Fibronectin Type III Domain-containing Protein 5 Research Articles

Irisin, A Fascinating and Multifunctional Protein: Implication for Health

BACKGROUND: Fibronectin type III domain-containing protein 5 (FNDC5), or also known as irisin, has been identified for two decades but almost completely disregarded for 10 years. It is present in skeletal muscle, heart, and brain, and in reaction to exercise can transform white adipose tissue into brown. Since then, irisin has gained a lot of attention for its potencies in treating metabolic disorders. In this review article, the potential future of irisin especially on metabolism and aging process will be discussed.CONTENT: Sedentary lifestyle is acknowledged as risk factor for type 2 diabetes mellitus, obesity, immune system issues, asthma, and neurological or heart illness. Irisin is secreted by muscle cells when exercising, produced after the proteolytic cleavage of FNDC5 protein. Irisin has positive impacts on maintaining physiological balance including reducing inflammation, keeping the bone homeostasis, as well as influencing metabolic processes and the neurological system function. Due to these many and advantageous characteristics, irisin could be a possible choice for preventing and managing disorders associated with modern society, and finding the agents to increase irisin can be beneficial.SUMMARY: Irisin offers a fresh potential basis for kinesitherapy and shows promise as a therapeutic target due to its various biological activities. Irisin pathway can be activated through dietary changes, the use of natural substances and drugs and can interact with this signalling pathway which involved peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and uncoupling protein mRNA 1 (UCP1) to resolve obesity and its metabolic comorbidities.KEYWORDS: irisin, FNDC5, exercise, inflammation, obesity, nervous system

Hydrogen Sulfide and Irisin, Potential Allies in Ensuring Cardiovascular Health

Irisin is a myokine secreted under the influence of physical activity and exposure to low temperatures and through different exogenous stimuli by the cleavage of its precursor, fibronectin type III domain-containing protein 5 (FNDC5). It is mainly known for maintaining of metabolic homeostasis, promoting the browning of white adipose tissue, the thermogenesis process, and glucose homeostasis. Growing experimental evidence suggests the possible central role of irisin in the regulation of cardiometabolic pathophysiological processes. On the other side, hydrogen sulfide (H2S) is well recognized as a pleiotropic gasotransmitter that regulates several homeostatic balances and physiological functions and takes part in the pathogenesis of cardiometabolic diseases. Through the S-persulfidation of cysteine protein residues, H2S is capable of interacting with crucial signaling pathways, exerting beneficial effects in regulating glucose and lipid homeostasis as well. H2S and irisin seem to be intertwined; indeed, recently, H2S was found to regulate irisin secretion by activating the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/FNDC5/irisin signaling pathway, and they share several mechanisms of action. Their involvement in metabolic diseases is confirmed by the detection of their lower circulating levels in obese and diabetic subjects. Along with the importance of metabolic disorders, these modulators exert favorable effects against cardiovascular diseases, preventing incidents of hypertension, atherosclerosis, heart failure, myocardial infarction, and ischemia–reperfusion injury. This review, for the first time, aims to explore the role of H2S and irisin and their possible crosstalk in cardiovascular diseases, pointing out the main effects exerted through the common molecular pathways involved.

FNDC5 inhibits malignant growth of human cervical cancer cells via restraining PI3K/AKT pathway.

Cervical cancer (CxCa) is the fourth most frequent cancer in women. This study aimed to determine the role and underlying mechanism of fibronectin type III domain-containing protein 5 (FNDC5) in inhibiting CxCa growth. Experiments were performed in human CxCa tissues, human CxCa cell lines (HeLa and SiHa), and xenograft mouse model established by subcutaneous injection of SiHa cells in nude mice. Bioinformatics analysis showed that CxCa patients with high FNDC5 levels have a longer overall survival period. FNDC5 expression was increased in human CxCa tissues, HeLa and SiHa cells. FNDC5 overexpression or FNDC5 protein not only inhibited proliferation, but also restrained invasion and migration of HeLa and SiHa cells. The effects of FNDC5 were prevented by inhibiting integrin with cilengitide, activating PI3K with recilisib or activating Akt with SC79. FNDC5 inhibited the phosphorylation of PI3K and Akt, which was attenuated by recilisib. PI3K inhibitor LY294002 showed similar effects to FNDC5 in HeLa and SiHa cells. Intravenous injection of FNDC5 (20 μg/day) for 14 days inhibited the tumor growth, and reduced the proliferation marker Ki67 expression and the Akt phosphorylation in the CxCa xenograft mouse model. These results indicate that FNDC5 inhibits the malignant phenotype of CxCa cells through restraining PI3K/Akt signaling. Upregulation of FNDC5 may play a beneficial role in retarding the tumor growth of CxCa.

Can SLU-PP-332 be a new drug to prevent COVID-19?

Given the fact that the forecasts show the continuation of the occurrence of cases of coronavirus disease 19 (COVID-19) and the evolution towards Long COVID, the identification of a chemoprophylactic agent is of major importance. For this purpose, we propose SLU-PP-332, an estrogen-related receptor alpha (ERRα) agonist, which, besides the effect of stimulating mitochondrial biogenesis, it is possible to inhibit angiotensin-converting enzyme 2 (ACE2), stimulate immunity, inhibit pro-inflammatory cytokines, reduce the number of entry points into cells of SARS-CoV-2 at the level of adipose tissue through fibronectin type III domain-containing protein 5 (FNDC5), and to protect vascular endothelium from oxidative stress. Considering the existence of experimental models for COVID-19, it is possible to test these effects, as well as the possibility of combining the administration of SLU-PP-332 with the performance of moderate-intensity physical exercises, this in order to accelerate the adaptation to exercise of the mitochondria of the whole body, a supposed prophylactic factor for severe forms of COVID-19.

FNDC5/irisin ameliorates bone loss of type 1 diabetes by suppressing endoplasmic reticulum stress‑mediated ferroptosis

BackgroundFerroptosis is known to play a crucial role in diabetic osteopathy. However, key genes and molecular mechanisms remain largely unclear. This study aimed to identify a crucial ferroptosis-related differentially expressed gene (FR-DEG) in diabetic osteopathy and investigate its potential mechanism.MethodsWe identified fibronectin type III domain-containing protein 5 (FNDC5)/irisin as an essential FR-DEG in diabetic osteopathy using the Ferroptosis Database (FerrDb) and GSE189112 dataset. Initially, a diabetic mouse model was induced by intraperitoneal injection of streptozotocin (STZ), followed by intraperitoneal injection of irisin. MC3T3-E1 cells treated with high glucose (HG) were used as an in vitro model. FNDC5 overexpression plasmid was used to explore underlying mechanisms in vitro experiments. Femurs were collected for micro-CT scan, histomorphometry, and immunohistochemical analysis. Peripheral serum was collected for ELISA analysis. Cell viability was assessed using a CCK-8 kit. The levels of glutathione (GSH), malondialdehyde (MDA), iron, reactive oxygen species (ROS), and lipid ROS were detected by the corresponding kits. Mitochondria ultrastructure was observed through transmission electron microscopy (TEM). Finally, mRNA and protein expressions were examined by quantitative real‐time PCR (qRT‐PCR) and western blot analysis.ResultsThe expression of FNDC5 was found to be significantly decreased in both in vivo and in vitro models. Treatment with irisin significantly suppressed ferroptosis and improved bone loss. This was demonstrated by reduced lipid peroxidation and iron overload, increased antioxidant capability, as well as the inhibition of the ferroptosis pathway in bone tissues. Furthermore, in vitro studies demonstrated that FNDC5 overexpression significantly improved HG-induced ferroptosis and promoted osteogenesis. Mechanistic investigations revealed that FNDC5 overexpression mitigated ferroptosis in osteoblasts by inhibiting the eukaryotic initiation factor 2 alpha (eIF2α)/activated transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) pathway.ConclusionsCollectively, our study uncovered the important role of FNDC5/irisin in regulating ferroptosis of diabetic osteopathy, which might be a potential therapeutic target.

Exercise-inducible circulating extracellular vesicle irisin promotes browning and the thermogenic program in white adipose tissue.

Exercise can reduce body weight and promote white fat browning, but the underlying mechanisms remain largely unknown. This study investigated the role of fibronectin type III domain-containing protein 5 (FNDC5)/Irisin, a hormone released from exercising muscle, in the browning of white fat in circulating extracellular vesicles (EVs). Mice were subjected to a 4 weeks of running table exercise, and fat browning was analyzed via histology, protein blotting and qPCR. Circulating EVs were extracted by ultrahigh-speed centrifugation, and ELISA was used to measure the irisin concentration in the circulating EVs. Circulating EVs that differentially expressed irisin were applied to adipocytes, and the effect of EV-irisin on adipocyte energy metabolism was analyzed by immunofluorescence, protein blotting, and cellular oxygen consumption rate analysis. During sustained exercise, the mice lost weight and developed fat browning. FNDC5 was induced, cleaved, and secreted into irisin, and irisin levels subsequently increased in the plasma during exercise. Interestingly, irisin was highly expressed in circulating EVs that effectively promoted adipose browning. Mechanistically, the circulating EV-irisin complex is transported intracellularly by the adipocyte membrane receptor integrin αV, which in turn activates the AMPK signaling pathway, which is dependent on mitochondrial uncoupling protein 1 to cause mitochondrial plasmonic leakage and promote heat production. After inhibition of the AMPK signaling pathway, the effects of the EV-irisin on promoting fat browning were minimal. Exercise leads to the accumulation of circulating EV-irisin, which enhances adipose energy metabolism and thermogenesis and promotes white fat browning in mice, leading to weight loss.

PGC-1α activation boosts exercise-dependent cellular response in the skeletal muscle

The role of Peroxisome proliferator-activated receptor-gamma coactivator alpha (PGC-1α) in fat metabolism is not well known. In this study, we compared the mechanisms of muscle-specific PGC-1α overexpression and exercise-related adaptation-dependent fat metabolism. PGC-1α trained (PGC-1α Ex) and wild-trained (wt-ex) mice were trained for 10 weeks, five times a week at 30 min per day with 60 percent of their maximal running capacity. The PGC-1α overexpressed animals exhibited higher levels of Fibronectin type III domain-containing protein 5 (FNDC5), 5' adenosine monophosphate-activated protein kinase alpha (AMPK-α), the mammalian target of rapamycin (mTOR), Sirtuin 1 (SIRT1), Lon protease homolog 1 (LONP1), citrate synthase (CS), succinate dehydrogenase complex flavoprotein subunit A (SDHA), Mitofusin-1 (Mfn1), endothelial nitric oxide synthase (eNOS), Hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), G protein-coupled receptor 41 (GPR41), and Phosphatidylcholine Cytidylyltransferase 2 (PCYT2), and lower levels of Sirtuin 3 (SIRT3) compared to wild-type animals. Exercise training increased the protein content levels of SIRT1, HSL, and ATGL in both the wt-ex and PGC-1α trained groups. PGC-1α has a complex role in cellular signaling, including the upregulation of lipid metabolism-associated proteins. Our data reveals that although exercise training mimics the effects of PGC-1α overexpression, it incorporates some PGC-1α-independent adaptive mechanisms in fat uptake and cell signaling.

FNDC5/Irisin protects neurons through Caspase3 and Bax pathways.

Irisin is a glycosylated protein formed from the hydrolysis of fibronectin type III domain-containing protein 5 (FNDC5). Recent studies have demonstrated that FNDC5/Irisin is involved in the regulation of glucose and lipid metabolism, it can inhibit inflammation and have neuroprotective effects. However, the effect and mechanism of FNDC5/Irisin on motor neuron-like cell lines (NSC-34) have not been reported. In this study, we used lipopolysaccharide to construct cellular oxidative stress injury models and investigated the potential roles of FNDC5/Irisin on neurons by different cellular and molecular pathways. Taken together, our findings showed that FNDC5/Irisin can protect neurons, and this effect might be associated with Caspase3 and Bax pathways. These results laid the foundation for neuronal protection and clinical translation of FNDC5/Irisin therapy.

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.

Type, Duration, and Intensity of Physical Exercise Modulate FNDC5/Irisin Expression in the Hippocampus

Introduction: Physical exercise can activate important biochemical processes in the human body, one of which is a myokine called irisin.   Objective: This review aims to identify the effect of exercise on the expression of FNDC5/irisin, a myokine secreted by skeletal muscles that is produced in response to physical activity. This hormone provides a protective function in the central nervous system, specifically the hippocampus. The effects of exercise on the brain are well known, but the duration, intensity and type of exercise as well as the underlying molecular mechanisms are not fully understood. This review will focus on Fibronectin type III domain-containing protein 5 (FNDC5) and its secreted form, myokine “irisin” with a mechanism of action in the hippocampus and the effect of exercise on irisin expression.   Method: A literature search was performed on several databases (PubMed, Scopus, and Sciencedirect) on the impact of training on irisin, resulting in 17 articles.   Results: This review shows that physical exercise increases plasma irisin levels in humans and brains in rats, including the hippocampus. Discussion; The relationship between exercise, FNDC5 (the gene that encodes irisin), and the hippocampus is an area of active research. FNDC5/irisin is a protein that has gained attention for its potential role in mediating some of the beneficial effects of exercise on the brain, including the hippocampus.   Conclusion: Irisin is expressed in plasma and hippocampus as a result of physical exercise that depends on the type, intensity, and duration of exercise that functions in the brain.

Serum ve Plazma Örneklerinde İrisin Seviyesini Ölçmeden Önce Aprotinin İlave Etmek Gerekir mi?

Irisin is a myokine with 112 amino acids and its blood concentration is regulated by peroxisome proliferator-activated receptor-γ coactivator1-α (PGC1-α). It is released into circulation from skeletal muscle tissue after a photolytic cleavage of extracellular domain of Fibronectin type III domain-containing protein 5 (FNDC5), a type I integral membrane protein. Aprotinin is a polyvalent serin protease inhibitor. It is added to sample solutions such as serum, plasma or tissue extracts in order to inhibit serine proteases found in the sample medium. Hence, degradation of the proteins to be measured can be prevented. This study has been carried out to obtain a preliminary data if any irisin loss could be seen in the serum samples which are kept at -80°C for a long duration. For this purpose, blood samples of 10 men and 10 women volunteers aged between 25-40 has been used. Aprotinin has been added to the plasma and the serum samples have been kept at -80°C for 3 months. At the end of 3 months, irisin levels of the samples with and without aprotinin have been determined by ELISA. Statistical analysis has shown no difference between the plasma samples with or without aprotinin (p=0.525). However, a significant decrease between the serum samples with and without aprotinin (p=0.009). In conclusion, with the results of this study, no net decision could have been achieved to add aprotinin to the samples for irisin determination with ELISA in plasma and serum kept at -80°C for about 3 months.

Exercise ameliorating myocardial injury in type 2 diabetic rats by inhibiting excessive mitochondrial fission involving increased irisin expression and AMP-activated protein kinase phosphorylation.

Though exercise generates beneficial effects on diabetes-associated cardiac damage, the underlying mechanism is largely unclear. Therefore, we prescribed a program of 8-week treadmill training for type 2 diabetes mellitus (T2DM) rats and determined the role of irisin signaling, via interacting with AMP-activated protein kinase (AMPK), in mediating the effects of exercise on myocardial injuries and mitochondrial fission. Forty 8-week-old male Wistar rats were randomly divided into groups of control (Con), diabetes mellitus (DM), diabetes plus exercise (Ex), and diabetes plus exercise and Cyclo RGDyk (ExRg). Ex and ExRg rats received 8 weeks of treadmill running, and the rats in the ExRg group additionally were treated with a twice weekly injection of Cyclo RGDyk, an irisin receptor-αV/β5 antagonist. At the end of the experiment, murine blood samples and heart tissues were collected and analyzed with methods of ELISA, Western blot, real-time quantitative polymerase chain reaction, as well as immunofluorescence staining. Exercise effectively mitigated T2DM-related hyperglycemia, hyperinsulinemia, lipid dysmetabolism, and inflammation, which could be diminished by Cyclo RGDyk treatment. Additionally, exercise alleviated T2DM-induced myocardial injury and excessive mitochondrial fission, whereas the beneficial effects were blocked by the administration of Cyclo RGDyk. T2DM significantly decreased serum irisin concentrations and fibronectin type III domain-containing protein 5 (FNDC5)/irisin gene and protein expression levels in the rat heart, whereas exercise could rescue T2DM-reduced FNDC5/irisin expression. Blocking irisin receptor signaling diminished the exercise-alleviated mitochondrial fission protein expression and elevated AMPK phosphorylation. Exercise is effective in mitigating diabetes-related insulin resistance, metabolic dysfunction, and inflammation. Irisin signaling engages in exercise-associated beneficial effects on myocardial injury and excessive mitochondrial fission in diabetes rats involving elevated AMPK phosphorylation.

Effects of Resistance Exercise and Fermented Soybean Intake on Protein Expression Markers Related to Browning of White Adipose Tissue in Diet-induced Obese Rats

PURPOSE: This study aimed to analyze the combined treatment effect of fermented soybean intake (for additional protein intake) and resistance exercise (for muscle metabolism activation) on the molecular biological response index of white adipose tissue (WAT) browning.METHODS: The study included twenty 50-week-old male Wistar rats, who were made obese by being fed a high-fat diet for 8 weeks and then were randomly divided into four groups, control (Con), fermented soybean intake (Soy), resistance exercise (RT), and fermented soybean intake and resistance exercise combination (Soy+RT). After 12 weeks of Soy and RT treatment, body composition, and protein expression patterns such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), fibronectin type III domain-containing protein 5 (FNDC5), interleukin-6 (IL-6), and uncoupling protein-1 (UCP1) were compared in extensor digitorum longus and retroperitoneal fat.RESULTS: The obese rats demonstrated a reduction in body weight and body fat mass, as well as maintenance of lean mass. Interestingly, the groups treated with Soy, RT, and Soy+RT displayed enhanced protein expression of PGC-1α, FNDC5, UCP1, and IL-6 in the extensor digitorum longus and retroperitoneal fat tissue than Con. In particular, the Soy+RT group displayed the most remarkable activation of the aforementioned protein levels in the muscle and adipose tissues.CONCLUSION: This study concluded that resistance exercise and fermented soybean intake can partly contribute to the browning of WAT.

Quercetin suppresses retinoblastoma cell proliferation and invasion and facilitates oxidative stress-induced apoptosis through the miR-137/FNDC5 axis

Retinoblastoma (RB) constitutes a prevalent malignancy in clinic and usually occurs in children under the age of 5 years old. The increased frequency of malignant tumor metastases and the delayed diagnosis and treatment caused unsatisfactory therapeutic efficiency. Quercetin was formerly identified to impede tumor growth in certain malignancies. Our study attempted to investigate the effects and mechanisms of quercetin in Rb development, in order to provide an effective clinical therapeutic approach. Rb cell lines (WER1-RB1 and Y79) were incubated with different concentrations of quercetin, and then cell proliferation, invasion, apoptosis, and oxidative stress were determined. It was showed that quercetin restrained Rb cell proliferation and invasion, and induced cell apoptosis and oxidative stress in a dose dependent manner. Moreover, we found that quercetin incubation upregulated miR-137 expression in Rb cells. MiR-137 inhibition abrogated quercetin-mediated inhibition of Rb cell progression. Furthermore, dual-luciferase reporter gene assay validated that fibronectin type III domain-containing protein 5 (FNDC5) was a target for miR-137. MiR-137 overexpression restrained proliferation and invasion, and enhanced apoptosis and oxidative stress in Rb cells, whereas FNDC5 overexpression abrogated these effects. Additionally, nude mice were injected with WER1-RB1 cells to establish a xenograft tumor model, and then treated with 50 or 100 mg/kg quercetin. Quercetin treatment mitigated xenograft tumor growth in nude mice. In conclusion, quercetin restrained proliferation and invasion, and induced apoptosis and oxidative stress in Rb cells through regulating the miR-137/FNDC5 pathway. We expected that our study could provide an effective approach for Rb treatment. However, quercetin and miR-137 may have off-target effects in Rb cells, and our study still has certain limitations. Therefore, we will investigate the effects of quercetin on other signaling pathways in Rb cells and explore the application of combination therapy in follow-up experiments, in order to provide a rigorous research basis for the treatment of Rb with quercetin.

FNDC5 Attenuates Atherosclerotic Plaque Formation and Regulates PPARα/HO-1 in ApoE−/− Mice

Introduction: This study attempted to observe the role of fibronectin type III domain-containing protein 5 (FNDC5) in atherosclerosis development and the underlying mechanism. Methods: After being fed a high-fat diet (HFD), ApoE^−/− mice were injected with saline, control adenovirus (Ad-vector), or FNDC5 overexpressing adenovirus (Ad-FNDC5). ApoE^−/− mice fed with a chow diet were considered the control. After 12 weeks of treatment, the levels of serum high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and irisin were detected by commercial kits. Results: Compared with the control, the serum TG, TC, and LDL-C levels, aortic plaque area, and weight were significantly increased, while serum HDL-C and irisin levels were reduced in HFD mice. Treating with Ad-FNDC5 could alleviate these changes in HFD mice and cause the activation of PPARα/HO-1 signaling in aortic tissue. After co-treating with GW6471, a PPARα antagonist, the effects of Ad-FNDC5 on the weight, serum LDL-C, TC, TG, and HDL-C levels, and aortic plaque of HFD mice were partly blocked. Conclusion: Elevated FNDC5 has a delaying effect on atherosclerotic plaque formation, which may be related to the upregulation of PPARα/HO-1 signaling.

Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans.

Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-β deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-β PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-β42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.

FNDC5/irisin expression stimulates neuroprotective pathways in hippocampal neurons and associates with Alzheimer’s disease pathology

AbstractBackgroundIrisin is an exercise‐linked myokine produced by cleavage of the membrane precursor fibronectin type III domain‐containing protein 5 (FNDC5) in skeletal muscle, brain, and other tissues. Recently, irisin has been identified as a key molecule for exercise‐induced neuroprotection in mouse models of Alzheimer’s disease (AD). However, the role of FNDC5/irisin in AD pathology has not yet been comprehensively explored. Here, we investigated potential mechanisms underlying neuroprotection induced by FNDC5/irisin in AD.MethodPrimary rat hippocampal neuronal cultures were transduced with adenoviral vectors to express FNDC5 (AdFNDC5) or GFP (as a control) or exposed to recombinant irisin (25 nM) for defined timepoints. Brain‐derived neurotrophic factor (BDNF) levels were measured by ELISA; extracellular signal‐regulated kinase 1/2 (ERK 1/2) phosphorylation was determined by Western blotting; and the effects of irisin on amyloid‐β oligomers (AβO)‐induced reactive oxygen species (ROS) accumulation was determined by the DCF fluorescence. Finally, we analyzed RNA‐seq data from human postmortem hippocampi within The Aging, Dementia and Traumatic Brain Injury Study to determine potential correlations between FNDC5 gene expression and AD pathology.ResultWe found that irisin stimulates extracellular BDNF accumulation, ERK 1/2 phosphorylation (i.e. activation) and prevents AβOs‐induced ROS accumulation in primary hippocampal neurons. Analysis of RNA‐seq data indicates that hippocampal FNDC5 gene expression is reduced with aging and tau (assessed by Braak neuropathological scale and hippocampal phospho‐tau immunoreactivity), but not with amyloid pathology in humans.ConclusionThese results indicate potential mechanisms by which FNDC5/irisin signaling promotes neuroprotection and support the notion that stimulation of irisin signaling may be beneficial against neurodegeneration in AD.

Irisin reduces orthodontic tooth movement in rats by promoting the osteogenic potential in the periodontal ligament.

Positive effects of irisin on osteogenic differentiation of periodontal ligament (PDL) cells have been identified previously, this study aims to examine its effect on orthodontic tooth movement (OTM) in vivo. The maxillary right first molars of male Wistar rats (n = 21) were moved mesially for 14 days, with submucosal injection of two dosages of irisin (0.1 or 1 μg) or phosphate-buffered saline (control) every third day. OTM was recorded by feeler gauge and micro-computed tomography (μCT). Alveolar bone and root volume were analysed using μCT, and plasma irisin levels by ELISA. Histological characteristics of PDL tissues were examined, and the expression of collagen type I, periostin, osteocalcin (OCN), von Willebrand factor (vWF) and fibronectin type III domain-containing protein 5 (FNDC5) in PDL was evaluated by immunofluorescence staining. Repeated 1 μg irisin injections suppressed OTM on days 6, 9, and 12. No significant differences were observed in OTM in the 0.1 μg irisin group, or in bone morphometric parameters, root volume or plasma irisin, compared to control. Resorption lacunae and hyalinization were found at the PDL-bone interface on the compression side in the control, whereas they were scarce after irisin administration. The expression of collagen type I, periostin, OCN, vWF, and FNDC5 in PDL was enhanced by irisin administration. The feeler gauge method may overestimate OTM. Submucosal irisin injection reduced OTM by enhancing osteogenic potential of PDL, and this effect was more significant on the compression side.

Therapeutic role of FNDC5/irisin in attenuating liver fibrosis via inhibiting release of hepatic stellate cell-derived exosomes.

Cleavage of fibronectin type III domain-containing protein 5 (FNDC5), a membrane-bound precursor protein, would cleave into a myokine, irisin, which is also expressed in the liver. FNDC5/Irisin has been reported to play a critical role in maintaining glucose and lipid homeostasis in the liver and in combating liver fibrosis. Recently, several studies have shown that extracellular vesicles (EVs) derived from hepatic stellate cells (HSCs) could modulate liver fibrosis; however, there is a large gap in understanding whether inhibition of fibrogenic EVs derived from HSCs could alleviate the progression of liver fibrosis. Here, we investigated the role of FNDC5/irisin in liver fibrosis and the mechanism of its inhibitory role in the release of HSC-derived fibrogenic EVs. Experiments were performed in wild-type and FNDC5-/- mice, primary mouse HSCs, and human hepatic stellate cell line (LX2). Mice were treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL) to induce liver fibrosis. EVs derived from HSCs were purified and injected intraperitoneally into mice. Our results showed that FNDC5 deficiency exacerbated CCl4-induced liver fibrosis and activation of HSCs in mice. Moreover, fibrogenic EVs derived from PDGF-BB-treated HSCs promoted HSC migration in vitro and liver fibrosis in vivo. However, administration of irisin, a cleavage of FNDC5, inhibited the release of fibrogenic EVs and activation of HSCs by promoting ubiquitylation degradation of Rab27b. In vivo, the promoting role of HSC-derived fibrogenic EVs in liver fibrosis was also reversed by irisin. All these results demonstrate that FNDC5/irisin is a novel therapeutic agent for chronic liver fibrosis.

FNDC5/Irisin Inhibits the Inflammatory Response and Mediates the Aerobic Exercise-Induced Improvement of Liver Injury after Myocardial Infarction

Myocardial infarction (MI) causes peripheral organ injury, in addition to cardiac dysfunction, including in the liver, which is known as cardiac hepatopathy. Aerobic exercise (AE) can effectively improve liver injury, although the mechanism and targets are currently not well established. Irisin, mainly produced by cleavage of the fibronectin type III domain-containing protein 5 (FNDC5), is a responsible for the beneficial effects of exercise training. In this study, we detected the effect of AE on MI-induced liver injury and explored the role of irisin alongside the benefits of AE. Wildtype and Fndc5 knockout mice were used to establish an MI model and subjected to AE intervention. Primary mouse hepatocytes were treated with lipopolysaccharide (LPS), rhirisin, and a phosphoinositide 3-kinase (PI3K) inhibitor. The results showed that AE significantly promoted M2 polarization of macrophages and improved MI-induced inflammation, upregulated endogenous irisin protein expression and activated the PI3K/ protein kinase B (Akt) signaling pathway in the liver of MI mice, while knockout of Fndc5 attenuated the beneficial effects of AE. Exogenous rhirisin significantly inhibited the LPS-induced inflammatory response, which was attenuated by the PI3K inhibitor. These results suggest that AE could effectively activate the FNDC5/irisin-PI3K/Akt signaling pathway, promote the polarization of M2 macrophages, and inhibit the inflammatory response of the liver after MI.