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ABSTRACT FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.
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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.
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Animals , Mice , Tacrolimus , Liver , Cholesterol, LDL , Autophagy , Disease Models, AnimalABSTRACT
Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.
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Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β 3-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue.
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FGF21-164 is a fusion protein obtained by structural modification and coupling of endogenous FGF21. It is a candidate drug used in the treatment of glucose and lipid metabolic disorders caused by obesity. In this study, the candidate peptide mass spectrometry information of the protein hydrolyzed by trypsin was predicted by Skyline software and verified by high resolution mass spectrometry. The specific surrogate peptide (YLYTDDAQQTEAHLEIR) with the best mass response was selected after optimizing ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Under ESI positive ion mode, the parent ion m/z 689.3 with 3 charge and the product ion m/z 738.4 with single charge can be monitored. After dilution by PBS, the serum samples were denatured under 60 ℃ and alkylated to reduce the matrix effect, then incubated with trypsin at 37 ℃ for 2 h, to obtain the surrogate peptide. The chromatographic separation was carried out on an EclipsePlus C18 column (2.1 mm×50 mm, 1.8 μm) using aqueous solution containing 0.1% formic acid (phase A) and acetonitrile solution containing 0.1% formic acid (phase B). Finally, the concentration of FGF21-164 fusion protein in mouse serum was quantitatively analyzed by external standard method by monitoring the above ion pairs using triple quadrupole mass spectrometer. This method showed a good linearity in the range of 2.50-500 μg·mL-1 (r = 0.998 8), and was successfully applied to the pharmacokinetic study of FGF21-164 fusion protein in mice. This experiment was approved by the Experimental Animal Ethics Committee of Shanghai Institute of Materia Medica, Chinese Academy of Sciences (batch number: 20180004040450). Compared with the endogenous FGF21, the t1/2 of FGF21-164 fusion protein was prolonged from 0.5 h to 2.6 h, which is expected to prolong the therapeutic efficacy of this protein.
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ABSTRACT Objective Fibroblast growth factor 21 (FGF21) is among the activators that can stimulate thermogenesis in the white adipose tissue and brown adipose tissue. People with obesity have elevated blood levels of FGF21, but also develop resistance to its action, impairing its beneficial role. Inversely, clinical treatments to weight loss has been pointed out as an important therapy for increasing and recovering sensitivity to FGF21. The aim was to analyse the effect of long-term weight loss interdisciplinary intervention on FGF21 and body composition. Subjects and methods Eighty-six post-pubertal obese adolescents (14-19 years-old), were submitted to 20 weeks of weight loss therapy (clinical, nutritional, psychological and physical exercise support). Anthropometric measures, body composition and rest metabolic rate (RMR) by bioelectrical impedance, and serum FGF21 sample by ELISA were evaluated. The adolescents were grouped according to FGF21 individual delta variations after therapy: Higher Increase (HI); lower increase (LI); lower decrease (LD); higher decrease (HD). Results All groups present weight loss. Only in FGF21 ≥ 76,5 pg/mL variation the free-fat-mass and rest metabolic rate were preserved and to others group these variables were significantly reduced. Conclusion High increase in FGF21 can contribute to preservation of FFM and RMR after weight loss therapy, could have important implications for energy balance regulation. Future studies are necessary to continue determining the role of magnitude effects of FGF21 levels in obesity to improve clinical practice, especially in paediatrics population.
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Humans , Adolescent , Weight Loss , Fibroblast Growth Factors/blood , Obesity , Energy Metabolism , Adipose Tissue, WhiteABSTRACT
Aim To investigate the role and mechanism of NLRP3 on hypolipidemic effect and anti-inflammative effect of apigenin. Methods Triton-WR 1339-induced hyperlipidemia was applied to wide type C57BL/6 and NLRP3"'" mice, which was treated with apigenin of 6.25 mg • kg"1 • day"1 for five days. Blood and liver tissueswere collected for detecting TC, TG, HDL, LDL, IL-1B, IL-6, MCP-1 and the liver underwent HE staining. The expressions of NLRP3, I L 4, ASC, CD36, CYP7A1 and FGF21 were tested using RT-qPCR. Results Compared with NLRP3 "'" model group, serum contents of TC, TG, HDL, LDL, IL-1B, IL-6, MCP-1 were reduced in NLPR3"'" treated with apigenin of 6. 25 mg • kg"1 (P < 0. 05). The percentage of hepatic steatosis wasdown-regulated by apigenin in pathogenesis observation. However, all these phenotype changes were not observed in WT mice treated with apigenin. Moreover, up-regulation of CD36 and vLDLR and down-regualtion of ASC and IL-4 were founded in both WT and NLRP3"'" model group (P < 0. 05), while down-regulation of FGF21 and up-regulation of CYP7A1 were only seen in NLRP3"/ _ model group but not in WT group. Conclusions Knockout of NLRP3 enhances hypolipidemic effect and anti-inflammative effect of apigenin in triton-1339 IP-induced hyperlipidemia mice, which may be associated with apigenin-regulated FGF21/CYP7A1 pathway without NLRP3 inflammasome interruption.
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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.
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Members of the fibroblast growth factor (FGF) family play pleiotropic roles in cellular and metabolic homeostasis. During evolution, the ancestor FGF expands into multiple members by acquiring divergent structural elements that enable functional divergence and specification. Heparan sulfate-binding FGFs, which play critical roles in embryonic development and adult tissue remodeling homeostasis, adapt to an autocrine/paracrine mode of action to promote cell proliferation and population growth. By contrast, FGF19, 21, and 23 coevolve through losing binding affinity for extracellular matrix heparan sulfate while acquiring affinity for transmembrane α-Klotho (KL) or β-KL as a coreceptor, thereby adapting to an endocrine mode of action to drive interorgan crosstalk that regulates a broad spectrum of metabolic homeostasis. FGF19 metabolic axis from the ileum to liver negatively controls diurnal bile acid biosynthesis. FGF21 metabolic axes play multifaceted roles in controlling the homeostasis of lipid, glucose, and energy metabolism. FGF23 axes from the bone to kidney and parathyroid regulate metabolic homeostasis of phosphate, calcium, vitamin D, and parathyroid hormone that are important for bone health and systemic mineral balance. The significant divergence in structural elements and multiple functional specifications of FGF19, 21, and 23 in cellular and organismal metabolism instead of cell proliferation and growth sufficiently necessitate a new unified and specific term for these three endocrine FGFs. Thus, the term "FGF Metabolic Axis," which distinguishes the unique pathways and functions of endocrine FGFs from other autocrine/paracrine mitogenic FGFs, is coined.
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Insulin resistance refers to a decrease in the physiological utilization of normal concentrations of insulin by target organs such as liver and adipose tissue.Insulin resistance is central to a variety of metabolic diseases caused by obesity.FGF21 is a novel regulator of glycolipid metabolism,which has the effects of improving insulin resistance,reducing body weight,regulating blood lipids,promoting fatty acid oxidation,and increasing energy consumption.Metabolic surgery is effective in the treatment of obesity and insulin resistance,and the level of FGF21 changes after surgery.This article will review the possible mechanisms of metabolic surgery to mediate FGF21 to improve insulin resistance.
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@#In order to improve the brain distribution of fibroblast growth factor 21(FGF21), TAT-FGF21 fusion protein was designed and its neuroprotective activity was investigated. The recombinant plasmid of pET28a-TAT-FGF21 was constructed and transformed into E. coli BL-21(DE3)sensitive bacteria. The TAT-FGF21 fusion protein was purified by Ni-NTA affinity chromatography column after IPTG induced expression. The SH-SY5Y cell damage model was induced by Aβ25-35, and the TAT-FGF21 fusion protein was used to intervene. The effects of Aβ25-35 and TAT-FGF21 induced on SH-SY5Y cell viability were determined using MTT method; DCFH-DA fluorescent probe was used to detect the intervention effect TAT-FGF21 on reactive oxygen species(ROS)generation induced by Aβ25-35 in SH-SY5Y cells; the effects of Aβ25-35 and TAT-FGF21 on mitochondrial membrane potential in SH-SY5Y cells were detected with JC-1 fluorescent probe. The results showed that TAT-FGF21 could improve the viability of SH-SY5Y cells, reduce the intracellular ROS production level of SH-SY5Y cells, and enhance the mitochondrial membrane potential of SH-SY5Y cells, which indicate that TAT-FGF21 could protect neurons on SH-SY5Y cell injury induced by Aβ25-35 through alleviating oxidative damage.
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Aim To investigate the effect of liraglutide on expression of fibroblast growth factor 21 in white ad-ipose tissues and its mechanisms. Methods Male SD rats were subjected to a standard control diet or high-fat diet ( HFD) for 12 weeks, then the HFD group was in-jected introperitoneally with 30 mg · kg-1 streptozoto-cin to induce type 2 diabetes mellitus model. Half number of rats of type 2 diabetes mellitus were injected with liraglutide ( DM +LRG, 0. 4 mg · kg-1 · d-1 , two times one day ) for another 6 weeks. Serum bio-chemical indices and FGF21 levels were detected. The pathological changes in epididymal adipose tissues were detected by HE staining. The mRNA and protein ex-pression and phosphorylation of FGF21 , peroxisome proliferator-activated receptor γ ( PPARγ) , fibroblast growth factor receptor 3 (FGFR3),β-Klotho, liver ki-nase B1(LKB1), AMP-activated kinase (AMPK), a-cetyl-CoA carboxylase ( ACC ) and phosphorylation of signaling molecules in MAPK pathway were assessed by RT-PCR, immunohistochemistry and Western blot re-spectively. Results Body mass and serum lipid, ALT and AST levels increased in DM group, while FGF21 level decreased, and the volume of adipose cells in ep-ididymal adipose tissues was expanded. Expressions of FGF21, PPARγ, p-FGFR3, β-Klotho, p-LKB1, p-AMPK, p-ACC were down-regulated, while p-ERK, p-JNK and p-p38 expression were all increased. These indices were reverted by liraglutide treatment. Conclu-sion Liraglutide has significant lipid-lowering effect, which maybe related with increased FGF21 expression, activating AMPK pathway and inhibiting MAPK path-way.
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Objective To explore the characteristics of the effect of echinacoside on lipid metabolism in type 2 diabetic mice,and to investigate the content of growth factor 21 in liver tissue of diabetic mice,providing further insight into the possible way of regulating blood lipid metabolism in type 2 diabetic mice with Echinacea.Methods Twenty db/db mice (6-week-old) were randomly divided into two groups:experimental group and model group;while six db/m mice (SPF) (6-week-old) were control group.We detected the fasting blood glucose after 2 weeks that was higher than 16.7mmol/L in experiment.Each group was given sterilized distilled water,echinaco side,sterilized distilled water.The serum total,cholesterol,triglyceride,high density lipoprotein,low density lipoprotein,alanine aminotransferase level,aspartate,aminotransferase level,and the liver tissue measurement of fibroblast growth factor 21 levels were detected after eight weeks.Results The model group serum TG,TC and LDL were significantly higher than the control group (P ＜ 0.01).The content of serum HDL was significantly lower than the control group (P ＜ 0.01).Experimental group of serum TG,TC and LDL levels were significantly lower than the model group (P ＜ 0.01).The content of serum HDL was significantly higher than that in the model group (P ＜ 0.01).The expression of FGF21 in model group in liver were significantly lower than that of control group (P ＜ 0.01).The experimental group the expression of FGF21 in mouse liver was significantly higher than that in the model group (P ＜ 0.01).The content of ALT and AST in serum of model group was significantly higher than the control group (P ＜ 0.01).Experimental group serum ALT,AST were significantly lower than the experimental group (P ＜ 0.01).Conclusion After 8 weeks of administration,the serum lipid metabolism disorder of db/db diabetic mice was significantly improved,and the liver function damage was not increased.The mechanism of FGF21 may be related to the improvement of the expression level of liver tissue.
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Objective To explore the relationship between fibroblast growth factor 21(FGF21) and islet β cell function in pregnant women with different glucose tolerance status.Methods A total of 441 pregnant women were selected in this study from our hospital.Their 50 g GCT at 24~28 gestational weeks were all positive.One week later,all the subjects were treated with 75 g OGTT,and divided into three groups according to their test results:GDM group (n=228),GIGT group (n=112) and GNGT group (n=91).Serum FGF21 level was tested by ELISA.Islet β cell function was evaluated by HOMA-IR,ISI-Matsuda,HOMA-IS,Stumvoll first,second phase secretion and ISSI.The correlation between FGF21 and islet β cell function was evaluated by Pearson correlation analysis.Results (1) BMI,0 h,1 h,2 h,3 hPG and 1 h,2 h,3 hIns were higher in GDM group and GIGT group than in GNGT group,and highest in GDM group (P0.05).(3)Pearson correlation analysis showed that FGF21 was positively correlated with HOMA-IR(r=0.255,P=0.030) and was negatively correlated with ISI-Matsuda,HOMA-β,Stumvoll first,second phase secretion and ISSI(r=-0.289,-0.256,-0.224,-0.230,-0.277,P=0.019,0.037,0.045,0.040,0.023).Conclusion Along with the worsening of glucose metabolic damage,the FGF21 level is increased gradually.FGF21 is related to islet β cell function,and may enroll in the occurrence and development of GDM.
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Objective To explore the mechanism of insulin resistance regulated by fibroblast growth factor 21 (FGF21)and identify its role in oxidative stress.Methods High-fat diet-induced obese mice were treated with FGF21 ,and hepatic oxidative stress markers such as iNOS and insulin signaling molecules such as IRS-1 and Akt were assessed by Western blot and co-immunoprecipitation.Meanwhile,liver steatosis was assessed in liver sections stained with oil red O.Results Obese mice in FGF21 group showed reduced body weight,blood glucose and serum insulin levels,and improved insulin sensitivity as measured by glucose tolerance testing (GTT)and insulin tolerance testing (ITT)compared with obese mice in vehicle group.Meanwhile,FGF21 treatment in obese mice decreased protein expressions of iNOS and TNF-α,and increased insulin-stimulated IRS-1 tyrosine phosphorylation and Akt Ser-473 phosphorylation,indicating that FGF21 inhibited hepatic oxidative stress and restored impaired insulin signaling.Additionally,we found significantly reduced lipid accumulation in liver sections stained with oil red O in FGF21-treated obese mice.Conclusion Our results support the notion that FGF21 is an important regulator of insulin resistance and that FGF21 may reduce lipid accumulation in the liver,restore hepatic insulin signaling and improve insulin sensitivity in obese mice,at least in part,by inhibiting hepatic oxidative stress.Therefore,FGF21 has a potential value in clinical application.
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Almost 50 percent of Noonan syndrome patients, characterized by short stature, present activating mutations of the citoplasmatic phosphatase SHP-2, which induce hyperactivation of the Ras/MAPK pathway. On the other hand, the fibroblast growth factor 21 (FGF-21), recently suggested as a FGF with endocrine function, would affect longitudinal growth inhibiting growth hormone signaling at chondrocytes level. Union and activation of FGF-21 to its receptor is regulated by the co-factor beta Klotho (KLB). Aims: To determine if FGF-21 and/or FGF-21+KLB are able to modify the genetic expression of SHP-2 ina human skin fibroblast cell line (Malme-3). Methods: cells were incubated with or without FGF-21, FGF-21 + KLB. At 12 and 24 hours after induction total RNA was extracted andSHP-2 mRNA levels were determine by quantitative PCR. Expression of GADPH gene was employed for normalization. Results: Incubation with FGF-21 produce a 36 percent (p = < 0,05)increment in SHP-2 expression, which was not modified with KLB co-incubation. Discussion: it is shown by the first time that FGF-21 is able to produce an increase in SHP-2 gene expression in human fibroblast, which was independent of KLB presence...
Subject(s)
Humans , Male , Adult , Female , Fibroblast Growth Factors/physiology , Fibroblast Growth Factors/genetics , /physiology , Cells, Cultured , DNA, Complementary , Gene Expression , Polymerase Chain ReactionABSTRACT
Insulin resistance in insulin sensitive organ results in metabolic disorder such as hyperglycemia, hyperinsulinemia and hyper triglyceridemia which are common features of type 2 diabetes.Insulin resistance in liver cells mainly causes impaired glycogen synthesis, failed to suppress glucose production which is the major contribution to hyperglycemia.FGF-21 as a new metabolic regulator can control fasting blood glucose.The mechanism of FGF-21 effects on regulating plasma glucose has little to known.In order to establish an in vitro insulin resistant model of liver cells and evaluate the effects and mechanism of FGF-21 on glucose metabolism in the cell model, HepG2 cells were incubated with 10-7 mol/L insulin for 24 h to build insulin-resistant cell model.To evaluate the cells for insulin resistance, the cells were stimulated with fresh insulin for 24 h and the glucose uptake by these cells was carried out.The insulin-resistant cells were treated with different concentrations of FGF-21 for 24 h and insulin-treated cells were used as a control.The glucose uptake by the cells was detected by the method of glucose oxidizes/peroxides(GOD-POD);the synergy between insulin and FGF-21 was evaluated.The mRNA expression of GLUT1 in the insulin-resistant cells was detected by the real-time PCR.Glycogen synthesis of the cells was examined by the anthrone method.The results showed that HepG2 cells treated with 10-7 mol/L insulin for 24 h became resistant to insulin and the insulin resistance status was maintained for 48 h without change of cell morphology.FGF-21 could stimulate glucose consumption of the insulin-resistant model in a dose-dependent manner.The glucose consumption and glycogen synthesis of the insulin-resistant model were significantly improved by FGF-21 treatment.FGF-21 showed strong synergy with insulin in glucose uptake and glycogen synthesis of the model cells.While the cells became resistant to insulin, FGF-21 could increase the mRNA expression of GLUT1.Thus, It is concluded that FGF-21 stimulates glucose uptake in insulin resistant HepG2 cells through GLUT1 expression, stimulates glycogen synthesis and improves the glucose metabolism in the insulin resistant liver cell model.
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Fibroblast growth factor(FGF)-21 is a novel insulin-independent glucose regulator,and can be a potential therapeutics for treatment of type Ⅱ diabetes.Although FGF-21 was discovered recently,the insight into its biology and therapeutic utility is rapidly evolving.A number of key metabolically-linked molecules and pathways have been suggested to be involved in the mechanism of action of FGF-21,which enables us to renew the understanding of the FGF-21.The aim of this review is to report the update research outcomes.