Fibroblast Growth Factor 21 Concentrations Research Articles

Fibroblast Growth Factor 21 Is Associated With Bone Mineral Density, but not With Bone Turnover Markers and Fractures in Chinese Postmenopausal Women

Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF subfamily and an important metabolic regulator that has multiple beneficial effects on glucose homeostasis and lipid metabolism. However, it was unclear whether FGF21 would induce bone defects in humans. This study evaluated the associations of FGF21 levels, bone mineral density (BMD), osteoporotic fracture, and bone turnover marks (BTMs) in postmenopausal women. A total of 1342 postmenopausal Chinese Han women (511 cases of fragility fracture in the case group and 831 cases in nonfragility fracture group) were enrolled. Serum FGF21 concentration was measured by ELISA (Quantikine), serum calcium (Ca), phosphate (P), alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone, β-crosslinked C-telopeptide of type l collagen, were measured using an automated Roche electro-chemiluminescence system. BMD was measured using dual-energy X-ray absorptiometry. The association with age, BMD, 25-hydroxyvitamin D, parathyroid hormone, β-crosslinked C-telopeptide of type l collagen, and FGF21 levels were also evaluated in postmenopausal women. In nonfracture group and fragility fracture group, postmenopausal women's FGF21 level was 226.57pg/mL (149.11–354.43 pg/mL) and 219.43pg/mL (147.21–323.74 pg/mL), respectively. There is no significant difference in serum FGF21 levels between the fragility fracture group and the nonfracture group (p = 0.160). There was a significant statistical difference in BMD between the fragility fracture group and the nonfracture group (p = 0.000). In multiple linear regression analysis, FGF21 levels were significantly positive associated with lumbar BMD in postmenopausal women (L1-4, p = 0.007), independent of other factors, especially in fragility fracture group (L1-4, p = 0.001). In addition, a significant positive association was also observed between serum FGF21 levels and age in postmenopausal women (p < 0.05). We reveal a positive correlation between serum FGF21 concentrations with lumbar BMD in Chinese Han postmenopausal women. No significant correlations are present between serum FGF21 and bone turnover marks or serum FGF21 and fragility fracture in our study.

Circulating Fibroblast Growth Factor 21 is Associated with Subsequent Renal Injury Events in Patients Undergoing Coronary Angiography

Fibroblast growth factor 21 (FGF21) is a regulator of glucose homeostasis, and is suggested to have protective effect on diabetic nephropathy. Its impact on non-diabetic kidney disease is unclear. To investigate the impact of FGF21 on contrast-induced nephropathy (CIN), 531 subjects underwent elective coronary angiography (CAG) were enrolled. Baseline creatinine and FGF21 were obtained before CAG. Patients were grouped into tertiles according to their FGF21 concentration. Creatinine was obtained 48 hours after CAG, and every 6 months in the follow-up period. Renal function decline was defined as >30% reduction of eGFR from baseline. All subjects were followed up till December 2016, or till the occurrence of major adverse cardiovascular events (MACE). Patients with higher FGF21 concentration were older, had higher incidence of hypertension, diabetes, chronic kidney disease, and heart failure. Thirty-four cases of CIN and 111 cases of renal function decline were identified during mean follow-up of 2.3 ± 1.3 years. Circulating FGF21 level was independently associated with CIN (aOR: 4.66, 95% CI: 1.29–16.86, p = 0.019) and renal function decline (aHR: 7.98, 95% CI: 4.07–15.66, p < 0.001) whether diabetes was present or not. In conclusion, circulating FGF21 level is independently associated with the incidence of CIN and subsequent kidney injury in patients undergoing CAG.

Serum hepatokines in dairy cows: periparturient variation and changes in energy-related metabolic disorders

BackgroundDuring peripartum period, dairy cows are highly susceptible to energy metabolism disorders such as fatty liver and ketosis. Angiopoietin-like protein 4 (ANGPTL4) and fibroblast growth factor 21 (FGF21), known as hepatokines, play important roles in lipid metabolism. The purposes of our study were to evaluate variations of serum ANGPTL4 and FGF21 concentrations in periparturient dairy cows and changes in these serum analyte concentrations of energy-related metabolic disorders in early lactation dairy cows.This study was divided into two experiments. Experiment I: Blood parameters were measured in healthy periparturient Holstein cows from 4 wk antepartum to 4 wk postpartum (n = 219). In this experiment, weekly blood samples were obtained from 4 wk before the expected calving date through 4 wk after calving. Experiment II: Blood parameters were measured in healthy cows (n = 30) and cows with clinical ketosis (n = 29) and fatty liver (n = 25) within the first 4 wk of lactation. In the present study, all blood samples were collected from the coccygeal vein in the early morning before feeding.ResultsSerum ANGPTL4 and FGF21 concentrations peaked at parturition, and declined rapidly over the following 2 wk Serum ANGPTL4 and FGF21 concentrations were positively correlated with serum non-esterified fatty acids (NEFA) concentration (r = 0.856, P = 003; r = 0.848, P = 0.004, respectively). Cows with clinical ketosis and fatty liver had significantly higher serum ANGPTL4 and FGF21 concentrations than healthy cows (P < 0.01).ConclusionSerum ANGPTL4 and FGF21 concentrations were elevated during peripartum period, suggesting that energy balance changes that were associated with parturition contributed significantly to these effects. Although FGF21 and ANGPTL4 could play important roles in the adaptation of energy metabolism, they may be involved in the pathological processes of energy metabolism disorders of dairy cows in the peripartum period.

Fibroblast growth factor 21, adiposity, and macronutrient balance in a healthy, pregnant population with overweight and obesity

ABSTRACTAim of the study: The regulation and actions of fibroblast growth factor 21 (FGF21) are responsive to energy status and macronutrient balance, and investigations of FGF21 in normal pregnancy, which could be informative for FGF21 biology, are seldom. The goal of our study was to examine FGF21 levels in a contemporary healthy, pregnant population.Methods: We phenotyped 43 women with overweight and obesity during pregnancy for weight, body composition, and fasting blood. Serum FGF21 was measured during the first and third trimesters. Placentas were collected at delivery.Results: Maternal FGF21 concentrations were positively correlated with body mass index and adiposity, but not lean mass or glucose homeostasis. FGF21 concentrations significantly increased from the first to third trimester of pregnancy (0.105 vs. 0.256 ng/mL, p < 0.0001). Changes in FGF21 concentrations across pregnancy were not associated with changes in body weight or composition but inversely with the change in fasting glucose. FGF21 mRNA levels in placenta were very low and do not likely contribute to FGF21 in the maternal circulation.Conclusions: FGF21 increases throughout pregnancy in our healthy cohort with overweight and obesity, independent of the placenta, and does not appear to be sensing the changes in energy balance (reflected in the change in maternal energy stores), but changes in macronutrient status. Thus, we propose FGF21 may be a potential signal of maternal nutrient status in pregnancy.

Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning.

Both ovarian E2 and hepatic fibroblast growth factor 21 (FGF21) are critical for energy homeostasis and white adipose tissue browning. Estrogen receptor α (ERα) is abundantly expressed in liver. However, whether FGF21 has a role in E2-induced white adipose tissue browning remains uncertain. In this study, we showed that hepatic Fgf21 expression and secretion during estrus cycle changed with the tetradian oscillatory secretion of circulation E2 in adult, female mice, with their peak expressions and secretions at the proestrus. In addition, exogenous E2 robustly stimulated liver Fgf21 expression and elevated serum FGF21 concentrations, which induced browning gene expression and reduced the tissue weight in subcutaneous white adipose in mice with ovariectomies. The inhibitor of mammalian target of rapamycin (mTOR) and of ERα blocked the induction effect of E2 on the expression of Fgf21 in primary hepatocytes, which revealed that E2 might stimulate FGF21 expression via the ERα-mTOR pathway. Furthermore, FGF21 liver-specific deficiency abolished E2-induced white adipose browning in mice with ovariectomies. This study indicates that ovarian E2 increased liver FGF21 expression directly, which in turn, functioned as an endocrine signal to influence inguinal white adipose tissue browning.-Hua, L., Zhuo, Y., Jiang, D., Li, J., Huang, X., Zhu, Y., Li, Z., Yan, L., Jin, C., Jiang, X., Che, L., Fang, Z., Lin, Y., Xu, S., Li, J., Feng, B., Wu, D. Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning.

The influence of adiposity and acute exercise on circulating hepatokines in normal-weight and overweight/obese men.

Hepatokines are liver-secreted proteins with potential to influence glucose regulation and other metabolic parameters. This study investigated differences in adiposity status on 5 novel hepatokines and characterised their response to acute moderate-intensity exercise in groups of normal-weight and overweight/obese men. Twenty-two men were recruited into normal-weight and overweight/obese groups (body mass index: 18.5 to 24.9 and 25.0 to 34.9 kg·m-2). Each completed 2 experimental trials, exercise and control. During exercise trials, participants performed 60 min of moderate-intensity treadmill exercise (∼60% peak oxygen uptake) and then rested for 6 h. Participants rested throughout control trials. Circulating fibroblast growth factor-21 (FGF21), follistatin, leukocyte cell-derived chemotaxin 2 (LECT2), fetuin-A, and selenoprotein-P (SeP) were measured throughout. Fasted (resting) FGF21 and LECT2 were higher in overweight/obese individuals (129% and 55%; P ≤ 0.01) and correlated with indices of adiposity and insulin resistance; whereas circulating follistatin was lower in overweight/obese individuals throughout trial days (17%, P < 0.05). In both groups, circulating concentrations of FGF21 and follistatin were transiently elevated after exercise for up to 6 h (P ≤ 0.02). Circulating fetuin-A and SeP were no different between groups (P ≥ 0.19) and, along with LECT2, were unaffected by exercise (P ≥ 0.06). These findings show that increased adiposity is associated with a modified hepatokine profile, which may represent a novel mechanism linking excess adiposity to metabolic health. Furthermore, acute perturbations in circulating FGF21 and follistatin after exercise may contribute to the health benefits of an active lifestyle.

Negative energy balance up‐regulate the levels of hepatokines in dairy cows during the peripartum period

IntroductionThe periparturient period is vitally important to the health status and the reproductive performance of dairy cows. Negative energy balance (NEB) is considered as the pathological basis of energy metabolic disorders. Serum non‐esterified fatty acids (NEFA) and β‐hydroxybutyrate (BHBA) concentrations are the indicators of energy balance status. Angiopoietin‐like protein 4 (ANGPTL4) and fibroblast growth factor 21 (FGF21), known as hepatokines, play essential roles in lipid metabolism. However, in vivo the kinetics of ANGPTL4 and FGF21 are not entirely clear of dairy cows, particularly in dairy cows with ketosis and fatty liver. The purposes of this project were to evaluate the variations in serum concentrations of ANGPTL4 and FGF21 in periparturient dairy cows, and to examine the correlations between serum NEFA, BHBA concentrations and ANGPTL4, FGF21 concentrations, respectively, in the serum of experimental cows. Moreover, the serum concentrations of hepatokines from cows with spontaneous ketosis and fatty liver, and healthy cows were compared.MethodsExperiment IBlood parameters were measured in healthy periparturient Holstein cows from 4 wk antepartum to 4 wk postpartum (n=219). In this experiment, weekly blood samples were obtained from 4 wk before the expected calving date to 4 wk after calving.Experiment IIBlood parameters were measured in healthy cows (n=30), cows with ketosis (n=29) and fatty liver (n=25) within the first 4 wk of lactation. In this present study, all blood samples were collected from the coccygeal vein in the early morning before feeding.ResultsSerum concentrations of ANGPTL4 and FGF21 peaked at parturition, and declined rapidly over the following 2 wk. Serum ANGPTL4 and FGF21 concentrations were positively correlated with serum NEFA concentration (ANGPTL4 and NEFA: r=0.856, P=003; FGF21 and NEFA: r=0.848, P=0.004). However, the correlations between serum BHBA concentration and the serum concentrations of ANGPTL4 and FGF21 were not observed in experimental cows. Cows with ketosis and fatty liver had significantly higher serum concentrations of ANGPTL4 and FGF21 when compared with healthy cows (P&lt;0.01).ConclusionSerum concentrations of ANGPTL4 and FGF21 were elevated during peripartum period in dairy cows, demonstrating that the energy balance changes that were associated with parturition contributed significantly to these effects. We propose that blood ANGPTL4 and FGF21 concentrations could be used as supplementary biomarkers of “energy balance” status in postpartum dairy cows. Although FGF21 and ANGPTL4 could play important roles in the adaptation of energy metabolism, they may be involved in the pathological processes of energy metabolism disorders of dairy cows in the peripartum period.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE−/− mice

Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE−/− mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the β3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE−/− mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis.

Association of serum betatrophin with fibroblast growth factor-21 in women with polycystic ovary syndrome.

Betatrophin and fibroblast growth factor-21 (FGF-21), which are recently discovered members of hepatokine/adipokine family, have been proposed to be associated with some metabolic disorders in which insulin resistance plays a major role. We aimed to investigate serum betatrophin and FGF-21 concentrations in women with polycystic ovary syndrome (PCOS). In this cross-sectional study, we recruited 31 women with PCOS and 34 women as healthy controls. Serum betatrophin level and its relationship with serum FGF-21 level as well as metabolic parameters were examined. Serum betatrophin level was significantly higher in women with PCOS‏ than the control group [1.10 (0.20-4.20) vs 0.70 (0.20-3.50)ng/ml, p=0.004], whereas FGF-21 did not differ between the groups [74.80 (7.80-435.90) vs 119.30 (10.50-443.40)pg/ml, p=0.13]. Serum betatrophin correlated positively with LH levels (r=0.26, p=0.03). After controlling BMI, there was a significant positive correlation between betatrophin and FGF-21 (r=0.25, p=0.04). Multivariate regression analysis revealed that FGF-21 and presence of PCOS were the significant predictors of betatrophin concentrations (R2=0.22, F=2.56, p=0.03). Our results indicate that betatrophin levels are increased and associated with LH and FGF-21 levels, but not with insulin resistance, in women with PCOS.

Association of Serum Betatrophin with Fibroblast Growth Factor-21 in Women with Polycystic Ovary Syndrome

Betatrophin and fibroblast growth factor-21 (FGF-21), which are recently discovered members of hepatokine/adipokine family, have been proposed to be associated with some metabolic disorders in which insulin resistance plays a major role. We aimed to investigate serum betatrophin and FGF-21 concentrations in women with polycystic ovary syndrome (PCOS). In this cross-sectional study, we recruited 31 women with PCOS and 34 women as healthy controls. Serum betatrophin level and its relationship with serum FGF-21 level as well as metabolic parameters were examined. Serum betatrophin level was significantly higher in women with PCOS‏ than the control group [1.10 (0.20–4.20) vs 0.70 (0.20–3.50) ng/ml, p = 0.004], whereas FGF-21 did not differ between the groups [74.80 (7.80–435.90) vs 119.30 (10.50–443.40) pg/ml, p = 0.13]. Serum betatrophin correlated positively with LH levels (r = 0.26, p = 0.03). After controlling BMI, there was a significant positive correlation between betatrophin and FGF-21 (r = 0.25, p = 0.04). Multivariate regression analysis revealed that FGF-21 and presence of PCOS were the significant predictors of betatrophin concentrations (R2 = 0.22, F = 2.56, p = 0.03). Our results indicate that betatrophin levels are increased and associated with LH and FGF-21 levels, but not with insulin resistance, in women with PCOS.

The Role of Insulin Resistance on FGF-21 and Inflammatory Markers in Obese Adolescents Undergoing Multicomponent Long-Term Weight Loss Therapy

Objective: The purpose of this study was to investigate the effects of a long-term weight loss therapy in two groups (insulin resistance [IR] and non-insulin resistance [non-IR]) of obese adolescents based on metabolic profile, biomarkers of inflammation, and fibroblast growth factor-21 (FGF-21) concentrations. Methods: Obese adolescents (15–19 years) were randomised into two groups (IR=8 and non-IR=9) and monitored through clinical, exercise training, nutritional, and psychological counselling over 1 year. Measurements of inflammatory biomarkers and FGF-21 were performed. The effects of therapy were verified by two-way ANOVA and post hoc analyses were performed (α ≤5%). Results: A reduction in body mass, visceral fat, and an increase in adiponectin in both groups was found. Only the non-IR group demonstrated improved BMI, body fat mass, lean body mass, and waist circumference. Indeed, in the non-IR group, FGF-21 presence was positively correlated with high-density lipoprotein cholesterol and lean body mass and inversely correlated with plasminogen activator inhibitor-1 and triglycerides. In the IR group, there was a reduction in FGF-21 concentration, adiponectin/leptin ratio, insulin, total cholesterol, low-density lipoprotein cholesterol, and plasminogen activator inhibitor-1. FGF-21 was negatively correlated with delta-triglycerides, waist circumference, and low-density lipoprotein cholesterol. The IR prevalence reduced from 47% to 23.5% in the studied population. Conclusions: Although the multicomponent clinical approach improves, in both analysed groups and in both metabolic and inflammatory states, the presence of IR resulted in a reduction in both FGF-21 concentration and adiponectin/leptin ratio. Additionally, in the IR group, FGF-21 was negatively correlated with proinflammatory markers, and in the non-IR group it was positively associated with high-density lipoprotein, suggesting its role in the control of inflammation counteracting IR. In this way, we suggest that IR can impair the anti-inflammatory effects of FGF-21. It will be helpful if these results can be confirmed in a large cohort, underlying physiological mechanisms to explore how these results can help in setting up more prospective studies.

Fibroblast Growth Factor 21 in Patients with Acromegaly.

Introduction The goal of the study was to investigate fibroblast growth factor-21 (FGF-21) levels in acromegalic patients in relation to the disease activity and to compare them with controls. Further, we aimed to evaluate the associations between FGF-21 and random growth hormone (GH), insulin-like growth factor-1 (IGF-1), metabolic and anthropometric parameters. Materials and methods The study group consisted of 50 acromegalic patients divided into 3 subgroups on the basis of disease activity (AA - active acromegaly, CD - controlled disease, CA - cured acromegaly). 27 subjects were assigned to the control group (CG). Blood samples were obtained from all participants to assess FGF-21, GH, IGF-1, lipids, glucose and insulin levels. Body mass, body mass index and body composition were also evaluated. Results There were no statistically significant differences in FGF-21 concentrations across all groups despite of subjects classification. FGF-21 correlated positively with random GH in the groups: CA, CD+CA, AA+CD+CA (r=0.48, p=0.049; r=0.39, p=0.023; r=0.33, p=0.02; respectively); with IGF-1 in the AA+CD+CA group (r=0.29, p=0.041); with triglycerides in the following groups: CD, CD+CA, AA+CD+CA (r=0.63, p=0.08; r=0.44, p=0.01; r=0.37, p=0.007; respectively) and with age in the CG and CD+CA groups (r=0.41, p=0.029; r=0.42, p=0.029; respectively). There were statistically significant negative correlations between FGF-21 and HDL-cholesterol levels in the groups: CD, CD+CA, AA+CD+CA (r=-0.53, p=0.03; r=-0.37, p=0.032; r=-0.29, p=0.036, respectively). Conclusions FGF-21 levels were similar in patients with acromegaly compared to controls. However, our results indicate that FGF-21 may have a potential role in the development of acromegaly complications.

Use of FGF-21 as a Biomarker of Mitochondrial Disease in Clinical Practice.

Recent work has suggested that fibroblast growth factor-21 (FGF-21) is a useful biomarker of mitochondrial disease (MD). We routinely measured FGF-21 levels on patients who were investigated at our centre for MD and evaluated its diagnostic performance based on detailed genetic and other laboratory findings. Patients’ FGF-21 results were assessed by the use of age-adjusted z-scores based on normalised FGF-21 values from a healthy population. One hundred and fifty five patients were investigated. One hundred and four of these patients had molecular evidence for MD, 27 were deemed to have disorders other than MD (non-MD), and 24 had possible MD. Patients with defects in mitochondrial DNA (mtDNA) maintenance (n = 32) and mtDNA rearrangements (n = 17) had the highest median FGF-21 among the MD group. Other MD patients harbouring mtDNA point mutations (n = 40) or mutations in other autosomal genes (n = 7) and those with partially characterised MD had lower FGF-21 levels. The area under the receiver operating characteristic curve for distinguishing MD from non-MD patients was 0.69. No correlation between FGF-21 and creatinine, creatine kinase, or cardio-skeletal myopathy score was found. FGF-21 was significantly associated with plasma lactate and ocular myopathy. Although FGF-21 was found to have a low sensitivity for detecting MD, at a z-score of 2.8, its specificity was above 90%. We suggest that a high serum concentration of FGF-21 would be clinically useful in MD, especially in adult patients with chronic progressive external ophthalmoplegia, and may enable bypassing muscle biopsy and directly opting for genetic analysis. Availability of its assay has thus modified our diagnostic pathway.

Effect of circulating glucagon and free fatty acids on hepatic FGF21 production in dairy cows.

Modern dairy cows meet the energy demand of early lactation by calling on hormonally driven mechanisms to increase the use of lipid reserves. In this context, we recently reported that fibroblast growth factor-21 (FGF21), a hormone required for efficient use of lipid reserves in rodents, is upregulated in periparturient dairy cows. Increased plasma FGF21 in early lactation coincides with elevated circulating concentrations of glucagon (GCG) and nonesterified fatty acids (NEFA). To assess the relative contribution of these factors in regulating FGF21, two experiments were performed in energy-sufficient, nonpregnant, nonlactating dairy cows. In the first study, cows were injected with saline or GCG every 8 h over a 72-h period. GCG increased hepatic FGF21 mRNA by an average of fivefold over matched controls but had no effect on plasma FGF21. In the second study, cows were infused and injected with saline, infused with Intralipid and injected with saline, or infused with Intralipid and injected with GCG. Infusions and injections were administered intravenously over 16 h and subcutaneously every 8 h, respectively. Intralipid infusion increased plasma NEFA from 92 to 550 µM within 3 h and increased plasma FGF21 from 1.3 to >11 ng/ml 6 h later; FGF21 mRNA increased by 34-fold in liver but remained invariant in adipose tissue. GCG injections during the Intralipid infusion had no additional effects on plasma NEFA, liver FGF21 mRNA, or plasma FGF21. These data implicate plasma NEFA as a key factor triggering hepatic production and increased circulating concentrations of FGF21 in early lactation.

Fibroblast growth factor 21 ameliorates high glucose-induced fibrogenesis in mesangial cells through inhibiting STAT5 signaling pathway

Fibroblast growth factor 21 (FGF21) is a member of the FGF family and acts as a potent regulator of glucose and lipid homeostasis, but its effect on renal fibrosis and the underlying mechanisms are totally unknown. The purpose of this study was designed to investigate whether FGF21 has effect on high glucose-induced fibrogenesis in human mesangial cells (HMCs) and the underlying mechanism. High glucose is well known to stimulate the expression of extracelluar matrix (ECM) in human mesangial cells. In humans, overexpression and deposition of ECM lead to renal fibrosis. Thus, in this study, HMCs were incubated in high glucose with or without various concentrations of FGF21. Results demonstrated that the expression of FN, Col, TGF β1 and α-SMA were significantly up-regulated in HMCs. Whereas, treatment with FGF21 down-regulated the expression of FN, Col, TGF β1 and α-SMA. In addition, growth factors are considered to be an important driving force for the pathogenesis of renal fibrosis. Significantly increased PDGF, VEGF and CTGF expression were found in HMCs induced by high glucose. FGF21 treatments significantly decreased these growth factors expression by down-regulating the phosphorylation level of STAT5. Here, we reported for the first time that FGF21 decreases ECM expression by inhibiting STAT5 signal pathway and consequently decreasing the expression of PDGF, VEGF and CTGF.

Baseline Circulating FGF21 Concentrations and Increase after Fenofibrate Treatment Predict More Rapid Glycemic Progression in Type 2 Diabetes: Results from the FIELD Study.

It is not known whether circulating fibroblast growth factor 21 (FGF21) concentrations are associated with glycemic progression in patients with established type 2 diabetes. This study reports this relationship in type 2 diabetes patients participating in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. Plasma FGF21 was quantified in 9697 study participants. Among patients with lifestyle-only glucose control measures at baseline, glycemic progression was defined as the initiation of oral hypoglycemic agents or insulin therapy. We assessed the relationship of FGF21 concentrations with glycohemoglobin (Hb A1c), the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), and glycemic progression. Among 2584 patients with lifestyle-only glycemic therapy at baseline, plasma FGF21 concentrations were positively associated with HOMA-IR (5.1% increase per 100% increase in FGF21 concentrations). Patients with higher baseline plasma FGF21 concentrations had higher risk of glycemic progression over a 5-year period (P = 0.02), but the association was not significant after further adjusting for alanine aminotransferase (ALT) enzyme activity. During the fenofibrate active run-in phase, higher tertiles of fenofibrate-induced increase in FGF21 concentrations were associated with higher risk of glycemic progression (adjusted hazards ratio = 1.09 and 1.18 for tertiles 2 and 3, respectively, P for trend = 0.01), even after adjusting for ALT enzyme activity. This association was statistically significant in the fenofibrate group only (P = 0.01). Higher baseline and fenofibrate-induced increase in FGF21 concentrations predict more rapid glycemic progression in type 2 diabetes patients. This association may be partly explained by hepatic function.

FGF21 functions as a sensitive biomarker of APAP-treated patients and mice.

Acetaminophen (APAP) is a common medication that induces hepatocellular damage in a time- or dose-dependent manner. Fibroblast growth factor 21 (FGF21) exerts a series of biological effects, including cellular repair. Compared to clinical diagnosis parameters, we aimed to evaluate whether FGF21 can serve as a sensitive biomarker for APAP-induced liver impairment. In the present study, we discussed comparable data from APAP-treated patients and parallelly established APAP-exposed mice for investigation. The resulting human serological data showed that APAP-treated patients have a visible reduction of FGF21 expression in undetected liver impairment of clinical diagnosis. In the animal study, APAP-exposed livers exhibited normal metabolic functions and liver functions, as revealed by biochemical test and histopathological examination. Endogenous FGF21 concentrations in APAP-treated mice were decreased in sera and liver cells. Moreover, comparable immunoassay data showed that hepatocellular FGF21 expression was reduced in a time-dependent manner. Taken together, these findings elucidate the involvement of abnormal FGF21 expression in early APAP-induced liver impairment. Interestingly, FGF21 may be a promising biomarker of APAP-exposed livers.

Alterations in 3-Hydroxyisobutyrate and FGF21 Metabolism Are Associated With Protein Ingestion-Induced Insulin Resistance.

Systemic hyperaminoacidemia, induced by either intravenous amino acid infusion or protein ingestion, reduces insulin-stimulated glucose disposal. Studies of mice suggest that the valine metabolite 3-hydroxyisobutyrate (3-HIB), fibroblast growth factor 21 (FGF21), adiponectin, and nonesterified fatty acids (NEFAs) may be involved in amino acid-mediated insulin resistance. We therefore measured in 30 women the rate of glucose disposal, and plasma 3-HIB, FGF21, adiponectin, and NEFA concentrations, under basal conditions and during a hyperinsulinemic-euglycemic clamp procedure (HECP), with and without concomitant ingestion of protein (n = 15) or an amount of leucine that matched the amount of protein (n = 15). We found that during the HECP without protein or leucine ingestion, the grand mean ± SEM plasma 3-HIB concentration decreased (from 35 ± 2 to 14 ± 1 µmol/L) and the grand median [quartiles] FGF21 concentration increased (from 178 [116, 217] to 509 [340, 648] pg/mL). Ingestion of protein, but not leucine, decreased insulin-stimulated glucose disposal (P < 0.05) and prevented both the HECP-mediated decrease in 3-HIB and increase in FGF21 concentration in plasma. Neither protein nor leucine ingestion altered plasma adiponectin or NEFA concentrations. These findings suggest that 3-HIB and FGF21 might be involved in protein-mediated insulin resistance in humans.

High Casein Diet Differentially Alters FGF21 Levels in Plasma and Cardiac Tissue in Rats

Fibroblast growth factor‐21 (FGF21) is a cytokine that has been demonstrated to regulate metabolism and have cardioprotective effects in response to obesity and other cardiac stressors. High protein diets have been used to reduce body fat and ameliorate metabolic disorders, however the effects of high protein diets on FGF21‐mediated signaling in cardiac tissue are not well known. We hypothesized that high protein diets will increase circulating levels of FGF21, leading to enhanced FGF21‐mediated signaling in cardiac tissue. Male Sprague‐Dawley rats were placed into one of three dietary groups: 1) control diet (20% of kcal from protein; CON; n=8), 2) high soy protein diet (40% of kcal from soy; SOY; n=8), or high casein protein diet (40% of kcal from casein; CAS; n=8). Food consumption and body mass were recorded weekly. After 15 weeks, blood was collected and hearts were excised after an overnight fast. Western immunoblotting was performed on cardiac homogenates and analyzed for: FGF21, FGF receptor‐1 (FGFR1), phospho‐FGFR1Tyr654, phospho‐ERK1/2Thr202/Tyr204, phospho‐AktSer473, phospho‐AMPKThr172, phospho‐p38 MAPKThr180/Tyr182, and 4‐hydroxynonenal (4‐HNE), a marker of oxidative stress. There was no difference in daily food intake or terminal body mass between dietary groups. Plasma concentrations of FGF21 were significantly (P&lt;0.05) greater for CAS (742.1±149.9 pg/ml) compared to CON (213.6±37.7 pg/ml), determined by ELISA. FGF21 protein levels in the heart were significantly (P&lt;0.05) lower for CAS compared to CON and SOY groups. Phospho‐AktSer473 was significantly (P&lt;0.05) greater in SOY compared to CON and CAS groups. There were no other significant differences between dietary groups for any other analyte measured. These data indicate that high protein diets composed of differing protein sources have non‐uniform effects on plasma and cardiac levels of FGF21. Additionally, 15‐weeks of high protein diet consumption does not appear to alter body mass or FGF21‐mediated signaling in the rat heart.Support or Funding InformationCentral Michigan University Herbert H. and Grace A. Dow College of Health Proffesions, and the Office of Research and Graduate Studies Early Career Award.

Negative correlation between cerebrospinal fluid FGF21 levels and BDI scores in male Chinese subjects

Fibroblast growth factor 21 (FGF21) is an important metabolic regulator of glucose homeostasis and lipid metabolism. Recently, FGF21 has been shown to play a robust neuroprotective role and act as a mediator of the effects of mood stabilizers. In the present study, we measured the concentration of FGF21 in human cerebrospinal fluid (CSF) and investigated the relationship of FGF21 levels with depression and anxiety emotions. Sixty-seven Chinese volunteers were recruited from Beijing Jishuitan Hospital. A significant negative association was found between CSF FGF21 levels and Beck Depression Inventory (BDI) scores in male subjects. Our findings provide evidence of the role of FGF21 in mood regulation.