Relationship of irisin expression with metabolic alterations and cardiovascular risk in type 2 diabetes mellitus: a preliminary study

SUMMARY OBJECTIVE: The aim of this study was to investigate the role of irisin in type 2 diabetes mellitus and its association with metabolic alterations and obesity. METHODS: A cross-sectional case-control study was conducted on participants treated at Centro Universitário FMABC between August 2018 and July 2019, by comparing a control group (n=14) with type 2 diabetes mellitus patients (n=16). The control group consisted of participants aged above 21 years with no chronic diseases, diabetes, smoking, or illicit drug use. The type 2 diabetes mellitus group included patients aged above 21 years, who were diagnosed with type 2 diabetes for at least 5 years (glycated hemoglobin>7%). Exclusion criteria were not willing to continue, recent hospitalization, and failure to meet inclusion criteria. Biochemical parameters included blood glucose, glycated hemoglobin, plasma irisin levels, and irisin gene expression in peripheral blood. RESULTS: Type 2 diabetes mellitus patients exhibited significantly higher plasma glucose levels [143 (40) vs. 92 (13) mg/dL, *p<0.05] and glycated hemoglobin levels [7.1% (1.6) vs. 5.6% (0.5), *p<0.05] compared to the control group. Irisin gene expression in type 2 diabetes mellitus patients was lower 0.02288 (0.08050) than the control group 8.506e-006 (1.412e-005) (p=0.06). Correlation analysis revealed a positive association between irisin expression and body mass index in type 2 diabetes mellitus (Rho=0.5221, 95%CI -0.058 to 0.838, p=0.06), while plasma irisin showed a negative correlation with body mass index (Rho=-0.656, 95%CI -0.836 to 0.215, p=0.03). No significant correlations were found between plasma glucose or glycated hemoglobin levels and irisin expression. CONCLUSION: The data suggests that body mass index directly influences plasma irisin levels and the regulation of irisin gene expression, possibly linking irisin to adiposity changes observed in obesity-related type 2 diabetes mellitus.

FNDC5 Regulates the Adipogenic Differentiation of C3H10T1/2 Cells by Inhibiting the Phosphorylation of ERK1/2 / 中国生物化学与分子生物学报

The aim of this study was to explore the regulatory mechanism of Type Ⅲ domain-containing protein5 (FNDC5) on adipogenic differentiation in C3H10T1/2 cells. qRT-PCR and Western blot were used to detect the expression of FNDC5 during adipogenic differentiation of C3H10T1/2 cells. The lentivirus-coated overexpression and interference vector of FNDC5 were constructed and transfected into C3H10T1/2 cells. qRT-PCR was used to detect the expression of the key genes of adipogenic differentiation. Oil red O staining was used to detect the formation of lipid droplets; Western blot was used to detect the content of ERK1/2 and ERK1/2 phosphorylated protein (P-ERK1/2). After 8 days of adipogenic differentiation of C3H10T1/2 cells, the expression of Fndc5 increased significantly. After overexpression of FNDC5 in C3H10T1/2 cells, the expression of key genes for adipogenic differentiation, including peroxisome proliferator-activated receptor-酌 (PPAR酌), CCAAT enhancer binding protein beta (C/EBP茁), fatty acid binding protein 4 (FABP4) and CCAAT enhancer binding protein alpha (C/EBPα), all decreased significantly. The content of lipid droplets and P-ERK1/2 also decreased significantly. On the contrary, after interference of FNDC5 in C3H10T1/2 cells, the expression of key genes for adipogenic differentiation, including PPARγ, C/EBP茁, FABP4 and C/EBPα were significantly increased. Meanwhile, the content of lipid droplets and P-ERK1/2 also increased significantly. This study found that FNDC5 can inhibit the adipogenic differentiation of C3H10T1/2 cells by inhibiting the phosphorylation level of ERK1/2, which can provide reference data for the mechanism of FNDC5 in regulating fat deposition.

Expression of FNDC5/Irisin in pancreatic cancer and its relationship with clinicopathological features / 中华肝胆外科杂志

0bjective To investigate the expression and distribution of FNDC5/Irisin in pancreatic cancer tissues and adjacent tissues.and to analyze its correlation with clinicopathological features.Methods Collection of archived wax blocks from 64 patients diagnosed with pancreatic cancer after surgical treatment from January 2015 to December 2018 in the Department of Pathology,Affiliated Qingdao Municipal Hospital of Qingdao University,and 30 tissues collected intraoperatively from January 2016 to December 2018 Sam-ples,all collected samples included tumor tissue and corresponding adjacent tissues(＞2 am from the tumor edge).Real-time quantitative PCR(qRT-PCR)and immunohistochemistry were used to detect the expres-sion of FNDC5/Irisin mRNA and its positivity in pancreatic cancer tissues and adjacent tissues.and to ana-1yze its relationship with clinicopathological features of pancreatic cancer.Results qRT-PCR showed that the expression of FNDC5/Irisin mRNA in pancreatic cancer tissues was higher than that in the corresponding adjacent pancreatic tissues,the difference was statistically significant(P＜0.05).The immunohistochemis-try results showed that the positivity of FNDC5/Irisin in pancreatic cancer tissues was 59.4％.and the posi-tivity of FNDC5/Irisin in adjacent tissues was 28.1％.and the positivity of FNDC5/Irisin in cancer tissues and adjacent pancreatic tissues was significantly different(P＜0.05):the expression level of FNDC5/Irisin was not related with the gender,age,tumor size,degree of differentiation,and tumor stage.(P＞0.05),but FNDC5/Irisin expression was associated with liver and lymph node metastasis(P＜0.05).Conclusion The positivity of FNDC5/Irisin in pancreatic cancer tissues is significantly higher than that in adjacent pan-creatic tissues.and it is correlated with liver and lymph node metastasis in pancreatic cancer.

Expression of FNDC5/Irisin in pancreatic cancer and its relationship with clinicopathological features / 中华肝胆外科杂志

Objective@#To investigate the expression and distribution of FNDC5/Irisin in pancreatic cancer tissues and adjacent tissues, and to analyze its correlation with clinicopathological features.@*Methods@#Collection of archived wax blocks from 64 patients diagnosed with pancreatic cancer after surgical treatment from January 2015 to December 2018 in the Department of Pathology, Affiliated Qingdao Municipal Hospital of Qingdao University, and 30 tissues collected intraoperatively from January 2016 to December 2018 Samples, all collected samples included tumor tissue and corresponding adjacent tissues (>2 cm from the tumor edge). Real-time quantitative PCR (qRT-PCR) and immunohistochemistry were used to detect the expression of FNDC5/Irisin mRNA and its positivity in pancreatic cancer tissues and adjacent tissues, and to analyze its relationship with clinicopathological features of pancreatic cancer.@*Results@#qRT-PCR showed that the expression of FNDC5/Irisin mRNA in pancreatic cancer tissues was higher than that in the corresponding adjacent pancreatic tissues, the difference was statistically significant (P<0.05). The immunohistochemistry results showed that the positivity of FNDC5/Irisin in pancreatic cancer tissues was 59.4%, and the positivity of FNDC5/Irisin in adjacent tissues was 28.1%, and the positivity of FNDC5/Irisin in cancer tissues and adjacent pancreatic tissues was significantly different (P<0.05); the expression level of FNDC5/Irisin was not related with the gender, age, tumor size, degree of differentiation, and tumor stage.(P>0.05), but FNDC5/Irisin expression was associated with liver and lymph node metastasis (P<0.05).@*Conclusion@#The positivity of FNDC5/Irisin in pancreatic cancer tissues is significantly higher than that in adjacent pancreatic tissues, and it is correlated with liver and lymph node metastasis in pancreatic cancer.

Association between Circulating Irisin and C-Reactive Protein Levels: A Systematic Review and Meta-Analysis

BACKGROUND: Although previous studies have demonstrated that irisin plays an anti-inflammatory role in the body, conflicting results have been reported regarding the correlation between serum levels of irisin and C-reactive protein (CRP). The present meta-analysis was conducted to further investigate the correlation between irisin and CRP levels. METHODS: We systematically searched PubMed, the Cochrane Library, Web of Science, Embase, SCOPUS, and Ovid to retrieve studies assessing the correlation between irisin and CRP levels. Meta-analyses were performed using a random-effects model, and the I 2 index was used to evaluate heterogeneity. RESULTS: Of the 428 studies that were initially found, 14 studies with 2,530 participants met the inclusion criteria for the meta-analysis. The pooled effect size was calculated as 0.052 (95% confidence interval, −0.047 to 0.152; P=0.302). Subgroup analyses identified s ignificant, positive, but weak correlations between CRP and irisin levels in cohort studies, studies conducted among healthy participants, studies in which the male-to-female ratio was less than 1, in overweight or obese subjects, and in studies with a sample size of at least 100 participants. CONCLUSION: The present meta-analysis found no overall significant correlation between irisin and CRP levels, although a significant positive correlation was found in overweight or obese subjects. Well-designed studies are needed to verify the results of the present meta-analysis.

The diagnostic value of FNDC5/irisin in renal cell cancer

ABSTRACT Purposes: The aim of this study was to determine the diagnostic significance of fibronectin type III domain containing protein 5 (FNDC5)/Irisin levels in the sera of patients with renal cell cancer. Materials and Methods: In the study, 48 individuals were evaluated. The patient group included 23 subjects diagnosed with renal tumor, and the control group of 25 healthy individuals. Patients diagnosed with renal tumor received surgical treatment consisting of radical or partial nephrectomy. Blood specimens were collected and serum FNDC5/Irisin and carcinoembryonic antigen (CEA) levels were determined using enzyme-linked immunosorbent assay (ELISA). Results: FNDC5/irisin and CEA levels in renal cancer patients were significantly higher compared with the control group (p=0.0001, p=0.009, respectively). Also, FNDC5 levels was more sensitive and specific than CEA levels. The best cut-off points for FNDC5/irisin were >105pg/mL and CEA were >2.67ng/mL for renal cancer. Conclusions: FNDC5/Irisin may be used as a diagnostic biomarker for renal cancer.

Effects of Acute Exercises of Different Intensities on the FNDC5 and UCP-1 Expression in Epididymal WAT of Rats / 中国运动医学杂志

Objective To investigate the effect of acute exercises of different intensities on the "browning" of epididymal white adipose tissue(WAT) in rats.Methods Thirty Sprague-Dawley male rats were randomly divided into a control group(C,n=6) and an exercises group(E,n=24).Rats in group E were further randomly divided into a moderate intensity exercise (EM,n=12,V=15 m/min) group and a high intensity intermittent exercise(EH,n=12,V=35 m/min,6min's exercises followed by 5 min's rest,repeating 3 times) group.Right after and 6 hours after the acute exercises,the epididymal WAT was taken,and the fibronectin type Ⅲ domain-containing 5 protein(FNDC5) and the uncoupling protein 1(UCP-1) mRNA were detected using RT-qPCR,while the level of FNDC5 and UCP-1 protein was evaluated using Western Blotting.Results Right after the acute exercises,compared with group C,the level of FNDC5 mRNA in group EH increased significantly (P＜0.01),while that of UCP-1 mRNA in group E decreased immediately(P＜0.05) but increased significantly six hours later(P＜0.05).Compared with group C,the level of FNDC5 in groups EM and EH tended to rise,and that of group EM increased significantly(P＜0.05).Compared with group C,the level of UCP-1 in group EM and EH had the tendency to rise,and it increased significantly immediately after exercises in group EH (P＜0.05).Conclusion The acute exercise at different intensities can promote the level of FNDC5 and UCP-1 in epididymal white adipose tissue,"browning" and heat production from fat issues.The level of UCP-1 mRNA increased significantly at 6 hours after exercises,while that of FNDC5 mRNA increased most immediately after the high-intensity intermittent exercises.

Eight-week Climbing Ladder Exercise with Load Induces Differential Expression of PGC1α/FNDC5/ MSTN in Soleus and Extensor Digitorum Longus Muscle in SD Rats / 中国运动医学杂志

Objective To observe the effect of 8-week climbing ladder exercise with load on the expression of proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)/ fibronectin type Ⅲ domain containing 5 (FNDC5)/ myostatin (MSTN)in soleus and extensor digitorum longus muscle and the serum concentration of irisin in Sprague-Dawley (SD)rats.Methods Twenty SD rats were randomly divided into a control (Con,n=10)group and a climbing ladder (Lad,n=10)group.The Lad group took an 8-week and once-every-3-day program of resistance exercise using an improved model of climbing ladder with load.Then the soleus and extensor digitorum longus muscles were isolated at 48 h after exercise.The PGC1α/FNDC5/MSTN mRNA and protein expression in the skeleton muscle were detected using quantitative PCR and Western blotting respectively.The serum concentration of irisin was measured using enzyme-linked immunosorbent assay.Results Compared with Con group,the expression of PGC1α in the soleus muscle reduced significantly (P＜0.05),that of FNDC5 reduced but without significance and that of MSTN increased significantly (P＜0.05)in Lad group.However,the expression of PGC1α in the extensor digitorum longus muscle increased significantly (P＜0.05),that of FNDC5 increased but without significance and that of MSTN decreased significantly (P＜0.05)in Lad group compared with Con group.There were no significant differences in the serum concentration of irisin between the two groups.Conclusion Eight-week climbing ladder exercise with load on rats induces differential expression of PGC1α/FNDC5/MSTN in soleus and extensor digitorum longus muscle,but doesn't influence the serum concentration of irisin.It is suggested that there may be a complex mechanism of balancing and antagonism in the body after long-term resistance exercises.

Actualizaciones sobre "Irisina": la nueva mioquina / Irisin updates: the new myokine

In the continuous search of researchers to find an effective method to control obesity, a myokine called Irisin was found. Irisin is secreted mainly by skeletal muscle in response to exercise, either resistance, strength or high intensity, where High Intensity Interval Training (HIIT) is included. This polypeptide hormone acts mainly on subcutaneous adipose cells, turning white fat into brown fat. Brown fat is highly thermogenic, which enhance raising of total energy expenditure and helps maintaining or loosing corporal weight. Plasmatic Irisin levels are related positively with insulin sensitivity and weight loss. It has been also discovered that a greater plasmatic level of Irisin is related to the lengthening of telomeres, to a greater concentration of free tyrosine (T4) and it has been recently found that is related to an antitumoral effect on some types of cancer. All of the functions mediated by Irisin, have given it a protective action against different diseases, especially metabolic ones. The aim of this review was to update the knowledge about Irisin, and to show the effects that exercise has on its plasmatic levels, as well as comprehend how does the release of irisin influences different body systems. Counting with more information will allow the arising of new lines of investigation that will bring up non pharmacological therapeutic strategies for the treatment of non-communicable diseases.

En la búsqueda continua de los investigadores por combatir de manera más efectiva la obesidad, se descubre una mioquina llamada Irisina. La Irisina es secretada principalmente por el músculo esquelético en respuesta al ejercicio, ya sea aeróbico, de fuerza o de alta intensidad, donde se incluyen, ejercicios de intervalo de alta intensidad (HIIT). Esta hormona polipeptídica actúa principalmente sobre células adiposas subcutáneas, transformando grasa blanca en grasa parda. La grasa parda es altamente termogénica, lo que favorece el aumento del gasto energético total y ayuda a mantener o incluso a perder peso corporal. La concentración de Irisina plasmática se relaciona positivamente con la sensibilidad a la insulina y la pérdida de peso. Además, se ha descubierto que una mayor concentración de Irisina plasmática se relaciona con el alargamiento de los telómeros, y también, con una mayor concentración de T4 libre y con un recién descubierto efecto antitumoral en algunos tipos de cáncer. Todas las funciones mediadas por la Irisina, le atribuyen una acción protectora contra distintas enfermedades, especialmente metabólicas. El objetivo de esta revisión fue actualizar el conocimiento sobre la Irisina, evidenciando los efectos que tiene la realización de ejercicio sobre los niveles plasmáticos de ésta, así como también comprender como su liberación influye en distintos sistemas corporales. El contar con mayor información dará paso a nuevas líneas de investigación y permitirá contar con estrategias terapéuticas no farmacológicas que contribuyan en el tratamiento de enfermedades crónicas no transmisibles.

Circulating levels of irisin is elevated in hypothyroidism, a case-control study

Objective Our objective in this study was to determine the relationship between irisin hormone, which has a similar effect with thyroid hormones on adipose tissue and the metabolism, and the thyroid functions and the obesity secondary to thyroid disease. Subjects and methods Seventy-four patients were included in the study, of the patients, 37 were newly diagnosed with Hashimoto’s thyroiditis related hypothyroidism but not started on a treatment yet, and the remaining 37 were healthy volunteers without a known disease. Serum thyroid stimulating hormone (TSH), free thyroxin (fT4), anti-thyroglobulin and anti-thyroid peroxidase were measured and thyroid ultrasonography was performed in both groups. Serum irisin levels were measured using the commercially available ELISA kit. The hypothyroidism group had higher levels of irisin compared to the control group (2.77 ng/mL vs. 2.15 ng/mL respectively; p = 0.017). Results The hypothyroidism group had higher median levels of irisin in the obese patients than those in the control group (3.10 ng/mL vs. 2.10 ng/mL respectively; p = 0.013). Irisin level was negatively correlated with age in the whole population and patients with hypothyroidism (r = -0.255, p = 0.028; r = -0.346, p = 0.036 respectively). Irisin level was positively correlated with TSH (r = 0.247, p = 0.034) but negatively correlated with the fT4 (r = -0.316, p = 0.006) in the whole population. Obesity, fT4 and irisin levels were identified to be independent predictors in the diagnosis of hypothyroidism in the multivariable logistic regression analysis. Conclusion To the best of our knowledge, this study is the first in literature to identify that obesity, irisin level and fT4 level are independent risk factors for hypothyroidism.

Zinc finger protein 521 overexpression increased transcript levels of Fndc5 in mouse embryonic stem cells.

Zinc finger protein 521 is highly expressed in brain, neural stem cells and early progenitors of the human hematopoietic cells. Zfp521 triggers the cascade of neurogenesis inmouse embryonic stemcells through inducing expression of the early neuroectodermal genes Sox1, Sox3 and Pax6. Fndc5, a precursor of Irisin has inducing effects on the expression level of brain derived neurotrophic factor in hippocampus. Therefore, it is most likely that Fndc5 may play an important role in neural differentiation. To exhibit whether the expression of this protein is under regulation with Zfp521, we overexpressed Zfp521 in a stable transformants of mESCs expressing EGFP under control of Fndc5 promoter. Increased expression of Zfp521 enhanced transcription levels of both EGFP and endogenous Fndc5. This result was confirmed by overexpression the aforementioned vectors in HEK cells and indicated that Zfp521 functions upstream of Fndc5 expression. It is most likely that Zfp521 may act through the binding to its response element on Fndc5 core promoter. Therefore it is concluding that an enhanced expression of Fndc5 in neural progenitor cells is stimulated by Zfp521 overexpression in these cells.