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.
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.
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.
These results suggest that irisin/FNDC5 has a pleiotropic role in muscle and improvement of adipocyte metabolism in humans.
Physical inactivity results in increased risk of type 2 diabetes and cardiovascular disease,1,2 and therefore exercise and increased energy expenditure are regarded as an effective therapeutic approach.3,4 The complex mechanisms underlying the benefits of exercise can be explained either by local effect in muscle, including muscle growth and enhanced glucose/lipid metabolism,5 or by endocrine effect through exercise-induced cytokines, classified as ‘myokines’.6 Discovery of myokines has helped to understand the crosstalk between muscle and other metabolic organs such as adipose tissue and liver, but the impact of these myokines are not completely understood.
Irisin is a recently discovered myokine suggested to mediate the beneficial effects of exercise.7 There is limited evidence on the physiology of irisin, but it has been suggested that peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC1α) is an upstream regulator of irisin and induces browning in subcutaneous adipose tissue through upregulation of uncoupling protein 1 (UCP1).7 In mice, overexpression of the irisin precursor fibronectin type III domain-containing protein 5 (FNDC5) resulted in improvement of diet-induced insulin resistance.7 Therefore, irisin is an attractive target for the treatment of obesity and its related metabolic disorders.8, 9, 10, 11, 12 In another report, it was found in 3T3-L1 mouse adipocytes and rat primary adipocytes that recombinant irisin treatment upregulated browning-specific genes via p38 MAPK and ERK signaling pathway.13 Although the browning effect of irisin has been reported in mouse adipocytes, it remains to be shown whether these effects can be translated to humans. More importantly, besides browning gene expression and UCP1 induction, the functional outcome of irisin treatment on energy expenditure and metabolic function of human adipocytes remains to be elucidated.
The fact that irisin is predominantly expressed in muscle14 raises a hypothesis that irisin, like other myokines such as interleukin-6 (IL-6), IL-15, myonectin, etc.,15 could influence muscle cell metabolism. In the initial report by Bostrom et al., no evident effect of irisin on muscle gene expression was observed.7 Intriguingly, recent experimental evidence in mice demonstrated that deficiency of myostatin, a myokine that has an important role in negative regulation of muscle growth and development, leads to PGC1α activation and irisin secretion in muscle,16 resulting in browning of white adipocytes. Also, we have previously observed a positive correlation between circulating insulin-like growth factor 1 (IGF1) and irisin.14 Given the importance of IGF1-myostatin system in exercise-induced muscle growth,17 there is a possibility that irisin could be involved in exercise-induced muscle hypertrophy by acting directly on muscle cells.
Here, we examined the regulation of irisin/FNDC5 during myogenic differentiation and the effect of irisin on muscle hypertrophy in human skeletal muscle cells (HSMCs). In addition, we expand on the previous observation in mouse to human adipocytes to evaluate the effect of exogenous irisin on primary human preadipocyte differentiation and mature adipocyte function. Our data show that irisin treatment is able to not only regulate adipocyte metabolism but also muscle growth, both of which could potentially be used as a target for prevention and treatment of obesity, related metabolic diseases and muscle disorders.
Materials and methods
Primary human skeletal muscle cell culture
Thigh muscle (vastus lateralis) was collected from obese but apparently healthy subjects (age 41.0±7.9 years, BMI 43.5±1.7 kg m−2) and cultured as previously described.18 The morphology and growth of the isolated myocytes were normal and their characteristics were maintained until passage 7. During myogenic differentiation, media was changed every 24 h and the media was collected on day 0, 2, 5, 8, 12. For inhibition experiments, skeletal muscle cells were incubated with ERK inhibitor U0126 (10 μM, Cell Signaling, Danvers, MA, USA) 2 h before irisin treatment.
Primary human adipocyte culture
Subcutaneous human adipocytes were obtained from the same patients as above. Primary adipocyte culture was performed as described previously.19 To examine the effect on adipocyte differentiation, the cells were treated with 10 or 50 nM recombinant irisin (Aviscera Bioscience, Santa Clara, CA, USA) every 2 days, starting from 2 days before differentiation.
3T3-L1 adipocyte culture
3T3-L1 preadipocytes were cultured as previously described.20 During the first 2 days of differentiation, the medium was supplemented with 1 μM dexamethasone, 1 μg ml−1 insulin, and either 0.5 mM IBMX or 1 μM rosiglitazone. Recombinant irisin and FNDC5 (Aviscera Bioscience) were used to compare the effect on preadipocyte differentiation.
Gene expression analysis
Total RNA was extracted from adipocytes using Trizol (Invitrogen, Carlsbad, CA, USA) according to a standard protocol. mRNA levels were measured by real-time PCR using TaqMan Gene Expression Assays as described.14
Western blot analysis
Western blot analysis in adipocytes was performed as previously described.18 The membranes were incubated with primary antibody (aP2 and PPARγ from Cell Signaling; FAS, PGC1α, ATGL, Akt, ERK1/2 and β-actin from Santa Cruz Biotechnology, Dallas, TX, USA; UCP1 from Abcam, Cambridge, MA, USA) overnight.
ATP was measured in cell lysates with a bioluminescence kit (Promega, Madison, WI, USA). Glycolysis and lipolysis were measured by release of lactate and free fatty acid/glycerol in the media, respectively (Cayman Chemical, Ann Arbor, MI, USA, and Zen-Bio, Research Triangle Park, NC, USA). Irisin and IL-6 secretion in the culture media of skeletal muscle cells were measured with commercially available ELISAs (Phoenix Pharmaceuticals, Burlingame, CA, USA; R&D Systems, Minneapolis, MN, USA, respectively).
Human adipocyte samples were prepared as previously described21 and analyzed in the BIDMC Mass Spectrometry Core Facility. MetaboAnalyst22 was used to discover a biologically meaningful pattern (http://www.metaboanalyst.ca). For metabolite set enrichment analysis, data were mapped according to the Human Metabolome Database (http://www.hmdb.ca), and the Metabolic Pathway Library (currently 88 entries) was chosen to assess the data using the global test package.23
SPSS software 19.0 (SPSS Inc., Chicago, IL, USA) were used and data are shown as mean±s.e. unless stated otherwise. Mean values obtained from multiple experiments were compared by ANOVA with subsequent Fisher’s significant difference method. Metabolite changes were analyzed by Student’s t-test. P values of <0.05 were considered as statistically significant for all analyses.
Irisin/FNDC5 is increased during myogenic differentiation
In primary cultured human cells, myotube FNDC5 mRNA level was approximately 500 times higher compared with stromal vascular cells or adipocytes (Figure 1a). Also, the FNDC5 mRNA level in mature adipocytes was significantly lower than in stromal vascular cells. As myocytes undergo cell differentiation to become myotubes, the change in FNDC5 expression was monitored during myogenic differentiation. FNDC5 mRNA level was dramatically upregulated at early time points during differentiation, peaking at day 5 and reaching a plateau from day 8 onward (Figure 1b). This expression pattern was similar to those of myogenin and PGC1α, although the magnitude of FNDC5 increase was smaller, whereas another myokine IL-6 had no related pattern. In contrast to the early increase in FNDC5 mRNA levels, irisin secretion in the media was not increased until day 8 (Figure 1c). Following the pattern of gene expression level, IL-6 secretion was decreased until day 5 and significantly increased again at day 8. Basal irisin levels were higher than IL-6 in the media.
Irisin regulates genes related to muscle hypertrophy
To examine the hypothesis that irisin could regulate muscle growth, HSMCs were treated with low and high physiological doses of irisin (0, 10 and 50 nM irisin) for different time periods (2, 6 and 24 h). Gene expression analysis showed that at 6 and 24 h after treatment, irisin dose-dependently increased IGF1 and decreased myostatin mRNA levels (Figure 2a and Supplementary Figure 1), the two main factors for muscle growth. This was accompanied by upregulation of PGC1α4, their upstream regulator, confirming the positive effect of irisin treatment on muscle growth. It is interesting to note that 2 h treatment of irisin significantly upregulated FNDC5 expression (Supplementary Figure 1), but followed by significant reduction of FNDC5 and its upstream mediator, PGC1α, at 6 and 24 h.
Irisin regulates muscle growth through ERK pathway
Signaling studies in adipocytes have showed that the browning effect of irisin was mediated through p38 MAPK and ERK but not Akt pathway.13 In HSMCs, we observed that, similar to adipocytes, ERK was significantly phosphorylated as early as 10 min after irisin stimulation (Figure 2b), whereas phosphorylation of Akt was unaltered (Figure 2c). To confirm whether the growth-related gene induction was mediated through ERK, HSMCs were pretreated with ERK inhibitor (U0126). As a result, ERK inhibitor significantly reversed the induction of PGC1α4 and IGF1 gene expression (Figure 2d).
Irisin inhibits adipocyte differentiation in human and mouse adipocytes
In addition to the novel role of irisin on muscle growth, we next sought to examine the role of irisin on adipocyte metabolism. First, to investigate the effect of irisin on preadipocyte differentiation, stromal vascular cells from human subcutaneous adipose tissue were treated with low (10 nM) or high (50 nM) physiological concentrations of recombinant irisin throughout the differentiation period. As a result, irisin inhibited the lipid accumulation (Figure 3a), along with significantly reduced gene/protein expressions of adipocyte protein 2 (aP2), PPARγ and fatty acid synthase (FAS; Figures 3b–f). In mouse adipocytes, similar results were observed (Supplementary Figure 2). Comparing the effects of irisin and FNDC5 on mouse adipocytes showed that irisin exerted a more potent effect on the inhibition of differentiation. In addition, the reduced protein expression of aP2 and PPARγ, and gene expression of aP2, CCAAT/enhancer-binding protein α (C/EBPα), PPARγ and adiponectin by both irisin and FNDC5 were partially reversed by rosiglitazone supplementation during differentiation, suggesting that suppression of preadipocyte differentiation by irisin/FNDC5 is influenced, at least in part, via PPARγ-dependent mechanisms (Supplementary Figure 2).
Irisin alters metabolic gene expression in human adipocytes
FNDC5 treatment has been reported to induce ‘browning’ genes in mouse adipocytes.7 To expand, mature human adipocytes were treated with irisin in a time course of 8 days, and genes regulating adipocyte function were examined. The adipocytes were fully differentiated before treatment to exclude the effect of irisin on preadipocyte differentiation. As shown in Figure 4a, browning genes, including UCP1, PRDM16 and CIDEA, were induced the most after 8 days of treatment, and ELDVL3 after 2 days of treatment. Expression of adipokines and mitochondrial biogenesis-related genes was also increased by 4 and/or 8 days of irisin treatment (Figures 4b and c). Interestingly, genes encoding proteins involved in glucose and lipid metabolism, including GLUT4, CPT1a, PPARα and HSL, were also significantly increased (Figure 4d).
Irisin affects mature human adipocyte metabolism
In line with the transcriptional changes, irisin treatment induced UCP1 protein expression in human adipocytes (Figure 5a). As a result, intracellular ATP levels were depleted by irisin treatment, comparable to the effect of the oxidative phosphorylation uncoupler FCCP (Figure 5d). Morphological and colorimetric analyses revealed that irisin-treated adipocytes were smaller (Figure 5b) with less amount of lipid accumulation (Figure 5c). Because of limited oxidative respiration by uncoupling in the mitochondria, the glycolytic pathway was significantly induced in cells treated with 50 nM irisin, as determined by the secretion of lactate in the media (Figure 5e). Analysis of free fatty acid and glycerol secretion in the media revealed that irisin not only inhibited basal lipolysis but also isoproterenol-induced lipolysis in human adipocytes (Figures 5f and g). In view of elevated lipid utilization by browning, a reduction in lipolytic rate may seem unlikely. However, regarding the overall low lipid content of irisin-treated cells, adipocytes may have had lower output of lipids. Moreover, western blot results showed that adipose triglyceride lipase (ATGL) was increased, whereas FAS was decreased by irisin treatment (Figure 5a), implying that through induction of UCP1, irisin breaks down stored fat to be used for intracellular metabolism and at the same time inhibits the synthesis of lipids.
Irisin alters metabolite profile of human adipocytes
To add another dimension, changes in metabolites were analyzed. Relative changes in metabolites by irisin treatment are shown in Figure 6a. It is interesting to note that acetoacetyl-CoA, a product of fatty acid degradation, and some of the key intermediates of the tricarboxylic acid cycle, namely citric acid, cis-aconitic acid and isocitric acid, were elevated by irisin treatment. Metabolite set enrichment analysis showed that pathways related to glucose and lipid metabolism were largely enhanced (Figure 6b). Amino acid pathways were also affected by irisin treatment. The metabolome view confirmed that irisin causes profounding effects in adipocyte metabolism and therefore coincide with the functional data observed.
The discovery of irisin has pointed to a novel pathway for energy homeostasis and opened an opportunity for development of novel pharmaceutical compounds to treat metabolic diseases. Although a mouse study has revealed the beneficial role of irisin on systemic metabolism, which type of tissue or organs are affected by irisin and what the underlying mechanisms are remain largely unknown. Here, we provided evidence for the pleiotropic effect of irisin on not only adipocyte but also myocyte metabolism. The main findings are that (i) irisin secretion and FNDC5 mRNA expression is upregulated during myocyte differentiation, (ii) irisin induces expression of PGC1α4 and IGF1, and represses myostatin gene expression through ERK pathway, (iii) irisin not only shifts the gene expression and metabolic profile of mature human adipocytes toward increased energy expenditure but also inhibits differentiation of preadipocytes. Therefore, irisin exerts different benefits in various cell types, which could benefit not only obesity-related metabolic diseases but also muscle disorders.
Our results from human adipocytes clearly show at transcriptional, translational and metabolite level that irisin can induce browning and regulate energy homeostasis. Along with UCP1 induction and depletion of intracellular ATP levels, irisin turns on the mechanism to enhance energy circulation in adipocytes, as evidenced by upregulation in intermediates of citric acid cycle and lactate production. Increased ATGL may indicate that irisin is able to induce ‘melt down’ of stored fat but on the otherhand, reduced extracellular levels of fatty acids and glycerol by irisin treatment may imply that irisin is able to preserve adipocytes from ‘leaking’ deleterious lipids into other peripheral organs. It remains uncertain exactly how irisin regulates adipocyte metabolism, but the previous study suggested p38 MAPK and ERK to be the signaling target of irisin in mouse/rat adipocytes. Whether the same signaling pathway could be applied in humans remains to be further studied in detail.
Although a previous study has found that irisin has no effect on mouse preadipocyte differentiation,7 we have discovered a significant inhibitory effect of irisin on both human and mouse preadipocyte differentiation. This is somewhat surprising, as factors known to induce browning, such as bone morphogenetic protein 7, have been reported to accelerate preadipocyte differentiation.24 However, given that irisin promotes energy expenditure in mature adipocytes and inhibits lipid accumulation, it seems reasonable that preadipocytes are prohibited from accumulating lipids. This may be of value as dual role of irisin in anti-obesity effect, by inhibiting adipocyte formation and increasing metabolic rate in mature adipocytes.
Studies have implicated the possibility of irisin production from tissues other than skeletal muscle, such as white adipose tissue,25,26 cardiac muscle27 or neurons,28,29 in rodents and partly in humans. Our results from human myocytes demonstrate that FNDC5 gene expression level is much higher than adipocytes and that FNDC5 gene expression and irisin secretion is regulated during myocyte differentiation in humans. Further study is needed to dissect what percentage of circulating irisin is derived from skeletal muscle and whether other organs are also capable of irisin secretion in humans.
Myokines are key molecules in crosstalk between muscle and other metabolic organs, but many of the myokines are also known to exert autocrine/paracrine effect. For example, IL-15, which is also mainly expressed in muscle, has been reported to inhibit lipid accumulation and induce adiponectin secretion in adipocytes and also induce glucose/insulin sensitivity in muscle.6,30 Likewise, independent from the results on adipocyte browning, we provide evidence for the first time on irisin-induced muscle growth through increased IGF1 and decreased myostatin levels in a dose-dependent manner. Ruas et al.31 have recently shown that resistance exercise induces a novel isoform of PGC1α, PGC1α4, to mediate muscle hypertrophy. In line with this observation, PGC1α4 mRNA level was significantly increased by irisin treatment and regulated the downstream molecules, IGF1 and myostatin. IGF1 is a positive regulator and myostatin is a negative regulator of muscle growth17 and thus regulation of these genes by irisin imply that irisin could be mediating the effect of exercise that primarily act on enhancing muscle mass and strength. Study in myostatin knockout mice has led us to think that irisin could be related to IGF1-myostatin system and moreover, to muscle hypertrophy. Although the previous study suggested that lack of myostatin induces FNDC5 expression,16 our data claim that increased irisin could inhibit myostatin, implying a bilateral effect. Studies in humans so far have not observed a significant increase in either circulating irisin or muscle FNDC5 mRNA expression by resistance exercise,32,33 but the possibility remains that the local concentration of irisin could be much higher post-exercise, which would enable the autocrine/paracrine effect of irisin. The transcriptional effects observed in this study should be confirmed by protein expression and phenotypic changes in muscle.
Interestingly, irisin treatment resulted in upregulation of FNDC5 at 2 h, whereas more long-term treatment (6 and 24 h) resulted in downregulation of FNDC5 and PGC1α mRNA levels. Although direct evidence is needed, we speculate that exogenous stimulation may result in a negative feedback loop to decrease its endogenous expression. In the initial publication, it has been suggested that PGC1α is an upstream regulator of irisin, but now that several isoforms of PGC1α has been discovered,31 it has to be dissected which isoforms are responsible for irisin/FNDC5 regulation.
The present study has limitations in connecting the role of irisin in muscle growth and the benefits in the adipocytes. Although our results in vitro adds value to the therapeutic potential of irisin, whether irisin treatment can systematically ameliorate metabolic dysregulation needs to be studied in long-term in vivo studies. Especially, whether irisin-induced muscle gene expression results in translational/functional change in muscle needs to be examined. Assessing the direct cause-effect relationship between irisin treatment and metabolic effects will largely progress when genetically engineered mouse models for FNDC5 are developed. Discovery of the irisin receptor would also largely contribute to understanding the biological function of irisin in not only adipocytes but also other metabolic organs such as liver and pancreas.
In conclusion, we have explored the therapeutic potential of irisin on human cells and found that irisin could regulate muscle growth as well as adipocyte metabolism. The molecular, biochemical and metabolomic data on the effect of physiological doses of irisin have contributed in understanding the nature of irisin in humans. Although irisin may not replace the beneficial effects of exercise, it would still be an attractive tool for treating metabolic diseases and muscle disorders considering its effects on human adipocytes and myocytes.
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JYH researched data and wrote the manuscript. FD and EM researched data and reviewed the manuscript. CM designed the studies, supervised laboratory measurements and reviewed/edited the manuscript.
JYH is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
This study was supported by Award Number 1I01CX000422-01A1 from the Clinical Science Research and Development Service of the VA Office of Research and Development.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on International Journal of Obesity website
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Huh, J., Dincer, F., Mesfum, E. et al. Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans. Int J Obes 38, 1538–1544 (2014). https://doi.org/10.1038/ijo.2014.42
- muscle hypertrophy
- adipocyte browning
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