FNDC5 Gene Research Articles

Unravelling the maternal stress-induced orchestrations: Fndc5 gene expression dynamics across duodenum, stomach, and whole blood in offspring

Objective: Maternal stress is a known risk factor for a variety of adverse outcomes in offspring, including metabolic and behavioural abnormalities. The hormone irisin, encoded by the Fndc5 gene, is believed to mediate stress’s effects on metabolism. Two weeks of restraint stress causes stomach inflammation and increases oxidative stress in rodents. Irisin, coded by the Fndc5 gene, probably suppresses this oxidative stress. In this study, we examined the effect of early-life maternal stress on Fndc5 gene expression in the duodenum, stomach and whole-blood offspring. Materials and Methods: This study consists of three groups: a control, an unpredictable maternal separation (MS), and an unpredictable maternal separation combined with unpredictable maternal stress (MSUS). On postnatal (PND) days 1-14, randomly three hours a day, MS and MSUS were exposed to unpredictable maternal separation. MSUS was subjected to extra unpredictable maternal stress. Mice were sacrificed on PND35. Total RNA was isolated from duodenum, stomach, and whole blood samples by Phenol-Chloroform technique, and HiScript II 1st Strand cDNA Synthesis Kit was used for cDNA synthesis. Fndc5 and Gapdh genes expression level was measured by qPCR using FastStart Universal SYBR Green Master. The data obtained were analyzed using One-Way ANOVA tests in GraphPad Prism. Results: Fndc5 gene expression did not differ between groups in the duodenum (p>0.05), significantly increased in the MSUS group compared to the control (female p=0.0089, male p=0.0053) and MS (female p=0.0206, male p=0.026) groups in the stomach. In whole blood samples, it decreased in MS and MSUS group males (p=0.0011). In addition, a significant negative correlation (p= 0.0003) has been established between the stomach and whole blood. Conclusion: The findings assert the role of irisin in transmitting stress-related effects on metabolism, emphasizing the therapeutic potential of targeting the Fndc5 gene in preventing and treating stress-related disorders.

Mir-150-5p inhibits the osteogenic differentiation of bone marrow-derived mesenchymal stem cells by targeting irisin to regulate the p38/MAPK signaling pathway

PurposeTo study the effect of miR-150-5p on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs), and further explore the relationship between its regulatory mechanism and irisin.MethodsWe isolated mouse BMSCs, and induced osteogenic differentiation by osteogenic induction medium. Using qPCR to detect the expression of osteogenic differentiation-related genes, western blot to detect the expression of osteogenic differentiation-related proteins, and luciferase reporter system to verify that FNDC5 is the target of miR-150-5p. Irisin intraperitoneal injection to treat osteoporosis in mice constructed by subcutaneous injection of dexamethasone.ResultsUp-regulation of miR-150-5p inhibited the proliferation of BMSCs, and decreased the content of osteocalcin, ALP activity, calcium deposition, the expression of osteogenic differentiation genes (Runx2, OSX, OCN, OPN, ALP and BMP2) and protein (BMP2, OCN, and Runx2). And down-regulation of miR-150-5p plays the opposite role of up-regulation of miR-150-5p on osteogenic differentiation of BMSCs. Results of luciferase reporter gene assay showed that FNDC5 gene was the target gene of miR-150-5p, and miR-150-5p inhibited the expression of FNDC5 in mouse BMSCs. The expression of osteogenic differentiation genes and protein, the content of osteocalcin, ALP activity and calcium deposition in BMSCs co-overexpressed by miR-150-5p and FNDC5 was significantly higher than that of miR-150-5p overexpressed alone. In addition, the overexpression of FNDC5 reversed the blocked of p38/MAPK pathway by the overexpression of miR-150-5p in BMSCs. Irisin, a protein encoded by FNDC5 gene, improved symptoms in osteoporosis mice through intraperitoneal injection, while the inhibitor of p38/MAPK pathway weakened this function of irisin.ConclusionmiR-150-5p inhibits the osteogenic differentiation of BMSCs by targeting irisin to regulate the/p38/MAPK signaling pathway, and miR-150-5p/irisin/p38 pathway is a potential target for treating osteoporosis.

The Effect of Hypoxia on Irisin Expression in HL-1 Cardiomyocytes.

Cardiovascular diseases (CVD) are the leading cause of death worldwide. In 2019, 523 million people were diagnosed with CVD, with 18.6 million deaths. Improved treatment and diagnostics could reduce CVD's impact. Irisin (Ir) is crucial for heart function and may be a biomarker for heart attack. Ir is a glycoprotein with sugar residues attached to its protein structure. This glycosylation affects Ir stability, solubility, and receptor interactions on target cells. Its secondary structure includes a fibronectin type III domain, essential for its biological functions. Ir helps cardiomyocytes to respond to hypoxia and protects mitochondria. The aim of the study was to determine the FNDC5 gene expression level and the Ir level in HL-1 cardiomyocytes subjected to hypoxia. We examined the effect of hypoxia on the expression levels of the FNDC5 gene and those of Ir in mouse cardiomyocytes of the HL-1 cell line. Real-time PCR (RT-PCR) was used to estimate the expression levels of the FNDC5 gene. Western blot and immunofluorescence methods were used to analyze the Ir protein levels. Analyses showed an increased Ir level in HL-1 cardiomyocytes in response to hypoxia. This is the first study to confirm the presence of Ir in HL-1 cells. The observed increase in Ir expression in murine cardiomyocytes is associated with the hypoxic environment and can be potentially used to diagnose hypoxia and CVD.

The integrated analysis and underlying mechanisms of FNDC5 on diabetic induced cognitive deficits.

Chronic hyperglycemia is considered as an important factor to promote the neurodegenerative process of brain, and the synaptic plasticity as well as heterogeneity of hippocampal cells are thought to be associated with cognitive dysfunction in the early process of neurodegeneration. To date, fibronectin type III domain-containing protein 5 (FNDC5) has been highlighted its protective role in multiple neurodegenerative diseases. However, the potential molecular and cellular mechanisms of FNDC5 on synaptic plasticity regulation in cognitive impairment (CI) induced by diabetics are still need to known. To investigate the heterogeneity and synaptic plasticity of hippocampus in animals with CI state induced by hyperglycemia, and explore the potential role of FNDC5 involved in this process. Firstly, the single cell sequencing was performed based on the hippocampal tissue from db diabetic mice induced CI and normal health control mice by ex vivo experiments; and then the integrated analysis and observations validation using Quantitative Real-time PCR, western blot as well as other in vitro studies. We observed and clarified the sub-cluster of type IC spiral ganglion neurons expressed marker genes as Trmp3 and sub-cluster of astrocytes with marker gene as Atp1a2 in hippocampal cells from diabetic animals induced CI and the effect of those on neuron-glial communication. We also found that FNDC5\BDNF-Trk axis was involved in the synaptic plasticity regulation of hippocampus. In high glucose induced brain injury model in vitro, we investigated that FNDC5 significantly regulates BDNF expression and that over-expression of FNDC5 up-regulated BDNF expression (p<0.05) and can also significantly increase the expression of synapsin-1 (p<0.05), which is related to synaptic plasticity, In addition, the unbalanced methylation level between H3K4 and H3K9 in Fndc5 gene promoter correlated with significantly down-regulated expression of FNDC5 (p<0.05) in the hyperglycemia state. The current study revealed that the synaptic plasticity of hippocampal cells in hyperglycemia might be regulated by FNDC5\BDNF-Trk axis, playing the protective role in the process of CI induced by hyperglycemia and providing a target for the early treatment of hyperglycemia induced cognitive dysfunction in clinic.

Treadmill exercise with nanoselenium supplementation affects the expression of Irisin/FNDC5 and semaphorin 3A in rats exposed to cigarette smoke extract.

In the current study, we investigated the impacts of 6 weeks of aerobic interval training (AIT) with selenium nanoparticles (SeNPs) on muscle, serum, and lung irisin (FNDC5) and Sema3A in rats exposed to cigarette smoke extract (CSE). To this end, 49 male Wistar rats (8 weeks old) were divided into seven groups: control, SeNPs (2.5mg/kg b.w by oral gavage, 3days/week, 6weeks), AIT (49min/day, 5days/week for 6weeks, interval), SeNPs + AIT, CSE (150 µL by IP injection, 1day/week for 6weeks), CSE + AIT, and CSE + SeNPs + AIT. The CSE group showed a significant reduction in irisin and Sema3A serum levels, as well as a decrease in FNDC5 and Sema3A gene expression in lung tissue (p < 0.05). A combined treatment (AIT with SeNPs) significantly increased the serum level and the expression of muscle and lung irisin (FNDC5) and Sema3A in CSE received groups (p < 0.05). There was a positive and significant correlation between muscle FNDC5 and lung FNDC5 in the CSE + SeNPs + AIT group (r = 0.92, p = 0.025). In addition, there was a positive and significant correlation between serum Sema3A and lung Sema3A of CSE + SeNPs + AIT group (r = 0.97, p = 0.004). Seemingly, performing aerobic exercises with the antioxidant and anti-inflammatory supplement nano-selenium in the model of lung damage (similar to COPD) can boost myokine irisin and Sema3A, especially in serum and lung tissue. These results displayed the paracrine/endocrine regulatory function of these myokines on other tissues. In other words, these interventions emphasized the creation of crosstalk between skeletal muscles and damaged lung, focusing on its recovery; however, further research is needed.

FNDC5 Geni Polimorfizmleri, Serum İrisin Düzeyleri ve Alerjik Rinit Arasındaki İlişkinin Yokluğu

Aim: Allergic rhinitis (AR) is an inflammatory nasal mucosa disease caused by type 1 immunoglobulin E-mediated reactions to allergen exposure. Irisin is a hormone released by skeletal muscles in response to exercise. There are studies that demonstrate the relationship of irisin with inflammation. We aimed to investigate the potential association between irisin coding fibronectin type III domain 5 (FNDC5) gene polymorphisms, serum irisin levels, and AR. Method: A case-control study was designed, involving 100 AR patients and 100 healthy controls. Genotyping of rs726344 and rs1746661 SNPs within the FNDC5 gene was performed using PCR-RFLP method. Serum irisin levels were measured using ELISA. Results: Genotyping of rs726344 SNP in patients revealed 90% GG and 10% GA genotypes, while in controls, it was 94% GG and 6% GA. The AA genotype was not detected in any case. For rs1746661 SNP, patients had 57% GG, 39% GT, and 4% TT genotypes, while controls had 58% GG, 36% GT, and 6% TT genotypes. No significant difference was found in rs726344 and rs1746661 SNPs between the patients and the control group. Serum irisin level was 406.3±56.09 ng/ml in patients and 354.3±46.06 ng/ml in controls with no significant difference. Conclusion: This is the first study aiming to investigate the relationship between the irisin protein, its encoding gene, and AR. No significant association was identified between FNDC5 gene polymorphisms, serum irisin levels, and allergic rhinitis. While these findings suggest a limited role of these factors in AR, further studies are needed for more comprehensive understanding of the irisin-AR relationship.

AAV-mediated skeletal muscle specific irisin expression does not contribute to weight loss in mice

Obesity, a chronic disease, significantly increases the risk of various diseases, including diabetes, cardiovascular diseases, and cancers. Exercise is crucial for weight management not only through energy expenditure by muscle activity but also through stimulating the secretion of myokines, which affect various tissues. Irisin, derived from the proteolytic processing of fibronectin type III domain-containing protein 5 (Fndc5), is a well-studied myokine with beneficial effects on metabolism. This study explored the feasibility of adeno-associated virus (AAV)-mediated Fndc5 gene therapy to treat obesity in a mouse model using the AAV-DIO system to express Fndc5 specifically in skeletal muscle, and investigated its anti-obesity effect. Although Fndc5 was specifically expressed in the muscle, no significant impact on body weight under normal chow or high-fat diets was observed, and no change in thermogenic gene expression in inguinal white adipose tissue was detected. Notably, Fndc5 transduction did affect bone metabolism, consistent with previous reports. These findings suggest that AAV-mediated Fndc5 gene therapy may not be an efficient strategy for obesity, contrary to our expectations. Further research is needed to elucidate the complex mechanisms involved in irisin's role in obesity and related disorders.

High-Intensity Interval Training’s Effect on Cognitive Functions

HIIT has been known to improve cognitive function. In addition to its effect on the hippocampal area. After HIIT training, BDNF levels also increase in the spinal cord, cerebellum and several cortical areas through increasing levels of Insulin-like Growth Factor-1 (IGF-1). In neurons, BDNF is present not only in the cytoplasm, but also near the dendritic spines, which influences their development. BDNF stimulates the process of neuroplasticity, which is manifested in neurogenesis, stimulation of the plasticity of serotoninergic, dopaminergic, cholinergic or noradrenergic neurons, dendritogenesis, and synaptogenesis. Moreover, BDNF facilitates the growth and survival of neurons and microglial cells. It also participates in cell differentiation, potentiation of signal transmission, induction, and maintenance of long-term potentiation of the synapse enhancement. Because of these properties, BDNF enhances cognition and takes part in emotional processes, spatial orientation and learning, as well as body coordination. Evidence suggests that IGF-1 is a major determinant of the effect of physical exercise on BDNF levels and thus on cognition more generally. There is an upregulation of Fndc5 gene expression in skeletal muscle and an increase in irisin after prolonged resistance training in rats and humans following HIIT training. When hippocampal Fndc5 was upregulated during exercise, BDNF and other neuroprotective genes were also activated in the rat hippocampus. Exercise-induced adult hippocampal neurogenesis is associated with increased Fndc5 and BDNF genes thus enhancing cognition. Then, stroke is associated with neuroinflammation that affects the processes of neuroplasticity in the lesion core, penumbra and small areas such as the spinal cord.

The Preventive Effect of Specific Collagen Peptides against Dexamethasone-Induced Muscle Atrophy in Mice.

Muscle atrophy, also known as muscle wasting, is the thinning of muscle mass due to muscle disuse, aging, or diseases such as cancer or neurological problems. Muscle atrophy is closely related to the quality of life and has high morbidity and mortality. However, therapeutic options for muscle atrophy are limited, so studies to develop therapeutic agents for muscle loss are always required. For this study, we investigated how orally administered specific collagen peptides (CP) affect muscle atrophy and elucidated its molecular mechanism using an in vivo model. We treated mice with dexamethasone (DEX) to induce a muscular atrophy phenotype and then administered CP (0.25 and 0.5 g/kg) for four weeks. In a microcomputed tomography analysis, CP (0.5 g/kg) intake significantly increased the volume of calf muscles in mice with DEX-induced muscle atrophy. In addition, the administration of CP (0.25 and 0.5 g/kg) restored the weight of the gluteus maximus and the fiber cross-sectional area (CSA) of the pectoralis major and calf muscles, which were reduced by DEX. CP significantly inhibited the mRNA expression of myostatin and the phosphorylation of Smad2, but it did not affect TGF-β, BDNF, or FNDC5 gene expression. In addition, AKT/mTOR, a central pathway for muscle protein synthesis and related to myostatin signaling, was enhanced in the groups that were administered CP. Finally, CP decreased serum albumin levels and increased TNF-α gene expression. Collectively, our in vivo results demonstrate that CP can alleviate muscle wasting through a multitude of mechanisms. Therefore, we propose CP as a supplement or treatment to prevent muscle atrophy.

Irisin expression and FNDC5 (rs3480) gene polymorphism in type 2 diabetic patients with and without CAD

Background Irisin was found to correlate with coronary artery disease (CAD) in diabetic patients. This study investigated the association of irisin and FNDC5 (SNP rs3480) with the presence and severity of CAD in T2DM. Methods This cross-sectional study included 100 patients with T2DM divided into two groups, DM group (n = 50), including patients without CAD and CAD group (n = 50), including those confirmed to have CAD by coronary angiography. Irisin was measured. SNP rs3480 genotyping of FNDC5 was done. Results Irisin levels were significantly lower in the CAD group (p < 0.001). The CAD group had significantly higher HbA1c and lower HDL (p < 0.001). Patients with controlled DM had significantly higher irisin levels (p < 0.001). single nucleotide polymorphism (SNP) rs3480 was not associated with irisin levels, and the FNDC5 rs3480 AA reference allele was significantly associated with significant CAD. Conclusion Irisin appears to be protective against developing CAD in diabetic patients. Irisin level was an independent predictor of significant CAD in diabetic patients combined with the FNDC5 rs3480 genotype. Clinical trial registration number NCT04957823

Central irisin signaling is required for normal timing of puberty in female mice.

Timing of puberty requires exquisite coordination of genes, hormones and brain circuitry. An increasing level of body adiposity, signaled to the brain via the fat-derived hormone leptin, is recognized as a major factor controlling puberty onset. However, it is clear that leptin is not the only metabolic cue regulating puberty, and that developmental regulation of this process also involves tissues other than adipose, with muscle development potentially playing a role in the timing of puberty. The proteolytic processing of fibronetin type 2 domain-containing protein 5 (FNDC5) releases a hormone, irisin. Irisin is primarily produced by muscle and is released into circulation, where levels increase dramatically as puberty approaches. We investigated the effects of a global deletion of the Fndc5 gene on pubertal timing. The absence of irisin induced a delay in puberty onset in female knockout mice compared with controls, without affecting body weight or GnRH neuronal density. We next treated pre-pubertal wild-type male and female mice with an irisin receptor antagonist, cilengitide, for 7 days and observed a delay in first estrus occurrence compared to vehicle-treated control mice. Male puberty timing was unaffected. Next, we deleted the irisin receptor (integrin subunit alpha V) in all forebrain neurons and found a delay in the occurrence of first estrus in knockout females compared to controls. Taken together, these data suggest irisin plays a role in the timing of puberty onset in female mice via a centrally-mediated mechanism.

Association of Irisin/FNDC5 with ERRα and PGC-1α Expression in NSCLC.

The rapid growth and division of cancer cells are associated with mitochondrial biogenesis or switching to glycolysis. ERRα, PGC-1α and irisin/FNDC5 are some of the proteins that can influence these processes. The aim of this study was to determine the correlation of these proteins in non-small cell lung cancer (NSCLC) and to investigate their association with clinicopathological parameters. Immunohistochemistry reactions were performed on tissue microarrays (860 NSCLC, 140 non-malignant lung tissue). The normal fibroblast cell line (IMR-90) and lung cancer cell lines (NCI-H1703 and NCI-H522) were used as co-cultures. The mRNA levels of FNDC5 and ESRRA (encoding ERRα) were assessed in IMR-90 cells after co-culture with lung cancer cells. We observed a decreased level of ERRα with an increase in tumor size (T), stages of the disease, and lymph node metastases (N). In the adenocarcinoma (AC) subtype, patients with a higher ERRα expression had significantly longer overall survival. A moderate positive correlation was observed between FNDC5 mRNA and ESRRA mRNA in NSCLCs. The expression of FNDC5 mRNA in IMR-90 cells increased after 24 h, and ESRRA gene expression increased after 48 h of co-culture. The ERRα receptor with PGC-1α participates in the control of FNDC5/irisin expression. Normal fibroblasts revealed an upregulation of the FNDC5 and ESRRA genes under the influence of lung cancer cells.

Role of FNDC5 gene polymorphism in patients with diabetic nephropathy

Role of FNDC5 gene polymorphism in patients with diabetic nephropathy

The Effects of Irisin Hormone and the FNDC5 Gene on Brain Functions and Exercise: A Systematic Review

Introduction: The aim of this systematic review was to regroup all systematic reviews, non-systematic reviews and all original articles between 2017 and 2021 (including June) into one convenient publication that would facilitate the theoretical and applied scientific investigations directed on the efficacy of exercise and brain function on irisin hormone and FNDC5 gene. Evidence Acquisition: The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) method. A computer-based systematic search was conducted in July 2021 through Google Scholar, Pub Med, and Science Direct databases. The reliability of the systematic research was ensured by completely repeating the article selection process by a second author. Evidence Synthesis: Twenty-six articles that met the criteria out of 279 articles obtained specifically for keywords were included in the review. Results show that together with different types of exercise, irisin and FNDC5 may be new biomarkers that should be considered in reducing neurodegenerative disorders and improving neuromuscular and brain functions. Conclusion: Based on the articles included in this review, increasing the number of studies examining the potential of short and long-term exercises to stimulate irisin and FNDC5 gene in the future may help to understand the effects of exercise on Irisin and FNDC5 mediated brain functions. Keywords: Irisin, FNDC5, exercises.

FNDC5/irisin facilitates muscle−adipose−bone connectivity through ubiquitination-dependent activation of runt-related transcriptional factors RUNX1/2

In the past decade, the cleavage protein irisin derived from fibronectin type III domain–containing protein 5 (FNDC5) in exercise-stimulated skeletal muscle has increasingly become a biomarker associated with metabolic syndrome and osteoporosis in humans. However, it is unclear how this protein facilitates muscle−adipose−bone connectivity in metabolic and skeletal homeostasis. In this study, we unexpectedly observed that the FNDC5 gene can be markedly activated during the differentiation of brown adipocytes but not white adipocytes, and that FNDC5 is specifically expressed in mouse brown adipose tissues (BATs). But unlike it in the skeletal muscles, the expression of FNDC5/irisin in BAT is promoted by cold exposure rather than exercise in mice. Analysis of promoter activity and chromatin immunoprecipitation further showed that peroxisome proliferator–activated receptor γ coactivator-1α and thyroid hormone receptors cooperate on the FNDC5 gene promoter to induce its transcription. We found that FNDC5/irisin stimulates the runt-related transcriptional factors RUNX1/2 via a focal adhesion kinase–dependent pathway in both bone and subcutaneous white adipose tissues. Mechanistically, focal adhesion kinase is stimulated by FNDC5/irisin and then facilitates E3 ubiquitin–protein ligase WW domain–containing protein 2 to ubiquitinate and subsequently activate RUNX1/2, culminating in the activation of osteoblast-related or thermogenesis-related genes. Interestingly, the PR domain containing protein 16 that is crucial for subcutaneous white adipose “browning” and skeletal development was found to form a complex with RUNX1/2 in a WW domain–containing protein 2-dependent manner. These findings elucidate a signaling mechanism by which FNDC5/irisin supports the muscle−adipose−bone connectivity, especially BAT−bone connectivity.

Increased serum myonectin and irisin levels with myonectin and FNDC5 expressions in polycystic ovary syndrome: a case control study

The aim of this study is to assess the FNDC5 and myonectin expressions and serum levels of myonectin and irisin in women with PCOS. 90 participants were included in this case-control study. 45 of these participants were with PCOS, and 45 of them were healthy volunteers matched for age and body mass index (BMI). Serum irisin and myonectin levels were measured with commercially available enzyme-linked immune sorbent assay (ELISA) kits. Expression of the myonectin and FNDC5 genes were determined by RT-PCR analysis. It was found out that FSI, HOMA-IR, LH, LH/FSH, TT, serum irisin and serum myonectin levels, myonectin mRNA expression, and FNDC5 mRNA expression were higher in the PCOS group, whereas HDL-C level was lower in the PCOS group (p < .05). When the groups were compared, it was detected that IR and HA were significantly higher in the PCOS group (p < .05). Serum irisin and myonectin levels, and myonectin and FNDC5 mRNA expressions were increased in women with PCOS. These molecules can be target molecules in PCOS pathophysiology and treatment. IMPACT STATEMENT What is already known on this subject? Although the aetiology of PCOS is not fully understood, it is thought that insulin resistance may play a critical role. In recent studies, the relationship of cytokines secreted from skeletal muscle with insulin resistance has been shown. The effects of irisin and myonectin, which are members of the myokine family, on lipid and glucose metabolism are known. What do the results of this study add? Although there are many studies in the literature regarding serum irisin levels in women with PCOS, their results are confusing. There is a study in the literature investigating the relationship between myonectin and PCOS. In our study, we evaluated myonectin and FNDC mRNA expressions in addition to serum irisin and myonectin levels. As a result, we found that markers and their mRNA expressions were lower in patients with PCOS compared to controls. What are the implications of these findings for clinical practice and/or further research? We think that the results of our study will shed light on future studies. Due to their effects on adipose tissue, these markers may play a role in the aetiology of long-term complications of PCOS. Moreover, they can become pharmacological targets in preventing these complications.

FNDC5 induces M2 macrophage polarization and promotes hepatocellular carcinoma cell growth by affecting the PPARγ/NF-κB/NLRP3 pathway

PurposeThe purpose of this study was to investigate the effect of FNDC5 expression levels in hepatocellular carcinoma on the phenotypic changes of macrophages in tumor tissues. MethodsIn this study, we established an in vitro co-culture system of hepatocellular carcinoma cells and macrophages. Then we performed overexpression or knockdown of FNDC5 gene in hepatocellular carcinoma cells to observe the effect of changes in FNDC5 expression level on the phenotypic changes of THP-1 macrophages. And the conclusions obtained in the in vitro assay were further validated by a subcutaneous tumorigenic nude mice model. ResultsOur findings suggest that elevated FNDC5 expression in hepatocellular carcinoma cells lead to an increased M2 phenotype and decreased M1 phenotype in macrophages. This effect may be achieved by elevating PPARγ levels in macrophages while decreasing NF-κB and NLRP3 levels. These changes could be reversed by using PPARγ inhibitors. ConclusionWe preliminarily demonstrated that FNDC5 in hepatocellular carcinoma cells promotes the polarization of M2 macrophages by affecting the PPARγ/NF-κB/NLRP3 pathway.

Effect of Eight Weeks Caffeine Supplementation and High Fat Diet on PGC1-α, Fndc-5 and UCP-1 Gene Expression in Male Wistar Rats

Effect of Eight Weeks Caffeine Supplementation and High Fat Diet on PGC1-α, Fndc-5 and UCP-1 Gene Expression in Male Wistar Rats

AN OVERVIEW OF THE EFFECTS OF IRISIN ON METABOLIC DISORDERS

Obesity and obesity-related diseases including insulin resistance and metabolic syndrome (MetS) pose a great risk for cardiovascular diseases development. Skeletal muscle as an endocrine organ has pivotal role on secreting physiological factors such as hormones and myokines. Irisin that is one of these miyokines also known as hormone is secreted mainly from muscle tissue in response to exercise. It is dependent to fibronectin type III-containing protein 5 (FNDC5) that is a membran protein and encoded by FNDC5 gene. After discovering of FNDC5 by Boström et al., irisin’ metabolic effects have been investigated so far. Irisin has mainly effects on muscle, adipose tissue, pancreas, liver, nervous system and bone. In studies conducted to date, obtained findings regarding the relationship of irisin status with obesity, insulin resistance and MetS are contradictory. Although it was determined that irisin concentration is higher in individuals with metabolic disorders before mentioned in some studies, is lower irisin concentration were observed in some other studies. Additionally, the irisin molecule has no a receptor yet discovered. Therefore it is thought that the discovery of irisin molecule receptors and the determining of the tissues where these receptors are present will be useful in understanding the mechanism of action of the irisin. In this review, we aimed to investigate potential health effects of irisin on obesity, insulin resistance and MetS additionally examine underlying mechanisms of the association between circulating irisin and metabolic disorders.

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

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