Research Progress of β-Klotho in Energy Metabolism and Tumor Development / 中国生物化学与分子生物学报

β-Klotho (KLB) is a member of the Klotho protein family, which is mainly distributed in organs and tissues such as the liver, fat, pancreas, and brain. KLB is a single-pass transmembrane protein whose structural characteristics determine that KLB acts as a co-receptor for fibroblast growth factor (FGF) 19/21 targeting the activation of fibroblast growth factor receptor (FGFRs). KLB is involved in the regulation of blood glucose, lipids, body weight, bile acid circulation, and hepatocyte proliferation in the FGF21/19-KLB-FGFRs pathway. This paperwill review the structural characteristics and distribution of KLB, as well as the regulatory mechanism of material energy and its role in tumor formation in the FGF19/21-KLB-FGFRs pathways.

Fibroblast growth factor 21 (FGF21) attenuates tacrolimus-induced hepatic lipid accumulation through transcription factor EB (TFEB)-regulated lipophagy / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Tacrolimus (TAC), also called FK506, is one of the classical immunosuppressants to prevent allograft rejection after liver transplantation. However, it has been proved to be associated with post-transplant hyperlipemia. The mechanism behind this is unknown, and it is urgent to explore preventive strategies for hyperlipemia after transplantation. Therefore, we established a hyperlipemia mouse model to investigate the mechanism, by injecting TAC intraperitoneally for eight weeks. After TAC treatment, the mice developed hyperlipemia (manifested as elevated triglyceride (TG) and low-density lipoprotein cholesterol (LDL-c), as well as decreased high-density lipoprotein cholesterol (HDL-c)). Accumulation of lipid droplets was observed in the liver. In addition to lipid accumulation, TAC induced inhibition of the autophagy-lysosome pathway (microtubule-associated protein 1 light chain 3β (LC3B) II/I and LC3B II/actin ratios, transcription factor EB (TFEB), protein 62 (P62), and lysosomal-associated membrane protein 1 (LAMP1)) and downregulation of fibroblast growth factor 21 (FGF21) in vivo. Overexpression of FGF21 may reverse TAC-induced TG accumulation. In this mouse model, the recombinant FGF21 protein ameliorated hepatic lipid accumulation and hyperlipemia through repair of the autophagy-lysosome pathway. We conclude that TAC downregulates FGF21 and thus exacerbates lipid accumulation by impairing the autophagy-lysosome pathway. Recombinant FGF21 protein treatment could therefore reverse TAC-caused lipid accumulation and hypertriglyceridemia by enhancing autophagy.

Endogenous FGF21 attenuates blood-brain barrier disruption in penumbra after delayed recanalization in MCAO rats through FGFR1/PI3K/Akt pathway / 中南大学学报(医学版)

OBJECTIVES@#Restoration of blood circulation within "time window" is the principal treating goal for treating acute ischemic stroke. Previous studies revealed that delayed recanalization might cause serious ischemia/reperfusion injury. However, plenty of evidences showed delayed recanalization improved neurological outcomes in acute ischemic stroke. This study aims to explore the role of delayed recanalization on blood-brain barrier (BBB) in the penumbra (surrounding ischemic core) and neurological outcomes after middle cerebral artery occlusion (MCAO).@*METHODS@#Recanalization was performed on the 3rd day after MCAO. BBB disruption was tested by Western blotting, Evans blue dye, and immunofluorescence staining. Infarct volume and neurological outcomes were evaluated on the 7th day after MCAO. The expression of fibroblast growth factor 21 (FGF21), fibroblast growth factor receptor 1 (FGFR1), phosphatidylinositol-3-kinase (PI3K), and serine/threonine kinase (Akt) in the penumbra were observed by immunofluorescence staining and/or Western blotting.@*RESULTS@#The extraversion of Evans blue, IgG, and albumin increased surrounding ischemic core after MCAO, but significantly decreased after recanalization. The expression of Claudin-5, Occludin, and zona occludens 1 (ZO-1) decreased surrounding ischemic core after MCAO, but significantly increased after recanalization. Infarct volume reduced and neurological outcomes improved following recanalization (on the 7th day after MCAO). The expressions of Claudin-5, Occludin, and ZO-1 decreased surrounding ischemic core following MCAO, which were up-regulated corresponding to the increases of FGF21, p-FGFR1, PI3K, and p-Akt after recanalization. Intra-cerebroventricular injection of FGFR1 inhibitor SU5402 down-regulated the expression of PI3K, p-Akt, Occludin, Claudin-5, and ZO-1 in the penumbra, which weakened the beneficial effects of recanalization on neurological outcomes after MCAO.@*CONCLUSIONS@#Delayed recanalization on the 3rd day after MCAO increases endogenous FGF21 in the penumbra and activates FGFR1/PI3K/Akt pathway, which attenuates BBB disruption in the penumbra and improves neurobehavior in MCAO rats.

Effect of recombinant human fibroblast growth factor 21 on the mineralization of cementoblasts and its related mechanism / 华西口腔医学杂志

OBJECTIVES@#To investigate the effect of recombinant human fibroblast growth factor 21 (rhFGF21) on the proliferation and mineralization of cementoblasts and its mechanism.@*METHODS@#Hematoxylin eosin, immunohistochemical staining, and immunofluorescence were used to detect the expression and distribution of fibroblast growth factor 21 (FGF21) in rat periodontal tissues and cementoblasts (OCCM-30), separately. Cell Counting Kit-8 was used to detect the proliferation of OCCM-30 under treatment with rhFGF21. Alkaline phosphatase staining and Alizarin Red staining were used to detect the mineralization state of OCCM-30 after 3 and 7 days of mineralization induction. The transcription and protein expression of the osteogenic-related genes Runx2 and Osterix were detected by real-time quantitative polymerase chain reaction (PCR) and Western blot analysis. The expression levels of genes of transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) signaling pathway in OCCM-30 were detected through PCR array analysis.@*RESULTS@#FGF21 was expressed in rat periodontal tissues and OCCM-30. Although rhFGF21 had no significant effect on the proliferation of OCCM-30, treatment with 50 ng/mL rhFGF21 could promote the mineralization of OCCM-30 cells after 7 days of mineralization induction. The transcriptional levels of Runx2 and Osterix increased significantly at 3 days of mineralization induction and decreased at 5 days of mineralization induction. Western blot analysis showed that the protein expression levels of Runx2 and Osterix increased during mineralization induction. rhFGF21 up-regulated Bmpr1b protein expression in cells.@*CONCLUSIONS@#rhFGF21 can promote the mineralization ability of OCCM-30. This effect is related to the activation of the TGFβ/BMP signaling pathway.

Mediators of energy homeostasis in hyperthyroidism

ABSTRACT Objective: The aim of this study was to assess the effect of hyperthyroidism and its treatment on body weight and composition, insulin resistance, and mediators of appetite and energy homeostasis, namely ghrelin, leptin, adiponectin, and fibroblast growth factor 21 (FGF21). Subjects and methods: Thirty-five adult patients (27 female and 8 male, aged 39.63 ± 9.70 years) with overt hyperthyroidism were evaluated for leptin, ghrelin, adiponectin, and FGF21 levels; insulin resistance; and body composition using DEXA both at baseline and a minimum of two months following normalization of serum thyroxin on carbimazole treatment. Comparison of means between the baseline and post treatment values was performed by the paired t test for normally distributed parameters and by the Wilcoxon signed-rank test for non-normally distributed data. Results: Hyperthyroidism correction resulted in an increase in weight from 51.15 ± 8.50 kg to 55.74 ± 8.74 kg (P < 0.001), paradoxically accompanied by a decrease in insulin resistance as measured by HOMA-IR from 1.35 (1.02-1.72) to 0.73 (0.52-0.93) ( P < 0.001). Correction of hyperthyroidism was also associated with a decrease in FGF21 from 58 (55-64) to 52 (47-58) pg/mL ( P < 0.001) and in leptin levels from 17 (7-36) to 11 (4.6-28) ng/mL ( P = 0.03). Conclusion: Despite lower body weight, thyrotoxicosis is associated with insulin resistance. High levels of thermogenic hormones, leptin, and FGF21 were observed in thyrotoxicosis and may be partly responsible for the excessive heat production typical of this condition.

Effect of voglibose combined with exenatide on blood glucose control and serumfibroblast growth factor 21expression in patients with type 2 diabetes mellitus / 中国医师进修杂志

Objective:To investigate the effect of voglibose combined with exenatide on blood glucose control and serum fibroblast growth factor 21 (FGF-21) expression in patients with type 2 diabetes mellitus (T2DM).Methods:Three hundred and eighty patients with T2DM admitted to Qingdao Municipal Hospital from October 2018 to September 2020 were selected and randomly divided into the control group and the observation group, with 190 patients in each group. The control group was treated with voglibose, and the observation group was treated with voglibose and exenatide. Both groups were treated for 16 weeks. Blood glucose, blood fat, insulin and other indicators as well as serum FGF-21 levels were compared between the two groups before and after the treatment, and the efficacy of drugs and the incidence of adverse reactions were compared.Results:The total effective rate in the observation group was higher than that in the control group: 97.89%(186/190) vs. 93.16%(177/190), χ2 = 5.00, P<0.05. After treatment, the levels of fasting plasma glucose (FPG), 2 h plasma glucose (2 h PG) and glycosylated hemoglobin (HbA 1c) in the observation group were lower than those in the control group: (6.95 ± 1.03) mmol/L vs. (8.29 ± 1.15) mmol/L, (7.88 ± 2.07) mmol/L vs. (10.03 ± 3.24) mmol/L, (7.17 ± 1.08)% vs. (8.13 ± 1.21)%, P<0.05. After treatment, the levels of triacylglycerol (TG), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in the observation group were lower than those in the control group: (2.13 ± 0.23) mmol/L vs. (2.93 ± 0.34) mmol/L, (3.10 ± 1.01) mmol/L vs. (3.98 ± 1.14) mmol/L, (1.93±0.38) mmol/L vs. (2.73±0.54) mmol/L, P<0.05. After treatment, the level of islet β cell function index (HOMA-β) in the observation group was higher than that in the control group: 111.56 ± 20.78 vs. 102.23 ± 20.14, P<0.05. After treatment, the level of serum FGF-21 in the observation group was lower than that in the control group: (142.09 ± 26.82) ng/L vs. (150.22 ± 30.21) ng/L, P<0.05. The incidence of adverse reactions between the two groups had no significant difference ( P>0.05). Conclusions:Voglibose combined with exenatide has a definite effect on T2DM patients with metformin failure, which can effectively control their blood glucose level, reduce serum FGF-21 level, improve insulin resistance and glucose and lipid metabolism, and reduce body mass, with high safety.

Therapeutic effect of liraglutide on non-alcoholic fatty liver disease rats and its influence on the expression of FGF21 / 中国医师杂志

Objective:To study the therapeutic effect of liraglutide on rat models with non-alcoholic fatty liver disease (NAFLD) and its influence on the expression of fibroblast growth factor 21 (FGF21).Methods:Thirty five Sprague Dawley (SD) rats were randomly divided into normal control group (15 rats) and control group (20 rats). They were fed with normal diet and high fat diet respectively. The NAFLD rat model was established by feeding the model group for 12 weeks. After successful modeling, the model group was randomly divided into liraglutide group and model group. 600 μg/(kg·d) liraglutide and equal volume normal saline were injected intraperitoneally respectively. All rats were killed at the 16th week. Serum FGF21, alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose (FBG), triglyceride (TG) and total cholesterol (TC) were measured; Hematoxylin-eosin (HE) staining was used to observe the pathological changes of rat liver tissue, and real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of FGF21 mRNA in rat liver tissue.Results:The liver index and serum ALT, AST, TC and TG contents in model group were significantly higher than those in normal control group (all P<0.05). The above indexes in liraglutide group were significantly lower than those in model group (all P<0.05). There was no significant difference in serum FBG level among the three groups ( P>0.05). HE staining showed that there were no abnormal pathological changes in liver of normal control group. Steatosis and inflammatory cell infiltration occurred in liver cells of model group. Compared with model group, liver steatosis and inflammatory cell infiltration in liraglutide group were significantly reduced. The level of FGF21 in serum and mRNA expression of FGF21 in liver tissue in model group were significantly higher than those in normal control group ( P<0.05). The levels of FGF21 in serum and FGF21 mRNA in liver tissue in liraglutide group were lower than those in model group ( P<0.05). Conclusions:Liraglutide can effectively delay the development of NAFLD in rats, and its mechanism may be related to the regulation of the expression of FGF21.

The role of FGF21 in inhibition of heart failure with empagliflozin and related mechanisms / 药学学报

The aim of this study is to investigate the role of fibroblast growth factor 21 (FGF21) in empagliflozin (EMP) in treatment of heart failure and the related mechanisms. FGF21 knockout (FGF21 KO) and littermate wild-type (WT) mice induced by doxorubicin (Dox) were used to establish heart failure mouse model in vivo. The experiment process and animal welfare follow the regulations of Animal Ethics Committee of Hefei University of Technology strictly. The results suggest that Dox (5 mg·kg-1) induced typical heart failure symptoms in both WT and FGF21 KO mice. In WT mice, EMP (10 mg·kg-1) significantly improved Dox-induced cardiac atrophy, decreased myocardial systolic function, decreased left ventricular ejection fraction and shortened fraction; EMP treatment also significantly inhibited the increase of Dox-induced cardiotoxicity indexes (aspartate amino transferase, creatine kinase, hydroxybutyrate dehydrogenase, lactate dehydrogenase) in mice. Dox induced cardiac fibrosis, inflammation and oxidative stress were also significantly improved by EMP. However, in FGF21 KO mice, the therapeutic effects of EMP on heart failure was significantly inhibited. The results suggest that the function of EMP in treating heart failure partly depends on the presence of FGF21, and the mechanism may be related to the effect of FGF21 on improving fibrosis, inflammation and oxidative stress.

Effects of different exercise on liver lipid accumulation and FGF21 secretion in obese rats / 中国应用生理学杂志

Objective: To investigate the effects of continuous exercise training (CT) and high-intensity interval exercise training (HIIT) on liver lipid metabolism and the correlation of the level of fibroblast growth factor 21(FGF21) in serum and liver tissues. Methods: Male SD rats were randomly divided into normal diet group (N) and obesity model group (H) after 1 week of adaptive feeding. Rats in the obesity model group were fed with 45% high-fat diet for about 8 weeks, and 20% weight increase compared with normal rats was considered as obesity. The rats were divided into normal diet control group (LC), normal diet HIIT group (LHI), normal diet CT group (LCT), High fat diet-induced obese control group (OC), obese HIIT group (OHI), and obese CT group (OCT) (n=10). Exercised rats were given weight-bearing swimming training intervention for 8 weeks. Blood samples were collected at least 24h after the last exercise intervention to detect the serum levels of inflammatory factors and FGF21. Liver tissue samples were collected to detect the lipid content, lipid metabolic enzyme content and FGF21 expression level. Results: Compared with LC group, the body weight, serum inflammatory factors levels and hepatic triglyceride content were increased significantly (P＜0.05). Hepatic triglyceride content was downregulated in LHI group and FGF21 expression level was enhanced in LCT group (P＜0.05). Compared with OC group, the body weight and hepatic triglyceride content were decreased significantly (P＜0.05), mitochondrial CPT-1β and β-HAD enzyme contents in liver were increased significantly (P＜0.05) in OHI group, the contents of LPL and FAT/CD36 enzyme in liver and the levels of FGF21 in serum and liver of OCT group were increased significantly (P＜0.05). Conclusion: Both exercise modes can reduce the body weight in normal and obese rats, and lipid deposition in the liver of obese rats. HIIT has a more significant effect on alleviating liver lipid deposition in obese rats by upregulating mitochondrial lipid oxidation level in normal and obese rats. CT improves the levels of FGF21 in serum and liver tissues of normal and obese rats, enhances enzyme contents that involved in fatty acids uptake to the liver, which has limited effect on alleviating lipid deposition in liver of obese rats.

Correlation between erectile dysfunction and serum FGF21 level in patients with type 2 diabetes / 中国医师杂志

Objective:To study the correlation between the occurrence of diabetes mellitus complicated with erectile dysfunction (DMED) and serum fibroblast growth factor-21 (FGF21) level, analyze the role of FGF21 in the occurrence of DMED, and explore its predictive and diagnostic value for DMED.Methods:61 male patients with type 2 diabetes in Tai′an Central Hospital from January 2017 to June 2018 were selected as subjects. They were divided into 2 groups: DMED group ( n=30) and type 2 diabetes mellitus group (DM group, n=31). And 32 healthy persons were selected as control group. The general data of all subjects were collected, physical examination, genital examination and blood sampling were carried out for biochemical analysis. The erectile function was measured by International Erectile Function Index-5 (IIEF-5) questionnaire, and serum FGF21 level was detected by automatic biochemical analyzer. The correlation between IIEF-5 score with FGF21 and other indicators were analyzed by Spearman correlation analysis. Multiple linear regression analysis was used to analyze the related risk factors affecting DMED. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of FGF21 level for DMED. Results:(1) The serum level of FGF21 in the DMED group, DM group, control group were (112.5±9.2)pg/ml, (103.9±6.2)pg/ml and (91.9±3.9)pg/ml respectively, with significant differences (all P<0.05). (2) Spearman correlation analysis showed that IIEF-5 score was negatively correlated with FGF21, age, smoking, drinking, systolic blood pressure, diastolic blood pressure, glycated hemoglobin A1c (HbA 1c), fasting plasma glucose (FPG), total cholesterol (TC), total glyceride (TG), low density lipoprotein cholesterol (LDL-C), fasting insulin (FINS), homeostasis model insulin resistance index (HOMA-IR), and positively correlated with high density lipoprotein cholesterol (HDL-C) and testosterone( all P<0.05). The serum FGF21 level was positively correlated with smoking, drinking, systolic blood pressure, diastolic blood pressure, HbA 1c, FPG, TC, TG, LDL-C, FINS, HOMA-IR, and negatively correlated with HDL-C and testosterone ( P<0.05). (3) Multiple linear regression analysis showed that FGF21, HbA 1c, HOMA-IR and IIEF-5 were independent risk factors for erectile function (all P<0.05). (4) According to ROC curve, when the optimal cutoff value of FGF21 level was 102.75 pg/ml, the predictive sensitivity and specificity for DMED were 0.867 and 0.714, respectively. Conclusions:Serum FGF21 level is closely related to the occurrence of diabetes mellitus and DMED, which is an independent risk factor of DMED.

MicroRNA-100-5p Regulates Melanogenesis in Alpaca Melanocytes by Targeting FGF21 / 中国生物化学与分子生物学报

Although many microRNAs (miRNAs) are known to function as regulators of coat color and melanogenesis, the underlying molecular mechanisms of miR-100-5p governing melanogenesis were not completely known.The goal of this study was to determine the effect of miR-l()()-5p on melanogenesis in alpaca melanocytes.Fibroblast growth factor 21 (FGF21) is a predicted target gene of miR-100-5p and the luciferase reporter assay demonstrated that miR-100-5p regulates FGF21 by binding to its 3' untranslated region (3'UTR).In this study, alpaca melanocytes were transfected with miR-100-5p, inhibitor and negative control plasmid.Results showed that miR-100-5p overexpression significantly decreased mRNA and protein expression of FGF2\.Meanwhile, the ERK signal pathway was inhibited, with subsequent up-regulation of microphthalmia-associated transcription factor (MITF) , tyrosinase (TYR) and tyrosinase-related protein 2 (TYRP2), which increased melanin production.The results suggest that miR-100-5p may regulate melanogenesis by targeting FGF21 via extracellular regulated MAP kinase (ERK) signaling pathway.

Research progress of fibroblast growth factor 21 in diabetic retinopathy / 国际眼科杂志(Guoji Yanke Zazhi)

@#As a newly discovered endogenous regulator, fibroblast growth factor 21(FGF21)becomes hot topic in recent professional research. It plays an important role in diabetic retinopathy recently. Moreover, FGF21 has attracted more and more attention in recent years. This paper discussed the molecular structure of FGF 21, biological function, relationship between FGF21 and inflammatory response and role in the pathological process of diabetic retinopathy.

Current status and perspectives of fibroblast growth factor 21 in nonalcoholic fatty liver disease / 临床肝胆病杂志

Fibroblast growth factor 21 (FGF21) is a peptide hormone predominantly secreted by the liver and plays a crucial role in maintaining whole-body energy metabolism and regulating insulin sensitivity. A large number of clinical studies have demonstrated that serum FGF21 levels are increased in obese patients with non-alcoholic fatty liver disease (NAFLD), and high circulating FGF21 is a sensitive biomarker for predicting the onset and progression of NAFLD. Injection of exogenous FGF21 can effectively alleviate pathological process in both animal models and NAFLD patients. This review aims to describe the molecular mechanism underlying the hepatoprotective effects of FGF21; to summarize the current data and challenges of the clinical trials on FGF21 analogs and receptor agonists in the treatment of NAFLD and nonalcoholic steatohepatitis (NASH); and to speculate the future directions of FGF21 as a diagnosis and treatment for NAFLD.

Aerobic and Resistance Exercises Modulate Fibroblast Growth Factor-21 Level in Menopause Women with Type II Diabetes

ABSTRACT Objectives: To determine the relationship between exercises with the serum fibroblast growth factor 21 (FGF21) levels and glucose and lipid profile in menopausal type II diabetic women. Methods: Menopausal women with type II diabetes mellitus were divided into three groups including control (n = 14), aerobic exercise (n = 14) and resistance exercise groups (n = 14). The mean levels of serum glucose, LDL-C, HDL-C, insulin, TG and cholesterol were measured in all participants after 8 weeks of exercise. Serum FGF21 was also measured by ELISA method. Results: The mean of FGF21 levels after exercise was increased significantly in the both aerobic (p < 0.001) and resistance exercise (p = 0.001) groups. The mean of glucose, LDL-C, TG and cholesterol was decreased significantly after exercise in the both exercised groups (p < 0.01). A significant decline had been found for insulin levels and also insulin resistance in the both aerobic (p = 0.001) and resistance (p = 0.003) groups. There was a negative and significant correlation between FGF21 levels with total cholesterol contents (p = 0.001). Conclusion: Aerobic and resistance exercises increase the mean value of FGF21 levels and as the result decline the mean levels of glucose and lipids in blood of menopausal women with type II diabetic mellitus.

Fibroblast growth factor 21 regulates browning of white fat: The role of exercise / 中国组织工程研究

BACKGROUND: Fibroblast growth factor 21 (FGF-21) is a newly discovered metabolic regulator that has been expressed in various tissues and organs such as liver, fat and skeletal muscle. Numerous studies have shown that FGF-21 is involved in the browning of white fat, but there is less review of this aspect worldwide. Especially the mediation of exercise is still controversial. OBJECTIVE: To explore the inducing factors and mechanism of FGF-21 regulating the browning of white fat, especially the effects of exercise on it, in order to provide new targets for the treatment of obesity and related metabolic diseases. METHODS: A computer-based search of CNKI and PubMed databases was performed for relevant articles published from January 2001 to July 2019 using the keywords of “FGF-21, browning, exercise, fat” in Chinese and English, respectively. Finally, 45 eligible articles were included in results analysis according to the inclusion criteria. RESULTS AND CONCLUSION: FGF-21 can enter the blood in autocrine, endocrine and paracrine patterns to regulate glycolipid metabolism, improve insulin resistance, prevent liver disease, and promote the browning of white fat. Exercise can induce the secretion and expression of FGF-21, thereby effectively regulating the activation of brown fat and browning of white fat to achieve fat loss. Due to differences in exercise patterns, exercise intensity, and exercise time, the current process of exercise-mediated FGF-21 involvement in the browning of white fat needs further study.

Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study.METHODS: Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4′-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months.RESULTS: DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2).CONCLUSION: FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.

Fasting insulin and alanine amino transferase, but not FGF21, were independent parameters related with irisin increment after intensive aerobic exercising

Abstract Background Irisin is a protein cleaved from fibronectin type III domain-containing protein 5 and has been implicated in the beneficial effects of exercise. However, it is unknown which factors contribute to irisin increment after intensive exercising in humans. This study aimed to assess independent factors related with serum irisin after 2 weeks of supervised physical activity in young sedentary healthy women. Design and Methods We developed a comparative, interventional, longitudinal, and prospective study at a third-level specialty health center. Between March 2010 and August 2011, 82 sedentary young adult women, without chronic diseases or regular medical treatments, were recruited. A total of 38 women fulfilled selection criteria, and irisin concentrations were quantified before and after the intervention. Independent factors related with irisin increment were evaluated according to mild to moderate and vigorous intensity of physical activity. A supervised treadmill exercise test following the Bruce’s protocol was conducted from Monday to Friday during 2 weeks. In addition, anthropometric measurements were taken, and fibroblast growth factor 21 (FGF21), glucose, insulin, and liver transaminases were measured. Results Intensity of exercising was directly related to irisin (p = 0.02) and FGF21 (p = 0.01) serum levels. However, an independent and significant relationship between FGF21 and irisin was not confirmed. A novel association was found between alanine aminotransferase (ALT) and irisin, showing a positive and significant correlation (r = 0.37, p = 0.02). The association was particularly strong with higher intensity of aerobic exercising (r = 0.64, p = 0.01). Linear regression model adjusted for glucose and body mass index confirmed an independent association between ALT and irisin and also between insulin and irisin (adjusted R² = 0.12, p = 0.04). Such association increased after grouping in moderate to vigorous physical activity intensity (adjusted R² = 0.46, F = 4.7, p = 0.03). Conclusions Serum irisin and FGF21 levels significantly increased after 2 weeks of supervised physical activity. However, only fasting insulin and ALT, but not FGF21, were independent parameters explaining irisin increment, mainly after moderate to vigorous exercising.

Fibroblast growth factor 21 and childhood obesity / 国际儿科学杂志

Childhood obesity is an energy-metabolic disorder in which excessive accumulation of systemic fat is caused by various factors,and it has been confirmed that childhood obesity increases the risk factors of diseases such as immune system,cardiovascular system and endocrine system.Studies have confirmed that fibroblast growth factor 21 (FGF21) can reduce blood glucose,glucagon,triglyceride and improve islet cell function,which makes FGF21 a promising drug in the treatment of diabetes,childhood obesity and metabolic syndrome.However,the underlying mechanisms of FGF21 have not been fully elucidated.The half-life of exogenous FGF21 in the circulation is short and it is still unclear whether the pharmacological dose of FGF21 has side effects on the body.These problems showed that the safety and feasibility of long-term FGF21 therapy are challenging,so in this paper,the structure and function of FGF21 and its relationship with childhood obesity are reviewed,in order to provide a new perspective for the treatment of childhood obesity.

Effect and mechanism of FGF21 on astrocyte damage induced by Aβ25-35 / 中国药科大学学报

@#To investigate the effects and mechanism of fibroblast growth factor 21(FGF21)on astrocytes in AD-like lesions, Aβ25-35 was used to induce astrocyte model damaged. Cell model was established by inducing C6 astrocyte cell line and primary astrocyte damage with Aβ25-35. Different concentrations of FGF21 were used to intervene cell injury model induced by Aβ25-35, and cell viabilities were detected by MTT assay. Effects of FGF21 and Aβ25-35 on reactive oxygen species(ROS)levels in C6 cells were tested using DCFH-DA probe and flow cytometry. Western blot was used to assess the effects of FGF21 and Aβ25-35 on the activities of mitogen-activated protein kinases(MAPKs)in C6 cells. The results showed that FGF21 could reduce the damage of C6 cells and primary astrocytes induced by Aβ25-35, down-regulate the abnormal ROS level in C6 cells, and alleviate the abnormal phosphorylation levels of MEK1/2, ERK1/2 and p38 in C6 cells induced by Aβ25-35, suggesting that FGF21 may attenuate Aβ25-35-induced astrocyte damage by regulating ROS pathway and MAPKs signaling pathway.

The research advance of fibroblast growth factor 21 in anti-atherosclerosis / 中国胸心血管外科临床杂志

@#Fibroblast growth factor 21 (FGF21) is a multi-effect endocrine factor, mainly secreted in liver and adipose tissue, with the properties of lipid-lowering, anti-inflammatory, anti-oxidant and anti-atherosclerosis. Recent studies found that FGF21 can induce protective effect in cardiovascular disease, and plasma FGF21 levels in patients with disease cardiovascular are elevated. These studies have suggested the use of FGF21 as a biomarker for subclinical atherosclerosis and its potential role in the treatment of established atherosclerotic cardiovascular disease. This article will review the recent advances in the anti-atherosclerosis effect of FGF21.