Fibroblast Growth Factor 21 Levels Research Articles

Expression of bile acid receptors and transporters along the intestine of patients with type 2 diabetes and controls.

The enterohepatic circulation of bile acids depends on intestinal absorption by bile acid transporters and activation of bile acid receptors, which stimulates secretion of hormones regulating glucose and lipid metabolism and appetite. Distribution of bile acid transporters and receptors in the human gut and their potential involvement in type 2 diabetes (T2D) pathophysiology remain unknown. We explored the expression of genes involved in bile acid metabolism throughout the intestines of patients with T2D and matched healthy controls. Intestinal mucosa biopsies sampled along the intestinal tract in 12 individuals with T2D and 12 healthy controls were subjected to mRNA sequencing. We report expression profiles of apical sodium-dependent bile acid transporter (ASBT), organic solute transporter (OST) α/β, farnesoid X receptor (FXR), Takeda G receptor 5 (TGR5), fibroblast growth factor 19 (FGF19) and FGF receptor 4 (FGFR4). Expression of ASBT and OSTα/β was evident in the duodenum of both groups with increasing levels through the small intestine, and no (ASBT) or decreasing levels (OSTα/β) through the large intestine. The FXR expression pattern followed that of OSTα/β whereas FGFR4 were evenly expressed through the intestines. Negligible levels of TGR5 and FGF19 were evident. Patients with T2D exhibited lower levels of FGF19, FXR, ASBT and OSTα/β mRNAs compared with healthy controls, although the differences were not statistically significant after adjusting for multiple testing. We demonstrate distinct expression patterns of bile acid transporters and receptors through the intestinal tract with signs of reduced ASBT, OSTα/β, FXR and FGF19 mRNAs in T2D.

Effects of low fat diet on inflammatory parameters in individuals with obesity/overweight and non-alcoholic fatty liver disease: A cross-sectional study.

Nonalcoholic fatty liver disease (NAFLD) is considered one of the most important causes of chronic liver disorders in the world. Dietary pattern is a modifiable risk factor that represents the main target for the prevention and treatment of NAFLD. The aim of this cross-sectional study was to assess the impact of low-fat diet on anthropometric measurements, biochemical, and inflammatory parameters in individuals with obesity/overweight and NAFLD. A total of 108 individuals (n = 59 males and n = 49 females) aged between 19 and 65 years participated in the 12-week weight loss program. Dietary treatment plans including low-fat diets were randomly prescribed for each individual. Anthropometric measurements were collected by a trained dietitian at baseline and 12-week follow-up. Blood samples were collected for each individual at baseline and 3rd month for biochemical measurements and enzyme-linked immunosorbent assay analysis for tumor necrosis factor-α (TNF-α), interleukin (IL)-6, fibroblast growth factor-21 (FGF-21), chemerin, and irisin levels in plasma. At the end of the study, body weight, body mass index, body fat % body fat mass (kg) reduced significantly in females and males (P < .05). Moreover, reductions in waist, hip, and neck circumferences were significant in both groups. Changes in alanine aminotransferase and aspartate aminotransferase levels were significant in 3rd month. After 3 months, reductions in TNF-α, IL-6, and FGF-21 levels were significant in individuals with obesity/overweight and NAFLD. While no significant change in chemerin and irisin levels was found. These results show that low-fat diet over a 12-week period led to improvements in both anthropometric measurements and biochemical parameters in individuals with obesity/overweight and NAFLD.

Supplementation of yam bean (Pachyrhizus erosus L.) fiber ameliorates dyslipidemia, liver pathology and hypersecretion of metabolic hormones in mice fed a highfat diet

Introduction: Yam bean (Pachyrhizus erosus L.) offers numerous health benefits. However, the effects of its dietary fiber (yam bean fiber, YBF) on dyslipidemia, liver disease, and the overproduction of metabolic hormones, specifically glucagon-like peptide-1 (GLP1) and fibroblast growth factor 21 (FGF21), resulting from a high-fat diet (HFD) remain underexplored. Thus, our present investigation sought to address this gap. Methods: Adult male mice (n = 24) were randomly assigned into four different groups such as normal diet (ND) as a control group, HFD, and HFD supplemented with either 2.5% or 10% YBF. After a 12-week dietary regimen, plasma lipid profiles, liver histology and biochemistry, and the levels of FGF21 and GLP-1 were assessed. Results: YBF supplementation, especially at 10% dose, effectively lowered total serum cholesterol, triglyceride (TG), and low-density lipoprotein (LDL) compared with those fed HFD (P &lt; 0.05). YBF also reduced liver weight and mitigated the elevation of malondialdehyde (MDA) and the depletion of catalase (CAT) activity induced by HFD in liver tissues (P &lt; 0.05). Furthermore, 10% YBF supplementation effectively countered liver pathology, including central vein enlargement, hepatic steatosis, inflammation, abnormal sinusoids, and hepatocyte degeneration caused by HFD (P &lt; 0.05). YBF at 10% also attenuated the HFDinduced hypersecretion of FGF21 and GLP-1 hormones. Conclusion: Our findings indicate that YBF supplementation could counteract the adverse effects of HFD, particularly in terms of dyslipidemia, liver disease, and metabolic hormone imbalances. Incorporating YBF into diets may thus offer protective benefits against HFDinduced metabolic diseases and associated health issues.

FGF21 ameliorates septic liver injury by restraining proinflammatory macrophages activation through the autophagy/HIF-1α axis

IntroductionSepsis, a systemic immune syndrome caused by severe trauma or infection, poses a substantial threat to the health of patients worldwide. The progression of sepsis is heavily influenced by septic liver injury, which is triggered by infection and cytokine storms, and has a significant impact on the tolerance and prognosis of septic patients. The objective of our study is to elucidate the biological role and molecular mechanism of fibroblast growth factor 21 (FGF21) in the process of sepsis. ObjectivesThis study was undertaken in an attempt to elucidate the function and molecular mechanism of FGF21 in therapy of sepsis. MethodsSerum concentrations of FGF21 were measured in sepsis patients and septic mice. Liver injury was compared between mice FGF21 knockout (KO) mice and wildtype (WT) mice. To assess the therapeutic potential, recombinant human FGF21 was administered to septic mice. Furthermore, the molecular mechanism of FGF21 was investigated in mice with myeloid-cell specific HIF-1α overexpression mice (LyzM-CreDIO-HIF-1α) and myeloid-cell specific Atg7 knockout mice (Atg7△mye). ResultsSerum level of FGF21 was significantly increased in sepsis patients and septic mice. Through the use of recombinant human FGF21 (rhFGF21) and FGF21 KO mice, we found that FGF21 mitigated septic liver injury by inhibiting the initiation and propagation of inflammation. Treatment with rhFGF21 effectively suppressed the activation of proinflammatory macrophages by promoting macroautophagy/autophagy degradation of hypoxia-inducible factor-1α (HIF-1α). Importantly, the therapeutic effect of rhFGF21 against septic liver injury was nullified in LyzM-CreDIO-HIF-1α mice and Atg7△mye mice. ConclusionsOur findings demonstrate that FGF21 considerably suppresses inflammation upon septic liver injury through the autophagy/ HIF-1α axis.

Changes metabolic hormones and trace elements in CSF in active smokers indicate oxidative damage to brain cells.

This study aimed to reveal associations between metabolic hormones in cerebral spinal fluid (CSF) and cigarette smoking-induced weight gain and to explore the underlying mechanism. A total of 156 adult men were included in active smokers and nonsmokers. In addition to demographic information and body mass index (BMI), plasma levels of ApoA1 and ApoB, high-density lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol (CHO), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) in the participants were measured. Moreover, the metabolic hormones adiponectin, fibroblast growth factor 21 (FGF21), ghrelin, leptin, and orexin A, plus the trace elements of iron and zinc in CSF were assessed. Compared to non-smokers, active smokers showed higher BMI, elevated CSF levels of FGF21, Zn and Fe, but decreased levels of metabolic hormones adiponectin, ghrelin, leptin, and orexin A. Negative correlations existed between CSF FGF21 and ghrelin, between CSF Zn and ghrelin, as well as between CSF Fe and orexin A in active smokers. Furthermore, elevated CSF FGF21 and Zn predicted ghrelin level decrease in the smokers. These data relate the smoking-induced weight gain to its neurotoxic effect on the neurons that synthesize the metabolic hormones of adiponectin, ghrelin, leptin, or orexin A in the brain via disrupting mitochondrial function and causing oxidative stress in the neurons.

FGF21 protects against ischaemia reperfusion injury in normal and fatty livers.

Liver ischaemia/reperfusion (I/R) injury, which is an inevitable clinical problem of liver resection, liver transplantation and haemorrhagic shock. Fibroblast growth factor 21 (FGF21) was intimately coupled with multiple metabolic processes and proved to protect against apoptosis and inflammatory response in hepatocytes during hepatic I/R injury. However, the regulatory mechanisms of FGF21 in hepatic I/R injury remains unknown. Therefore, we hypothesize that FGF21 protects hepatic tissues from I/R injury. Blood samples were available from haemangiomas patients undergoing hepatectomy and murine liver I/R model and used to further evaluate the serum levels of FGF21 both in humans and mice. We further explored the regulatory mechanisms of FGF21 in murine liver I/R model by using FGF21-knockout mice (FGF21-KO mice) and FGF21-overexpression transgenic mice (FGF21-OE mice) fed a high-fat or ketogenic diet. Our results show that the circulating levels of FGF21 were robustly decreased after liver I/R in both humans and mice. Silencing FGF21 expression with FGF21-KO mice aggravates liver injury at 6 h after 75 min of partial liver ischaemia, while FGF21-OE mice display alleviated hepatic I/R injury and inflammatory response. Compared with chow diet mice, exogenous FGF21 decreases the levels of aminotransferase, histological changes, apoptosis and inflammatory response in hepatic I/R injury treatment mice with a high-fat diet. Meanwhile, ketogenic diet mice are not sensitive to hepatic I/R injury. The circulating contents of FGF21 are decreased during liver warm I/R injury and exogenous FGF21 exerts hepatoprotective effects on hepatic I/R injury. Thus, FGF21 regulates hepatic I/R injury and may be a key therapeutic target.

Serum fibroblast growth factor 19 level correlates inversely with clinical and endoscopic activity of inflammatory bowel disease.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic condition with relapsing-remitting course. Diarrhea and abdominal pain are the most common IBD symptoms. Fibroblast growth factor 19 (FGF19) is an endocrine factor that inhibits hepatic bile acid production and may be used as a diagnostic marker for bile acid malabsorption. To assess serum FGF19 levels in active and inactive phases of IBD and find a potential correlation between FGF19 and disease activity. Fasting serum FGF19 levels were measured in 105 IBD patients (47 UC patients, 41 CD patients without previous ileocecal resection (NR-CD), 17 CD patients after ileocecal resection (IR-CD), and 17 control subjects). The disease activity was assessed using clinical, laboratory and endoscopic criteria. Inverse correlations were found between FGF19 level and intensity of diarrhea (in UC), abdominal pain intensity (in UC and IR-CD) and inflammatory markers (in UC and IR-CD). Moreover, FGF19 concentration was inversely correlated with clinical and endoscopic activity indices in UC and CD. Fluctuations in FGF19 level related to clinical and endoscopic activity of UC and CD revealed a clear pattern of higher values in remission than in active disease phases. Fibroblast growth factor 19 may serve as a potential diagnostic biomarker and constitute a new therapeutic target in IBD.

Lactiplantibacillus plantarum strains KABP011, KABP012 and KABP013 modulate bile acids and cholesterol metabolism in humans.

Probiotics with high bile salt hydrolase (BSH) activity have shown to promote cardiovascular health. However, their mechanism(s) of action remain poorly understood. Here, we performed a pilot exploratory study to investigate effects of a 4-week intervention with escalating doses of a BSH-active formula containing Lactiplantibacillus plantarum strains KABP011, KABP012 and KABP013 on bile acid (BA), lipid profile and lipoprotein function. Healthy overweight individuals were included in this study. The probiotic intake was associated to a progressive decrease of conjugated BAs in serum, due to the reduction of tauro- and glyco-conjugated forms. Plasma levels of Fibroblast Growth Factor-19 (FGF-19) were significantly reduced, and correlated with BA changes. The probiotic induced significant changes in serum lipids, with reduction in non-HDL-cholesterol (non-HDLc) and LDL-cholesterol (LDLc) levels. The largest decrease was evidenced in the subgroup with higher baseline LDL levels (LDLc > 130 mg/dL). Fasting levels of circulating apolipoprotein(Apo) B100 and ApoB48 were significantly reduced. Importantly, the decrease in non-HDLc levels was associated with a significant reduction in small-LDL particles. Functional testing indicated that LDL particles had a significantly lower susceptibility to oxidation whilst HDL particles gained antioxidant capacity after the probiotic intake. The microbiota profile in faeces collected at the end of the study was enriched with members of class Desulfovibrio, a taurine-consuming bacteria, likely because of the increase in free taurine in the gut due to the BSH activity of the probiotic. The intervention with Lactiplantibacillus plantarum strains induces beneficial effects on BA signature and lipoprotein profile. It reduces ApoB and small-LDL levels and LDL susceptibility to oxidation, and increases HDL antioxidant capacity. These metabolic profile changes suggest increased protection against atherosclerotic disease.

Evaluation of serum pro/anti-angiogenic biomarkers in hyperglycemic rats treated with Securigera securidaca seeds, alone and in combination with Glibenclamide.

Herbal medicines are commonly used by many people with diabetes in addition to standard treatment. Plants contain numerous known and unknown compounds that may exacerbate or ameliorate diabetes complications. Therefore, it is crucial to be aware of the side effects of these herbs before prescribing them. This study aimed to investigate the effects of hydroalcoholic extracts of Securigera securidaca (HESS) seeds alone and in combination with glibenclamide on the angiogenic/anti-angiogenic balance in streptozotocin (STZ)-induced diabetic rats. Groups involved in this animal study included diabetic and healthy controls, three doses of HESS, glibenclamide, and combination therapy. Serum samples were collected and analyzed for a vascular endothelial growth factor (VEGF), fibroblast growth factor 21 (FGF21), fetal liver kinase 1 (FLK-1), soluble fms-like tyrosine kinase 1 (sFLT-1), and transforming growth factor -beta (TGF-β). Induction of diabetes increased VEGF, FGF21, and TGF-β serum levels and decreased circulating FLK-1 and sFLT-1 factors. Herbal extract, except TGF-β, had little effect on the above blood levels even at the highest doses. Glibenclamide was more effective than the highest dose of HESS in improving the vascular complications of diabetes. Combination therapy with the highest dose of HESS partly enhanced the glibenclamide effects. Compared with glibenclamide as a standard chemical drug, HESS had no significant effects on the blood levels of the pro/anti-angiogenesis factor in diabetic rats. Glibenclamide attenuated the levels of the biomarkers and its effects were somewhat enhanced in combination with the highest dose of HESS.

Effect Of Fibroblast Growth Factor-21 Molecule On Coronary Collateral Development.

Collateral arteries provide an alternative source to myocardium resulting from ischemia due to occlusive coronary artery disease and may help preserve myocardial function in the case of coronary artery disease (CAD)[1]. Although the collateral development is so important, its pathophysiology has not been fully elucidated. Until now, there is no study investigating the relationship between Fibroblast growth factor-21(FGF-21) and coronary collateral. This study aims to investigate the pathophysiology of coronary collateral development. In our study, which we planned as a case control, 60 consecutive patients with ≥90 stenosis in at least one large coronary artery as a result of coronary angiography (CAG) and 30 patients with normal coronary angiography were included in the study cross-sectional. Demographic, echocardiographic and laboratory data were recorded. Coronary collateral circulation was evaluated using the Rentrop-Cohen method [2]. FGF-21 levels were measured in all individuals. In the analysis, no significant difference was observed between the two groups in basic biochemical parameters other than HDL (p>0.05 for all). FGF-21 level was found to be statistically significantly higher in the patient group compared to the control group (p:0.003). Also, FGF-21 level was found to be statistically significantly higher in the good collateral circulation group to the poor collateral circulation group (p:0.006). Univariate and multivariate logistic regression analysis was performed to predict the presence of collateral. We found that FGF-21(p=0.006), C-reactive protein (p=0.020) predicted the presence of collateral independently. Collateral formation and cardiac prognosis are closely related. Our study is the first to investigate the relationship between collateral formation and FGF-21. Our study showed that FGF-21 level is an independent predictor of collateral formation. In addition, there was a significant difference between bad and good collateral formation in terms of FGF-21 levels.

The effect of soy isoflavones on non-alcoholic fatty liver disease and the level of fibroblast growth factor-21 and fetuin A

A two-arm randomized open labeled controlled clinical trial was conducted on 50 patients with non-alcoholic fatty liver disease (NAFLD). Subjects were randomized to either receive two tablets of soy isoflavone (100 mg/day) or placebo. At week 12, the serum levels of alanine amino transferase (ALT), aspartate amino transferase (AST) and controlled attenuation parameter (CAP) score were significantly decreased only in the soy isoflavone group (P < 0.05). A significant decline in the gamma glutamyl transferase (GGT) level was observed only in the placebo group (P = 0.017). A significant increase in the serum level of fetuin A was shown in both groups at the end of the trial with a significantly greater increment in the soy isoflavone group compared to the placebo group (P < 0.05). The changes in the serum level of FGF-21 were not significant in any of the two groups. Steatosis grade significantly improved only in the soy isoflavone group (P = 0.045). There was no significant change in the fibrosis grade in the groups. Soy isoflavone intake led to a decrease in ALT, AST, CAP score, steatosis grade and an increase in the level of fetuin A. However, no significant changes were observed in the fibrosis grade and serum levels of GGT and FGF-21.

The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice

Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in stroke recovery. However, the potential efficacy of SGLT2i to improve stroke recovery in T2D has not been investigated. Therefore, we determined whether a post-stroke intervention with the SGLT2i Empagliflozin could improve stroke recovery in T2D mice. T2D was induced in C57BL6J mice by 8 months of high-fat diet feeding. Hereafter, animals were subjected to transient middle cerebral artery occlusion and treated with vehicle or the SGLTi Empagliflozin (10 mg/kg/day) starting from 3 days after stroke. A similar study in non diabetic mice was also conducted. Stroke recovery was assessed using the forepaw grip strength test. To identify potential mechanisms involved in the Empagliflozin-mediated effects, several metabolic parameters were assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis and cerebral vascularization were analyzed using immunohistochemistry/quantitative microscopy. Empagliflozin significantly improved stroke recovery in T2D but not in non-diabetic mice. Improvement of functional recovery was associated with lowered glycemia, increased serum levels of fibroblast growth factor-21 (FGF-21), and the normalization of T2D-induced aberration of parenchymal pericyte density. The global T2D-epidemic and the fact that T2D is a major risk factor for stroke are drastically increasing the number of people in need of efficacious therapies to improve stroke recovery. Our data provide a strong incentive for the potential use of SGLT2i for the treatment of post-stroke sequelae in T2D.

FXR-FGF19 signaling in the gut–liver axis is dysregulated in patients with cirrhosis and correlates with impaired intestinal defence

Abstract Background and aims Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut–liver axis and their link to disease severity in patients with cirrhosis. Methods Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured. Results Systemic BA and FGF19 levels correlated significantly (r = 0.461; p &lt; 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p &lt; 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = −0.512, p &lt; 0.001) and BA (r = −0.487, p &lt; 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls. Conclusions FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut–liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis. Clinical trial number: NCT03267615 Graphical abstract Physiology of enterohepatic FXR-FGF19 signaling and its regulation in patients with advanced chronic liver disease (ACLD). (FXR) farnesoid X receptor; (FGF19) fibroblast growth factor 19; (BA) bile acids; (c/dACLD) compensated/decompensated advanced chronic liver disease; (FXR) farnesoid X receptor; (SHP) small heterodimer partner; (OST-α/-β) organic solute transporter subunit alpha/beta; (CYP7A1) cholesterol 7 alpha-hydroxylase; (NTCP) Na+-taurocholate cotransporting polypeptide; (CYP8B1) sterol 12-alpha-hydroxylase; (HVPG) hepatic venous pressure gradient; (TJ) tight junctions; (AMP) antimicrobial peptides; (ASBT) Apical Sodium Dependent Bile Acid Transporter; (ZO 1) zonula occludens-1; (OCLN) occluding; (DEFA5) alpha-5-defensin.

Association of circulating fibroblast growth factor 21 levels with all-cause and cardiovascular mortality: The multi-ethnic study of atherosclerosis

BackgroundFibroblast growth factor 21 (FGF21) levels are often elevated in cardiovascular disease (CVD). However, no study has assessed its association with cardiovascular and all-cause mortality in a population free of clinically evident CVD. MethodsA total of 5543 Multi-Ethnic Study of Atherosclerosis (MESA) participants (mean age 62.7 years, 47.5 % male), free of clinically evident CVD at baseline, were studied. From baseline (2000–2002), 1606 deaths (including 387 CVD deaths) were observed over a median follow-up of 17.7 years. Multivariable Cox regression analysis was performed to assess the association of plasma FGF21 levels with mortality. ResultsFGF21 levels at baseline were associated with all-cause mortality, even after adjustment for traditional risk factors, including demographic, socioeconomic and cardiovascular risk factors (adjusted hazard ratio 1.08 [95% confidence interval 1.01, 1.16] per 1 SD increase in ln-transformed levels; 1.27 for the highest vs, lowest quartile). Baseline FGF21 levels were significantly associated with both CVD and non-CVD mortality in unadjusted models. However, the association with non-CVD mortality, but not CVD mortality, remained statistically significant after adjusting for covariates. Similar results were obtained in FGF21 quartile analyses and also when using competing risk regression or matched case-control cohort in sensitivity analyses. ConclusionsIn subjects without clinically-evident CVD at baseline, over 17.7 years follow-up there is a modest association of baseline FGF21 levels with all-cause mortality. The finding that this is driven primarily by a significant association with non-CVD mortality over almost two decades merits further investigation.

Fibroblast growth factor 21 predicts arteriovenous fistula functional patency loss and mortality in patients undergoing maintenance hemodialysis

Background Arteriovenous fistula (AVF) dysfunction is a common complication in patients undergoing maintenance hemodialysis (MHD). Elevated serum levels of fibroblast growth factor 21 (FGF21) are associated with atherosclerosis and cardiovascular mortality. However, its association with vascular access outcomes remains elusive. The present study evaluated the relationship of serum FGF21 levels with AVF dysfunction and all-cause mortality in patients undergoing MHD. Methods We included patients undergoing MHD using AVF from January 2018 to December 2019. FGF21 concentration was detected using enzyme-linked immunosorbent assay. Patients were followed up to record two clinical outcomes, AVF functional patency loss and all-cause mortality. The follow-up period ended on April 30, 2022. Results Among 147 patients, the mean age was 58.49 ± 14.41 years, and the median serum level of FGF21 was 150.15 (70.57–318.01) pg/mL. During the median follow-up period of 40.83 months, the serum level of FGF21 was an independent risk factor for AVF functional patency loss (per 1 pg/mL increase, HR 1.002 [95% CI: 1.001–1.003, p = 0.003]). Patients with higher serum levels of FGF21 were more likely to suffer from all-cause mortality (per 1 pg/mL increase, HR 1.002 [95% CI: 1.000–1.003, p = 0.014]). The optimal cutoffs for FGF21 to predict AVF functional patency loss and all-cause mortality in patients undergoing MHD were 149.98 pg/mL and 146.43 pg/mL, with AUCs of 0.701 (95% CI: 0.606–0.796, p < 0.001) and 0.677 (95% CI: 0.595–0.752, p = 0.002), respectively. Conclusions Serum FGF21 levels were an independent risk factor and predictor for AVF functional patency loss and all-cause mortality in patients undergoing MHD.

Fructose-induced FGF21 secretion does not activate brown adipose tissue in Japanese young men: randomized cross-over and randomized controlled trials

BackgroundHuman brown adipose tissue (BAT) activity is associated with lower body fatness and favorable glucose metabolism. Previous studies reported that oral fructose loading induces postprandial fibroblast growth factor 21 (FGF21) secretion. FGF21 is a known inducer of adipose tissue thermogenesis; however, the effects of diet-induced FGF21 secretion on BAT thermogenesis remain to be elucidated.MethodsThe effects of both single load and daily consumption of fructose on BAT activity were examined using a randomized cross-over trial and a 2-week randomized controlled trial (RCT), respectively. In the cross-over trial, 15 young men consumed a single dose of fructose solution or water and then consumed the other on a subsequent day. The RCT enrolled 22 young men, and the participants were allocated to a group that consumed fructose and a group that consumed water daily for 2 weeks. BAT activity was analyzed using thermography with cold exposure. Plasma FGF21 level was determined by enzyme-linked immunosorbent assay.ResultsIn the cross-over single-load trial, plasma FGF21 levels were significantly increased at 2 h after oral fructose load (p < 0.01); however, there was no significant difference in BAT activity between the fructose load and drinking water. The 2-week RCT revealed that both plasma FGF21 levels and BAT activity were not significantly increased by daily fructose consumption compared to water. Correlation analyses revealed that BAT activity at the baseline and the final measurements were strongly and positively associated with the RCT (r = 0.869, p < 0.001). Changes in BAT activity were significantly and negatively correlated with changes in plasma glucose levels during the 2-week intervention (r = − 0.497, p = 0.022).ConclusionsOral fructose load induces a temporary increase in circulating FGF21 levels; however, this does not activate BAT thermogenesis in healthy young men. Further studies are needed to elucidate the effect of endogenous FGF21 on physiological function.Trial registrationThis study is registered with the University Hospital Medical Information Network in Japan (number 000051761, registered 1 August 2023, retrospectively registered, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000052680).

Protein biomarkers GDF15 and FGF21 to differentiate mitochondrial hepatopathies from other pediatric liver diseases.

Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children. Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, α1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls. GDF15 levels compared to controls were mildly elevated in patients with α1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93±0.04 and for FGF21 0.90±0.06. Simultaneous elevation of both markers >98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01). GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.

High-intensity interval training increases AMPK and GLUT4 expressions via FGF21 in skeletal muscles of diabetic rats

Background: In type 2 diabetes, a decrease in expression of glucose transporter type 4 (GLUT4) can result in decreased glucose uptake. The hormone fibroblast growth factor 21 (FGF21) promotes glucose uptake. The liver and other organs, such as the muscles, produce FGF21. Physical activity increases FGF21 secretion from skeletal muscles. FGF21 is thought to promote glucose uptake during exercise by activating AMP-activated protein kinase (AMPK). As a result, the goal of this study is to determine how HIIT affects glucose uptake via FGF21 signaling in diabetics. Methods: Twenty-four eight-week-old male Wistar rats were randomly divided into four categories: (1) without intervention (Con), (2) DM intervention (ConDM), (3) DM group undergoing continuous training (DM-CT), and (4) DM group undergoing high-intensity interval training (DM-HIIT). The trainings in the exercise groups (DM-CT and DM-HIIT) were performed six days a week for six weeks. We analyzed FGF21 levels in serum and muscles by ELISA. Measurement of phosphorylated AMPK in muscles used ELISA, and that of mRNA GLUT4 expression used RT-PCR. Results: Following HIIT interventions, the glucose level in plasma was closer to normal level. An increase in FGF21 levels aided in the reduction in blood glucose. The HIIT group had significantly higher FGF21 levels in serum and muscles. An increase in FGF21 was followed by an increase in AMPK phosphorylation and GLUT4 expression in the HIIT group. Conclusions: In diabetic rats, HIIT promotes glucose uptake via FGF21, which activates AMPK and increases GLUT4 expression.

Associations of Serum Irisin and Fibroblast Growth Factor-21 Levels With Bone Mineral Characteristics in Eumenorrheic Adolescent Athletes With Different Training Activity Patterns.

To describe serum irisin and fibroblast growth factor-21 (FGF-21) concentrations in healthy female adolescents with different training activity patterns and their associations with bone mineral properties and metabolic markers. A total of 62 adolescent girls aged 14-18years were recruited: 22 rhythmic gymnasts, 20 swimmers, and 20 untrained controls. Bone mineral characteristics by dual-energy X-ray absorptiometry, daily energy intake by dietary recall, serum irisin, FGF-21, undercarboxylated osteocalcin, and C-terminal telopeptide of type I collagen were measured in all girls. Whole body and lumbar spine areal bone mineral density and lumbar spine bone mineral content were higher in the rhythmic gymnasts group compared with swimmers and untrained controls groups (P < .05). Serum irisin, FGF-21, undercarboxylated osteocalcin, and C-terminal telopeptide of type I collagen levels were not significantly different between the groups. In the rhythmic gymnasts group, serum FGF-21 concentration was positively correlated with lumbar spine areal bone mineral density independently of confounding factors (r = .51; P = .027). Serum irisin and FGF-21 levels were not different between adolescent eumenorrheic girls with different training activity patterns. FGF-21 was positively associated with lumbar spine areal bone mineral density, which predominantly consists of trabecular bone in adolescent rhythmic gymnasts.

Grape seed-derived procyanidin inhibits glyphosate-induced hepatocyte ferroptosis via enhancing crosstalk between Nrf2 and FGF12

BackgroundGlyphosate (GLY) exposure induces hepatocyte ferroptosis through overproduction of reactive oxygen species, regarded as an important contributor to liver damage. Grape seed-derived procyanidin (GSDP) has been reported to be an effective antioxidant, but whether and, if any, how GSDP can attenuate GLY-induced liver injury via inhibiting ferroptosis is unclear. PurposeThe current study aimed to investigate the hepato-protective effects and possible mechanisms of GSDP. MethodsGLY-induced liver damage mice model was established to explore the hepatoprotective roles of GSPE in vivo. Subsequently, bioinformatics methodology was used to predict the key pathways and factors related to the action targets of GSPE against hepatocyte ferroptosis. Finally, we explored the roles of nuclear factor E2 related factor 2 (Nrf2) and fibroblast growth factor 21 (FGF21) in blunting GLY-induced liver damage via suppressing ferroptosis in vitro. ResultsGSDP exerts hepato-protective effects in vivo and in vitro through reduced oxidative stress and inhibited ferroptosis, which was related to the activation of Nrf2. Bioinformatics analysis showed an interaction between Nrf2 and FGF21. Furthermore, Nrf2 inhibition reduced FGF21 expression in the mRNA and protein levels. Fgf21 knockdown suppressed Nrf2 expression level, but recombinant FGF21 protein increased Nrf2 expression and promoted Nrf2 translocation into nucleus, suggesting a crosstalk between Nrf2 and FGF21. Intriguingly, the decreased levels of Nrf2 and FGF21 compromised the protective roles of GSDP against GLY-induced hepatocyte ferroptosis. ConclusionThese findings suggest that GSDP attenuates GLY-caused hepatocyte ferroptosis via enhancing the interplay between Nrf2 and FGF21. Thus, GSDP may be a promising natural compound to antagonize ferroptosis-related damage.