1107. 61. Liu JJ, Wong MD, Toy WC, et al. Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complications 2013; 27(4): 365–369. 62. Yi P, Park JS, Melton DA. Betatrophin: a hormone that controls pancreatic beta cell proliferation. Cell 2013; 153(4): 747–758. 63. Tagliaferri C, Wittrant Y, Davicco MJ, Walrand S, Coxam V. Muscle and bone, two interconnected tissues. Ageing Res Rev 2015; 21: 55–70. 64. Colaianni G, Cuscito C, Mongelli T, et al. Irisin enhances osteoblast differentiation in vitro. Int J Endocrinol 2014; 2014: 902186. 65. Anastasilakis AD, Polyzos SA, Makras P, et al. Circulating irisin is associated with osteoporotic fractures in postmenopausal
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Diabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review
Ning Chen1* Qingxue Li2,3 Jun Liu1 Shaohui Jia1 1
College of Health Science, Hubei Provincial Collaborative Innovation Center for Exercise and Health Promotion, Wuhan Sports University, Wuhan, China
2
Graduate School, Wuhan Sports University, Wuhan, China
3
College of Sports Science and Technology, Wuhan Sports University, Wuhan, China *Correspondence to: Ning Chen, Professor in Biochemistry and Molecular Exercise Physiology, College of Health Science, Hubei Provincial Collaborative Innovation Center for Exercise and Health Promotion, Wuhan Sports University, Wuhan 430079, China. E-mail: [email protected]
Received: 20 February 2015 Accepted: 23 April 2015
Copyright © 2015 John Wiley & Sons, Ltd.
Summary Irisin, as a new hormone-like myokine, is discovered in the presence of exerciseinduced 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. Keywords
irisin; myokine; exercise; metabolic disease; obesity; diabetes
Introduction In the high-speed development age, because of the fast rhythm or too much pressure of work and life as well as the change of lifestyle, more and more people spend less time on physical activity or regular exercise, thus resulting in the change of body compositions and high incidence of metabolic diseases such as diabetes, obesity and lipid metabolic syndrome [1,2]. Based on previous reports, physical inactivity could reduce the average life span of people for approximately 5–10 years when compared with that of people with regular physical activity or exercise [3]. It is well known that physical activity or regular exercise is an economical and environment-friendly style for accomplishing health promotion; however, its exact molecular mechanisms are still unclear, which cannot effectively provide scientific guidance for the intervention of diseases sometimes or the rational development of exercise-mimic drugs for some chronic diseases [4,5]. The research group of Spiegelman from Harvard University first discovered and reported a small peptide generated in muscle tissue in the presence of exercise-induced upregulation of peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) [6]. Once this small peptide as one of the myokines generates in muscle, it will secrete into blood stream and
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transport to adipose tissue or other tissues or organs for executing the regulation of energy metabolism, promoting the browning of white adipocytes, improving the activity of insulin and reducing the resistance of insulin, and optimizing the body compositions [7]. Because of its physiological regulation of exercise-induced irisin for health promotion and many diseases, exercise or corresponding strategies for inducing irisin or irisin-related products have gained tremendous attention for the prevention, intervention, or even treatment of metabolic diseases such as obesity and diabetes [8]. Although some investigations involved in energy metabolism, browning of white adipocytes, and insulin sensitivity or resistance in the presence of irisin in recent 2 years since it is discovered, the underlying mechanisms and corresponding signal pathways for these regulations are still unclear. It is highly desired to conduct further studies on irisin so that it will be better to facilitate human health promotion and disease prevention, intervention and treatment. In order to provide a systematic reference for further exploration of irisin, we have summarized and updated its structural characteristics, production and distribution in tissues and organs, and regulation and corresponding mechanisms for metabolic diseases or metabolismassociated health issues in this narrative review article.
Production and distribution of irisin It is well known that physical activity or exercise is a green and environment-friendly lifestyle for promoting human health and preventing and treating metabolic and cardiovascular diseases as well as improving the cognitive capacity of the brain [9–11]. All of these functions are highly correlated with the mitochondrial quality and bioenergetics of skeletal muscle or other tissues during exercise. Since the discovery of exercise-induced irisin, the attentions and studies on irisin have revealed an increasing explosion. The acute or long-term exercise training can obviously upregulate the expression of PGC-1α in skeletal muscle or cardiac muscle, which can promote the generation of its downstream fibronectin domain-containing protein 5 (FNDC5) and the proteolytic cleavage of FNDC5 to result in the production of irisin as a hormone-like myokine [12]. Although the first investigation has reported the generation of irisin in skeletal muscle and its release in blood circulation to regulate the functions of other tissues or organs, the ultimate location and distribution of irisin for its wide range of powerful physiological characteristics and roles are still unknown [6,13–17]. Currently, the distribution and corresponding levels of irisin in different target tissues or organs in human have revealed its physiological functions for promoting health Copyright © 2015 John Wiley & Sons, Ltd.
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or executing the regulation of metabolic diseases. Nowadays, irisin has been reported to be distributed in skeletal muscle, cardiac muscle, adipose tissue, liver, brain, bone, pancreas, kidney and ovary at various levels [18–20]. Most strikingly, the increased expression of PGC-1α can often benefit a lot of tissues besides muscle. However, the corresponding mechanisms are still unclear. Some scholars speculate that the expression of PGC-1α can stimulate the release of some special factors in skeletal muscle, which will be also benefit for other tissues [21]. In contrast, other investigations have reported that the male mice with the age of 13 weeks after a voluntary wheelrunning for 30 days reveals a high expression of irisin in cardiac muscle, brain, spinal cord and oxidative muscle such as soleus muscle, while lung, liver, spleen, kidney, interscapular brown adipose tissue (BAT) and inguinal white adipose tissue (WAT) exhibit a relatively low expression of irisin, suggesting that the generation and accumulation of irisin is highly correlated with the higher PGC-1α levels in oxidative muscle than that in glycolytic or mixed muscles such as gastrocnemius or quadriceps muscle. Therefore, the secretion of exerciseinduced irisin may be independent of the upregulation of PGC-1α, and these studies need to be further explored and validated. Previous studies have also demonstrated that circulating irisin is positively correlated with biceps circumference, body mass index, glucose, endogenous intestinal peptide (inhibiting the secretion of insulin) and insulinlike growth factor-1. On the other hand, irisin level is negatively correlated with age, and insulin, triglyceride and adiponectin levels, suggesting that irisin may be involved in compensatory mechanisms for metabolic regulation [22]. Based on our current knowledge, irisin is not only a myokine, but also an adipokine, with autocrine and paracrine functions [23]. The adipose tissues from different anatomic regions could reveal the various secretion styles and levels. For example, compared with visceral adipose tissue, subcutaneous adipose tissue has the lesser secretion of FNDC5/irisin. In addition, the expression of irisin in human WAT is only 5% of the expression level of irisin in skeletal muscle [12]. Similarly, physical activity or exercise can improve the cognitive function of brain at each age stage [24]. Moreover, physical activity or exercise not only can enhance cardiovascular and immune functions but also can improve neurotrophic factor pathway that is critical to cognitive capability [25–27]. Therefore, regular exercise training or physical activity plays an important role in the modulation of immune and anti-inflammation functions, which can enhance the cognitive capability of older people or individuals with neuropathy. Recent studies have demonstrated that the secretion and release of exercise-induced myokines in muscle can regulate the synthesis of brainDiabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
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derived neurotrophic factor (BDNF) in the dentate gyrus of hippocampus tissue [14]. Similarly, the mRNA expression of FNDC5 is extensively distributed in brain tissues including midbrain, pons, cerebellum and olfactory bulb, as well as hippocampus tissues, which may be positively correlated with the improvement of cognitive capability after regular physical activity or exercise [28].
Structural characterization of irisin Irisin, as a hormone-like polypeptide including 112 amino acid residues, is generally synthesized in muscle tissue after the proteolytic cleavage of its precursor, FNDC5. Its molecular weight is approximately 12 kDa [29]. FNDC5 is generated by a type I membrane protein undergoing proteolytic cleavage, which results in the release of N-terminal part of the protein into extracellular space [30]. FNDC5 is composed of three parts including a signal peptide, two fibronectin domains and a hydrophobic C-terminal domain. FNDC5 itself is a glycoprotein with glycosylation sites of 39K and 84A [31]. The X-ray crystallographic structure has demonstrated that irisin has an Nterminal fibronectin type III-like domain for forming a continuous intersubunit beta-sheet dimer and a flexible C-terminal tail. Biochemical data have confirmed that irisin is prone to dimerization without the influence from glycosylation. This finding suggests a possible mechanism for receptor activation by irisin domain as a preferred myokine dimer ligand or as a paracrine or autocrine dimerization module on FNDC5-like receptors. Irisin is released from muscle tissue in response to exercise. It is the secretion portion of FNDC5 protein and is able to promote the beige of WAT and prevent or inhibit many metabolic diseases in both human and mice [32].
Physiological functions Irisin-induced browning of white adipocytes Generally, adipose tissue includes two parts such as WAT, which functions as the dominant site for the storage of lipid, and BAT, which functions as the thermogenesis through uncoupled respiration [33]. Increasing documentation has demonstrated the physiological, metabolic and regulatory characteristics of WAT and BAT [34–39]. Adipocytes from WAT are the characteristics of unilocular lipid droplets, few mitochondria and relatively low metabolic rate; on the other hand, adipocytes from BAT are the characteristics of multilocular lipid droplets, plentiful mitochondria and relatively high metabolic rate [39]. Copyright © 2015 John Wiley & Sons, Ltd.
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Meanwhile, the large amount of uncoupling protein 1 (UCP1) generation results in the relatively high metabolic rate in BAT, while its expression can be negligible in WAT [39]. Because brown adipocytes in WAT of BALB/c mice have been detected after cold acclimatization, the browning of adipocytes in WAT has gained extensive investigations because of the attractive therapeutic potential for obesity and metabolic disease in the presence of enrichment and activation of BAT [40]. Subsequently, brown adipocytes have also been observed in multiple WAT fat pads of rats [41]. Later, some investigations have demonstrated that the stimulation of beta-adrenergic agents [41–43] or peroxisome proliferator-activated receptor gamma agonists can result in the pharmacological accumulation of UCP1 in WAT and the enrichment of BAT [44–46]. Recent evidence has demonstrated that the brown adipocytes in WAT are rich in UCP1 as the sub-population of white adipocytes and can be defined as the brown-in-white (brite) or beige adipocytes [33,44]. In the presence of treatment using peroxisome proliferator-activated receptor gamma agonists such as rosiglitazone, beige/brite adipocytes in co-culture experiments can be induced to differentiate into adipocytes with thermogenic potential in the absence of classical brown adipocyte-specific markers such as Zic2, Lhx8, Meox3 and PRDM16 [44]. In addition, these beige/brite adipocytes are also characterized as having the white adipocyte-specific marker Hoxc9 while lacking the white adipocyte-specific marker tcf21 [44]. Based on these observations, beige/brite adipocytes can be classified as a distinct subtype of white adipocytes with potential capacity for higher metabolic rate [44]. According to the first time demonstration, the beige/brite adipocytes can be emerged from non-myf-5 progenitor cells rather than brown adipocytes derived from myf-5 positive progenitor cells [33]. The exact regulation for the browning of white adipocytes in response to environmental, hormonal and metabolic stimuli is quite remarkable. In addition, the development and regulatory control of beige/brite adipocytes have recently been proposed [37,47]. Similar to BAT, the enrichment and activation of beige/brite adipocytes represent an attractive therapeutic strategy to combat obesity and metabolic diseases. The recent discovery of irisin and its potential to induce the browning of white adipocytes has gained much attention over the last 2 years [6]. Many investigations have demonstrated that irisin can enhance the browning of white adipocytes in mice [6,33], especially in white adipocytes with the high expression of CD137 [33]. However, recent evidence has a series of doubts associated with the physiological functions of irisin in human [48,49]. In 2012, the existence of beige/brite adipocytes has been confirmed in WAT depots in mice [33], and the beige/brite adipocytes in Diabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
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humans are distinct from classical brown adipocytes in mice as the specialized depots [37,47]. Currently, endurance exercise training combined with resistance exercise training has been reported to result in approximately twofold enhancement of circulating irisin level in older adults, thus exhibiting positively proportional to the increased mRNA expression of FNDC5 in skeletal muscle [6]. However, according to Timmons’s report, neither endurance training nor resistance training can improve the expression of FNDC5 mRNA in skeletal muscle of healthy adults. On the other hand, the elevated expression of FNDC5 is detected in a subset of exercise-trained older adults when compared with that of their sedentary counterparts, not in younger adults [49]. Raschke et al. have also conducted the experiments to evaluate the expression of FNDC5 using an in vitro model of endurance training (electrical pulse stimulation) in human myotubes and sedentary men subjected to aerobic interval training and strength training; similarly, the elevated expression of FNDC5 is not observed [48]. Moreover, a recently published randomized clinical trial composed of 102 middleaged participants (30–60 years) has also demonstrated that neither endurance training nor resistance training can increase circulating irisin levels after 26 weeks of training when compared with the controls [50]. An important observation that irisin may be prone to the degradation during the storage period can be achieved from this study [50]. Therefore, the dynamic change of circulating irisin levels in the absence of time-matched controls should be carefully considered. Similarly, another study has revealed the contradictory results in the elevated expression of PGC-1α and FNDC5, as well as the circulating irisin level in skeletal muscle during a bout of acute endurance exercise, chronic endurance exercise or chronic endurance coupled with resistance exercise [51]. In addition, although exercise training for 12 weeks could result in a significantly increased expression of FNDC5 in skeletal muscle, its little effect on the expression of genes such as UCP1, PRDM16, TBX1, TMEM26 or CD137 associated with the browning of WAT in subcutaneous WAT is observed [12]. Taken together, these results raise significant concerns regarding the muscle-specific effects of exercise training on the stimulation of irisin in human. Therefore, it is highly necessary for further conducting extensive exploration to confirm whether the achieved results in mice can be easily translated to human. In addition, it is highly desired for exploring the possibility, potential or location of the synthesis, secretion and distribution of irisin in human. Human exercise cohorts with the analysis of FNDC5 mRNA expression in skeletal muscle after different modes of exercise [52] show that sprints or treadmill exercise or cycling at 70% VO2max for dozens of minutes and endurance or strength or resistance training for several weeks can induce circulating irisin level directly after exercise. Copyright © 2015 John Wiley & Sons, Ltd.
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Contracting skeletal muscles are able to communicate to other organs via humoral factors, which are released into the blood circulation in the presence of different exercise training modes [53]. Such factors like irisin may directly or indirectly affect the functions of other organs including adipose tissue, liver, brain, bone, pancreas, kidney, cardiovascular system and immune system. Clinical research has confirmed that both non-inflammatory and inflammatory diseases are correlated with the basal level of irisin, which will be benefited from exercise-induced irisin, and reveal a cross-interaction between physical activity and these chronic diseases.
Improvement of insulin sensitivity The discovery of irisin has brought the prospect for obesity, diabetes and other metabolic diseases. The irisin-induced browning of white adipocytes can be accomplished through the overexpression of UCP1 and regulated through the activation of p38 mitogen activated protein kinase (p38 MAPK) and extracellular regulated protein kinase. When compared with the individuals without diabetes, the patients with diabetes reveal a lower level of circulating irisin [54,55]; in contrast, the mice transfected with recombinant irisin exhibit the obviously improved glucose resistance. Irisin mainly acts on WAT and functions as the improved energy consumption, which can reduce high-fat-dietinduced insulin resistance [56–58]. The investigation from Lopez-Legarre has demonstrated that 96 ultra-weight patients and metabolic syndrome patients subjected to 8-week treatment of low-energy diets reveal an obvious decrease in body weight and high basal irisin level. The high irisin level is highly correlated with the reduced glucose and insulin concentration as well as the decrease in the consumption of carbohydrates, thus suggesting that irisin is involved in the regulation of glucose metabolism of high-fat-dietinduced obesity individuals [59]. Kurdiova has found a higher level of FNDC5 mRNA in muscle before diabetes; however, once there is an occurrence of type II diabetes, the levels of FNDC5 mRNA in adipose tissue and plasma reveal the reduction by 40% and 50%, respectively [60]. Circulating irisin level is positively correlated with muscle mass, strength and metabolism and negatively correlated with fast blood glucose. Under the condition of cell culture in vitro, glucose and palmitic acids result in the reduction of FNDC5 mRNA expression. Moreno-Navarrete has found that in subcutaneous and visceral adipose tissue, the expression of FNDC5 gene is significantly reduced and is negatively correlated with obesity, and leptin, tumor necrosis factor-alpha and fat-specific protein 27 (brown gene inhibitor) on the contrary are positively correlated with BAT markers, insulin signal pathways, mitochondria and macrophage markers. Similarly, the negative correlation of Diabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
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circulating irisin levels is associated with obesity and insulin resistance [56]. In addition, many previous studies suggest that body weight loss and insulin sensitivity improvement are closely related to FNDC5 in skeletal muscle and serum irisin levels [54–56,61]. In 2013, a new hormone, insulin-regenerating hormone (betatrophin), is found and identified and can specifically accelerate the generation of mouse beta cells and increase the number of mouse beta cells. The regeneration of beta cells in human body will put forward a new avenue for the treatment of diabetes [62]. Based on these studies, a new hypothesis of signalling pathway, p38-PGC-1α-irisinbetatrophin beta cell signal pathway, is proposed. In this signal pathway, under the condition of muscle stimulation, the expression of PGC-1α reveals an obvious increase, thus correspondingly stimulating the expression and cleavage of FNDC5 to generate irisin, activating the expression of UCP1 in the presence of irisin, accelerating the browning of WAT, increasing energy consumption and promoting the regeneration of insulin, as well as completing the rebuilding of beta cells. The level of circulating irisin can improve glucose tolerance and reduce insulin resistance, which can initiate a novel strategy for the treatment of diabetes [57].
Regulation of bone metabolism Bone is the lever of skeletal muscle. The interaction between bone and skeletal muscle plays an important role in the movement of the body. In addition, the interaction between both tissues can be stimulated by secreted factors including insulin-like growth factor-1, fibroblast growth factor-2 and myostatin from skeletal muscle and prostaglandin E2 and Wnt3a from bone [63]. During the investigation of bone metabolism and differentiation, the enhanced expression of irisin is observed in myoblasts from the mice subjected to voluntary wheel-running training when compared the mice without exercise training. Similarly, exercise training can induce the differentiation of osteoblasts and improve the expression of alkaline phosphatase and type I collagen in osteoblasts in an irisin-dependent manner, thereby confirming that irisin reveals a direct involvement in bone metabolism to accelerate the transformation of matured osteoblasts from bone marrow stromal cells [64]. In addition, under post-menopausal women with low bone density, the level of circulating irisin is highly correlated with osteoporotic fracture but not related to bone mass. Denosumab and teriparatide used for treating osteoporosis have no obvious effect on irisin concentration [65]. Recent studies have also pointed out that irisin level is negatively correlated with the fracture because of osteoporosis, but no significant relationship between bone density and lean body mass, suggesting that irisin may be involved in the protection of bone health in a mineral density-independent Copyright © 2015 John Wiley & Sons, Ltd.
manner [66]. Therefore, the relationship between bone metabolism and irisin still needs to be further explored.
Enhancement of cognitive capacity Metabolic syndrome including obesity, hypertension, dyslipidemia and insulin resistance has common pathological and physiological characteristics, which also has extensively adverse effects on cognitive function of brain due to the metabolic dysfunction of nerve cells [67,68]. A large number of studies show that physical activity can effectively improve the cognitive function of the brain at each age stage, especially for the elderly who are the most susceptible to degenerative nerve disorder [69–71]. Physical activity not only can improve the function of cardiovascular and immune systems but also can improve the neurotrophic factor pathway because the structure and function of the nervous system are vital to human cognitive capability [25–27]. Recent studies suggest that the release of muscle cytokines during muscle movement will affect the synthesis of BDNF in hippocampal dentate gyrus, as a novel substance is considered as an important regulating factor for therapeutic implication [13,14]. Erickson has systematically investigated the correlation among physical activity, hippocampal volume and cognitive capability [19] and found that physical activity has direct correlation with cognitive capability due to the exerciseinduced increase in hippocampal volume, which has confirmed that physical activity can lead to the change in anatomic structure and physiological functions of the brain. Pajonk has conducted the studies using the patients with schizophrenia and found that physical activity can improve the hippocampus volume and spatial memory of patients [72]. During testing of healthy individuals, physical activity with higher level could result in the increased hippocampal volume, accelerated cerebellum blood flow and improved spatial memory [73]. Most of the current studies suggest that the excellent effect of exercise on cognitive function can mainly be realized through the improvement of neurotrophic factor [74,75]. BDNF is usually synthesized in vascular endothelial cells, T-cells, B-cells, monocytes and skeletal muscle. Once BDNF is released, it can pass through blood–brain barrier. BDNF is widely expressed in brain and can conveniently cross blood–brain barrier to accomplish the significant impact on the structure and function of hippocampus dentate gyrus, which is confirmed by the widespread expression of its receptor, TrkB, and reveals negative feedback on the regulation of FNDC5 synthesis. The striatum and cortex of PGC-1α-deficient mice show a sponge-like neurodegenerative change, and the symptoms of Parkinson’s disease and Huntington disease [76,77], which means that PGC-1α plays an important role in maintaining the function of the nervous system. Because PGC-1α Diabetes Metab Res Rev 2016; 32: 51–59. DOI: 10.1002/dmrr
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has the function of mitochondrial biogenesis, it may have the protective role in neuron. PGC-1α, as a transcription factor, without binding capability to DNA, can be associated with oestrogen receptor binding (oestrogen receptorrelated receptor, ERRα). Exercise can upregulate the expression of ERRα in brain [78]. Overexpression of PGC-1α leads to the increased expression of ERRα. The abnormity of ERRα/PGC-1α usually leads to the decreased expression of FNDC5; thus, the knockdown of ERRα can block the PGC-1α-induced FNDC5 gene expression [79]. In the rodent brain, FNDC5 mRNA exists mainly in midbrain, pons, cerebellum and olfactory bulb, and less expression of FNDC5 mRNA is observed in hippocampus [28]. Peripheral circulating irisin in skeletal muscle and myocardial cells has immune reaction. In the central nervous system, immune response to irisin exists only in the cerebellum and vestibular nucleus of medulla oblongata. In fact, immunoreaction of FNDC5 is only found in Purkinje neurons in the brain [80]. Therefore, FNDC5 mRNA translation process and mechanism still need to be further explored. Recent studies have found that FNDC5 is involved in the construction of dendritic spines [81]. Meanwhile, muscle movement can induce the expression of FNDC5 gene to improve the level of circulating irisin, and endurance training induces the expression of FNDC5 gene in hippocampus [14]. The exact function of FNDC5 remains to be further validated; however, one
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of the previous studies has found that FNDC5 can promote the expression of BDNF gene in cerebral cortex cells significantly. The intravenous injection of FNDC5 in mice leads to a significant enhancement of BDNF gene expression. On the contrary, the mice subjected to BDNF treatment reveals the decreased expression of FNDC5 in hippocampal neurons. The expression of FNDC5 gene in the liver leads to an increase in BDNF mRNA level in hippocampus, which reveals a positive correlation [14]. The knockout of FNDC5 gene in embryonic stem cells could result in the lower level of both neural progenitor cell differentiation and neural differentiation, indicating that FNDC5 is required for neutral differentiation of mouse embryonic stem cells [82]. Another report has demonstrated that irisin at physiological dose (5–10 nmol/L) has no obvious effect on the proliferation of mouse H19-7 hippocampal neurons; on the other hand, irisin at pharmacological concentration (50–100 nmol/L) can result in the enhancement of proliferation capability when compared with the control group. Hippocampus is a major region affected by Alzheimer’s disease, and the exercise-induced nerve regeneration can reduce the damage resulted from Alzheimer’s, Parkinson’s and other neurodegenerative diseases. Irisin may play a connecting role in exercise and brain health, which provides a new approach for the treatment of neurodegenerative diseases.
Figure 1. The regulation of exercise-induced irisin on metabolic diseases or metabolism-associated health issues. ‘×’ indicates the inhibition or blockage of signal pathways or diseases. PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1-alpha; FNDC5, fibronectin domain-containing protein 5; UCP1, uncoupling protein 1; ROS, reactive oxygen species Copyright © 2015 John Wiley & Sons, Ltd.
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Future remarks Obesity has become a worldwide epidemic disease, and many diseases related to obesity also reveal a gradual rising, including insulin resistance, metabolic syndrome, type II diabetes, hypertension, chronic kidney disease, cardiovascular disease, heart failure, cancer and nervous system diseases or health issues. Because irisin has gained tremendous insight in the field of life science, its potential therapeutic value in metabolic diseases or metabolismassociated health issues offers the prospects for the treatment of obesity, type II diabetes and other metabolic diseases, and the regulation of exercise-induced irisin on metabolic diseases or metabolism-related health issues is summarized in Figure 1. Although some conclusions have been achieved in rodent models, the molecular mechanisms of irisin in human still have many debates. Therefore, further studies are highly necessary. For example, the identification and functions of irisin receptors, characteristics and signal transduction pathway of irisin need to be further explored; irisin-like hormones may exist, and their functions should be explored; the interaction or cross-talk of irisin and other cytokines or other signal pathways including exercise-induced autophagy pathway is still unclear. Irisin can be activated, secreted and transported to a target on multiple tissues or organs for executing its corresponding physiological functions such as regulating WAT browning, improving energy consumption,
improving glucose utilization, reducing insulin resistance and synergistically treating metabolic diseases or metabolism-associated health issues such as obesity, diabetes and cognitive diseases. Therefore, irisin may be exploited as functional foods, drugs or a novel target for the treatment of metabolic diseases or metabolismassociated health issues; meanwhile, the strategies for modulating the upstream signal pathways of irisin may be also a creative thought for the control or intervention of human metabolic diseases or metabolism-associated health issues, so as to accomplish prevention of metabolic disease or metabolism-associated health issues and improvement of life quality. All of these strategies will be particularly important for the people with limited physical activity or regular exercise because of disability.
Acknowledgements This work is financially supported by Chutian Scholar Program awarded to N. C. from the Education Department of Hubei Province and Innovative Start-up Foundation to N. C. from Wuhan Sports University.
Conflict of interest The authors have no conflicts of interest.
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