Background & aims: Irisin, the cleaved extra-cellular fragment of the Fibronectin type III domain-containing protein 5 (FNDC5) is a myokine that is proposed to have favorable metabolic activity. We aimed to elucidate the currently undefined role of variants in the FNDC5 gene in non-alcoholic fatty liver disease (NAFLD).Methods: We prioritized single nucleotide polymorphisms in FNDC5 on the basis of their putative biological function and identified rs3480 in the 3' untranslated region (3'UTR). We studied the association of rs3480 with liver disease severity and the metabolic profile of 987 Caucasian patients with NAFLD. Functional investigations were undertaken using luciferase reporter assays of the 3'UTR of human FNDC5, pyrosequencing for allele-specific expression of FNDC5 in liver, measurement of serum irisin, and bioinformatics analysis.Results: The rs3480 (G) allele was associated with advanced steatosis (OR 1.29; 95% CI 1.08-1.55; p = 0.004), but not with other histological features. This effect was independent but additive to PNPLA3 and TM6SF2. The rs3480 polymorphism influenced FNDC5 mRNA stability and the binding of miR-135a-5P. Compared with controls, hepatic expression of this microRNA was upregulated while FNDC5 expression was downregulated. Elevated serum irisin was associated with reduced steatosis, and an improved metabolic profile.Conclusions: Carriage of the FNDC5 rs3480 minor (G) allele is associated with more severe steatosis in NAFLD through a microRNA-mediated mechanism controlling FNDC5 mRNA stability. Irisin is likely to have a favorable metabolic impact on NAFLD.
Irisin, a recently discovered myokine, has been considered a prognostic factor in several cardiovascular diseases. Nevertheless, no data are available on the role of irisin in patients with heart failure (HF), both with preserved (HFpEF) or reduced (HFrEF) ejection fraction. We have therefore evaluated the circulating irisin levels in HFpEF and HFrEF patients, correlating them with metabolic parameters and total antioxidant capacity (TAC), as index of oxidative stress. Irisin was significantly higher in HFpEF than in HFrEF patients (7.72 ± 0.76 vs 2.77 ± 0.77 ng/ml, respectively). An inverse correlation between irisin and TAC was found in HFpEF, but not in HFrEF. Conversely, no correlation was present with HOMA index. These data support the hypothesis that a different pathophysiological mechanism is involved in the two HF subtypes, and oxidative stress modulates irisin secretion.
Defective brain hormonal signaling has been associated with Alzheimer's disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisinattenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.
This publication used the irisin EIA kit (EK-067-29) from Phoenix Pharmaceuticals for CSF measurement in Alzheimer's patients.
Half a decade ago, transmembrane protein fibronectin type III domain-containing protein 5 (FNDC5) was found to be cleaved as a novel myokine irisin, which burst into prominence for browning of white adipose tissue during exercise. However, FNDC5, the precursor of irisin, has been paid relatively little attention compared with irisin despite evidence that FNDC5 is associated with the metabolic syndrome, which accounts for one-fourth of the world's adult population and contributes to diabetes, cardiovascular disease and all-cause mortality. Besides N-terminal and C-terminal sequences, the FNDC5 protein contains an irisin domain and a short transmembrane region. FNDC5 has shown to be widely distribute in different tissues and is highly expressed in heart, brain, liver, and skeletal muscle. Clinical studies have demonstrated that FNDC5 is essential for maintaining metabolic homeostasis and dysregulation of FNDC5 will lead to systemic metabolism imbalance and the onset of metabolic disorders. Growing evidence has suggested that FNDC5 gene polymorphisms are related to health and disease in different human populations. Additionally, FNDC5 has been found relevant to the regulation of metabolism and metabolic syndrome through diverse upstream and downstream signaling pathways in experimental studies. The present review summarizes the characteristics, clinical significance, and molecular mechanisms of FNDC5 in metabolic syndrome and proposes a novel concept that FNDC5 is activated by forming a putative ligand-receptor complex. Knowledge about the role of FNDC5 may be translated into drug development and clinical applications for the treatment of metabolic disorders.
Irisin is secreted by muscle, increases with exercise, and mediates certain favorable effects of physical activity. In particular, irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear, and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins, and biophysical studies identify interacting surfaces between irisin and αV/β5 integrin. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Genetic ablation of FNDC5 (or irisin) completely blocks osteocytic osteolysis induced by ovariectomy, preventing bone loss and supporting an important role of irisin in skeletal remodeling. Identification of the irisin receptor should greatly facilitate our understanding of irisin's function in exercise and human health.
Objective: The new adipokine, which is asprosin, affects glucose release from the liver to the blood, and thus, influences exercise metabolism. This is the first study assessing whether single anaerobic exercise affects asprosin secretion in women and men.
Methods: 10 men and 10 women (aged 21.64 ± 1.22 and 22.64 ± 1.49, respectively) performed a single 20-s bicycle sprint. Blood samples were collected before exercise and in the 3', 15', 30', and 60' of recovery, and 24 h after competition.
Results: Only in women did asprosin (P = 0.001) (15', 30', 60', and 24 h after exercise) and irisin (P < 0.001) (15', 30', and 60') concentrations increase. Leptin, however, decreased (P = 0.001) at 3', 15', and 30' in women. There was an increase in interleukin-6 (P < 0.001) at 3', 15', 30', and 60' of recovery in men, at 15', 30', 60', and 24 h of recovery in women, along with a simultaneous decrease in interleukin-1β (P < 0.001) at 15', 30', and 60' of recovery in men, and at 15' and 30' of recovery in women (r = -0.35, P < 0.001). There was a positive correlation between asprosin and adiponectin and a negative one between asprosin and leptin. The increase in irisin concentration at 30' of recovery was positively correlated with the increase in asprosin concentration and percentage fat content, while being negatively correlated with total and lean body mass (LBM).
Conclusion: The single anaerobic effort induced an increase in asprosin and irisin secretion while reducing leptin secretion in women. Adipocytokine concentration changes are inter-related. Regardless of sex, anaerobic efforts induce anti-inflammatory effects.
This publication used the irisin EIA kit (EK-067-16) from Phoenix Pharmaceuticals to measure the serum level of irisin.
|EK-067-29||Irisin, recombinant (Human, Rat, Mouse, Canine) - ELISA Kit||96 wells||$526|