Irisin, a hormone proteolytically processed from fibronectin type III domain-containing protein 5 (FNDC5), has been reported to induce the browning of subcutaneous adipocytes by increasing the level of uncoupling protein 1(Ucp1). In this study, we showed that activation of the nuclear receptor constitutive androstane receptor (CAR) induced FNDC5 mRNA expression in the liver and increased the circulating level of Irisin in mice. FNDC5/Irisin is a direct transcriptional target of CAR. Hepatic-released Irisin functioned as a paracrine/autocrine factor that inhibited lipogenesis and gluconeogenesis via the AMPK pathway. Adenovirus-overexpressed Irisin improved hepatic steatosis and insulin resistance in genetic-induced obese mice. Irisin transgenic mice were also protected against high fat diet-induced obesity and insulin resistance. In conclusion, our results reveal a novel pathway in regulating FNDC5/Irisin expression and identify a physiological role for this hepatic hormone in glucose and lipid homeostasis.
Mo L, Shen J, Liu Q et al., Mol Endocrinol. 2016 Mar 23:me20151292. [Epub ahead of print]
**Remark : The authors used Phoenix Pharmaceutical’s irisin ELISA kit (#EK-067-29) to measure irisin levels in human serum.**
The role of inflammation in pathogenesis of diabetic retinopathy (DR) is getting increasingly recognized. However, it is unclear whether and how non-proliferative diabetic retinopathy (NPDR) is affected by Interleukin-17A (IL-17A) and Interleukin-22 (IL-22), two well-known inflammatory factors, andirisin, a novel potential anti-inflammatory factor. Here we recruited 40 type 2 diabetes mellitus (T2DM) patients with NPDR, 60 T2DM patients without DR (no-DR), and 20 normal glucose tolerance (NGT) controls. Serum levels of IL-17A, IL-22, and irisin were examined. Compared with NGT and no-DR subjects, NPDR group had significantly higher IL-17A levels. Irisin levels were significantly lower in T2DM patients, while IL-22 levels were not significantly different across all three groups. Multiple logistic regression analysis revealed that IL-17A significantly increased the risk of NPDR (OR = 1.22, P < 0.05) before adjusting for irisin. When irisin was included in the model, neither irisin nor IL-17A was associated with NPDR. Further partial correlation analysis showed that irisin was intrinsically correlated with IL-17A even after multiple adjustment (r = -0.252; P = 0.018). These findings suggest that IL-17A is an independent risk factor of NPDR, and irisin could protect against DR through potential anti-IL-17A effects.
Wang C, Wang L, Liu J et al., Endocrine. 2016 Mar 3. [Epub ahead of print]
**Remark : The authors used Phoenix Pharmaceutical’s irisin ELISA kit (#EK-067-29) to measure irisin levels in human serum.**
BACKGROUND/OBJECTIVES: It has been reported that irisin regulated exercise-mediated adipocyte browning; however, the systematical effects ofirisin on the metabolism of glucose and lipid in diabetes are largely unknown. In the present study, we investigated the role and underlying mechanism of irisin in glucose utilization and lipid metabolism in diabetic mice.
METHODS: A mouse model of diabetes was established by feeding C57BL/6 mice with high-fat diet. The diabetic mice were then treated with irisin. To mimic type 2 diabetes in vitro, myocytes and hepatocytes were cultured in a medium of high glucose and high fat. Glucose uptake, fatty acidoxidation and the expression of related protein were evaluated.
RESULTS: Irisin improved glucose tolerance and glucose uptake as evidenced by increased (18)F-FDG accumulation and GLUT4 translocation in diabetic skeletal muscle. Irisin also increased glucose uptake in myocytes cultured in high glucose/high fatty acid medium. In contrast, irisin reduced the expression of PEPCK and G6Pase, which are involved in gluconeogenesis, in diabetic liver. Consistently, irisin reduced fat weight and serum total cholesterol and triglyceride levels in diabetic mice, but increased acetyl coenzyme A carboxylase-β phosphorylation in muscle tissue and uncoupling protein 1 expression in fat tissue. In addition, irisin increased the oxidation of fatty acid in myocytes. Knockdown of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) attenuated the effects of irisin on glucose uptake and fatty acid β-oxidation in myocytes. Similarly, inhibition of AMPK by a specific inhibitor reduced the effects of irisin on PEPCK and G6Pase expression in hepatocytes.
CONCLUSIONS: Our results suggest that irisin has an essential role in glucose utilization and lipid metabolism, and irisin is a promising pharmacological target for the treatment of diabetes and its complications.
Xin, C; Liu, J; Zhang, J; Zhu, et al., International Journal of Obesity. 40(3):443-451, March 2016
The fibronectin type III domain-containing protein 5 (FNDC5) discovered in 2002 has recently gained attention due to its potential role in protecting against obesity. In rat, no data exist regarding FNDC5 production and regulation in the stomach. The aim of the present work was to determine the expression of FNDC5 in the rat stomach and its potential regulation by body composition. The present data shows FNDC5 gene expression in the gastric mucosa. Immunohistochemical studies found FNDC5 immunopositivity in chief cells of gastric tissue. By the use of three different antibodies FNDC5 was found expressed in gastric mucosa and secreted by the stomach. The rate of gastric FNDC5 secretion parallels the circulating levels ofFNDC5. The body fat mass increase after intervention with high fat diet coincided with a decrease in the secretion of FNDC5 from the stomach and a diminution in the FNDC5 circulating levels. In summary, the present data shows, for the first time, the expression of FNDC5 in the stomach of rats and its regulation by body composition, suggesting a potential role of gastric FNDC5 in energy homeostasis.
Barja-Fernández S, Folgueira C, Castelao C et al., Sci Rep. 2016 Mar 10;6:23067. doi: 10.1038/srep23067.
**Remark : The authors used the antibody against C-terminal irisin (#H-067-17) to detect gastric secretoma at the 15 kDa band. They found its regulation to be identical to the 25 kDa band that can be detected using the antibody against FNDC5(149-178).
INTRODUCTION: Irisin, cleaved and secreted part of the transmembrane protein FNDC5, is a recently discovered adipo-myokine said to have a significant influence on body metabolism. Changes in thyrometabolic state may also alter serum irisin level. Since already reported data are not fully consistent, the aim of the present research is to evaluate the time-dependent changes in serum irisin level in patients affected by overt hypothyroidism.
MATERIAL AND METHODS: Study involved 36 subjects - two groups of 12 patients with long-lasting (AITD) and short-term (TC) overt hypothyroidism, and control group (CG) of 12 subjects, matched for age and gender. Serum irisin level, thyrometabolic state, creatine kinase (CK - muscle damage marker), glucose and insulin concentration were assessed and compared between groups.
RESULTS: Irisin level was significantly lower in AITD than in TC and CG (p=0.02; p<0.01; respectively), with no statistical difference between TC and CG (p>0.05). There was no significant difference between free triiodothyronine and free thyroxine level in AITD and TC (p>0.05). CK concentration was significantly higher in AITD and CG (p<0.01) with no difference between AITD and TC (p>0.05) as well as TC and CG (p>0.05). Additionally, CK level negatively correlated with irisin level (r= - 0.58; p<0.01).
CONCLUSIONS: In conclusion the irisin concentration changes during thyroid function impairment may be time-dependent. Patients with prolonged hypothyroidism have lower irisin level that those with short-term disorder.
Zybek-Kocik A, Sawicka-Gutaj N, Wrotkowska E, Sowiński J, Ruchała M, Endokrynol Pol. 2016 Feb 17. doi: 10.5603/EP.a2016.0030. [Epub ahead of print]
**Remark : The authors used Phoenix Pharmaceutical’s irisin ELISA kit (#EK-067-29) to measure irisin levels in human serum.**
BACKGROUND: Adipocyte fatty acid binding protein (FABP4) has been recently characterized as an adipokine that is closely associated with obesity and metabolic syndrome. Irisin, a novel myokine, activates thermogenesis by increasing the transformation of white adipocytes to brown, and it has improved glucose homeostasis in animal models. In this study, we aimed to explore the relationship between serum FABP4 and irisin in middle-aged Chinese subjects.
METHODS: A total of 111 normal residents (56 men and 55 women) of Fengxian District who were 40 to 60 years of age were recruited. Circulating FABP4 and irisin were determined by enzyme-linked immunosorbent assay. Anthropometric parameters, oral glucose tolerance test results, hemoglobin A1C (HbA1C), blood lipids, homeostasis model assessment of insulin resistance, homeostasis model assessment-β and body fat composition were also determined.
RESULTS: All participants were categorized by FABP4 tertiles. There were significant differences in blood pressure, body fat percentage, 2-h plasma glucose, and skeletal muscle mass among the three groups (P<0.05). Furthermore, FABP4 levels in the women were significantly higher than in the men (P<0.05). However, there was no sexual dimorphism in serum irisin (P>0.05). To exclude the effect of sex difference, partial correlations analysis showed that FABP4 was positively correlated with diastolic blood pressure (P<0.05) and body fat percentage (P<0.05) negatively correlated with skeletal muscle mass (P<0.05) and irisin (P<0.05), while irisin was positively correlated with HbA1c (P<0.05) and negatively correlated with creatinine (P<0.05). Multivariate regression analysis demonstrated that serum FABP4 was independently associated with skeletal muscle mass (P<0.001), diastolic blood pressure (P<0.05) and irisin (P<0.05) after adjustment for age, body mass index, body fat percentage, total cholesterol and HbA1C.
CONCLUSIONS: Elevated FABP4 levels increase the risks of obesity-related metabolic disorders and hypertension. Serum irisin might exert antagonistic effects on FABP4 in the middle-aged Chinese population.
Zhang S, Yang L, Chen P et al., PLoS One. 2016 Jan 11;11(1):e0146605. doi: 10.1371/journal.pone.0146605. eCollection 2016.
**Remark : The authors used Phoenix Pharmaceutical’s irisin ELISA kit (#EK-067-29) to measure irisin levels in human serum.**
Increased glucose production and reduced hepatic glycogen storage contribute to metabolic abnormalities in diabetes. Irisin, a newly identified myokine, induces the browning of white adipose tissue, but its effects on gluconeogenesis and glycogenesis are unknown. In the present study, we investigated the effects and underlying mechanisms of irisin on gluconeogenesis and glycogenesis in hepatocytes with insulin resistance, and its therapeutic role in type 2 diabetic mice. Insulin resistance was induced by glucosamine (GlcN) or palmitate in human hepatocellular carcinoma (HepG2) cells and mouse primary hepatocytes. Type 2 diabetes was induced by streptozotocin/high-fat diet (STZ/HFD) in mice. In HepG2 cells,irisin ameliorated the GlcN-induced increases in glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression, and glycogen synthase (GS) phosphorylation; it prevented GlcN-induced decreases in glycogen content and the phosphoinositide 3-kinase (PI3K) p110α subunit level, and the phosphorylation of Akt/protein kinase B, forkhead box transcription factor O1 (FOXO1) and glycogen synthase kinase-3 (GSK3). These effects of irisin were abolished by the inhibition of PI3K or Akt. The effects of irisin were confirmed in mouse primary hepatocytes with GlcN-induced insulin resistance and in human HepG2 cells with palmitate-induced insulin resistance. In diabeticmice, persistent subcutaneous perfusion of irisin improved the insulin sensitivity, reduced fasting blood glucose, increased GSK3 and Aktphosphorylation, glycogen content and irisin level, and suppressed GS phosphorylation and PEPCK and G6Pase expression in the liver. Irisinimproves glucose homoeostasis by reducing gluconeogenesis via PI3K/Akt/FOXO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via PI3K/Akt/GSK3-mediated GS activation. Irisin may be regarded as a novel therapeutic strategy for insulin resistance and type 2diabetes.
Tong-yan Liu, Chang-xiang Shi, Run Gao et al., Clinical ScienceJul 13, 2015, 2015 Nov;129(10):839-50. doi: 10.1042/CS20150009.
**Remark : The authors used Phoenix Pharmaceutical’s irisin ELISA kit (#EK-067-29) to measure irisin levels in human serum.**
