Fibroblast Growth Factor 21 Levels Research Articles

Fibroblast growth factor 21 alleviates unilateral ureteral obstruction-induced renal fibrosis by inhibiting Wnt/β-catenin signaling pathway

Fibroblast growth factor 21 (FGF21) is a key regulator of energy metabolism. Recent studies suggested that serum FGF21 levels increase with declining renal function. However, the link between FGF21 and kidney diseases and the direct effect of FGF21 in renal fibrosis remains unclear. In this study, FGF21 was upregulated in unilateral ureteral obstruction (UUO)-induced renal fibrosis and cellular fibrosis induced by transforming growth factor-β, and renal expression of FGF21 was positively correlated with fibrosis markers. Additionally, FGF21 was regulated by Wnt/β-catenin signaling pathway. The knockdown and overexpression of FGF21 in mouse tubular epithelial cells demonstrated that FGF21 alleviates renal fibrosis by inhibiting the Wnt/β-catenin signaling pathway. To investigate the effect of FGF21 on renal fibrosis in vivo, we established an overexpression model by injecting the plasmid in mice and found that FGF21 overexpression relieved UUO-induced renal fibrosis and renal inflammatory response. Taken together, FGF21 is upregulated with the activation of Wnt/β-catenin signaling pathway and alleviates renal fibrosis by inhibiting the activation of Wnt/β-catenin signaling pathway in a negative feedback mode. These results provide a new understanding for the source of elevated serum FGF21 in patients with chronic kidney disease and prove that FGF21 is a direct inhibitor of the progression of renal fibrosis, thus providing novel therapeutic intervention insights for renal fibrosis.

Characterization of Postprandial Bile Acid Profiles and Glucose Metabolism in Cerebrotendinous Xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disease characterized by sterol 27-hydroxylase (CYP27A1) deficiency and, thus, a lack of bile acid synthesis with a marked accumulation of 7α-hydroxylated bile acid precursors. In addition to their renowned lipid-emulgating role, bile acids have been shown to stimulate secretion of the glucose-lowering and satiety-promoting gut hormone glucagon-like peptide 1 (GLP-1). In this paper, we examined postprandial bile acid, glucose, insulin, GLP-1 and fibroblast growth factor 19 (FGF19) plasma profiles in patients with CTX and matched healthy controls. Seven patients and seven age, gender and body mass index matched controls were included and subjected to a 4 h mixed meal test with regular blood sampling. CTX patients withdrew from chenodeoxycholic acid (CDCA) and statin therapy three weeks prior to the test. Postprandial levels of total bile acids were significantly lower in CTX patients and consisted of residual CDCA with low amounts of ursodeoxycholic acid (UDCA). The postprandial plasma glucose peak concentration occurred later in CTX patients compared to controls, and patients' insulin levels remained elevated for a longer time. Postprandial GLP-1 levels were slightly higher in CTX subjects whereas postprandial FGF19 levels were lower in CTX subjects. This novel characterization of CTX patients reveals very low circulating bile acid levels and FGF19 levels, aberrant postprandial glucose and insulin profiles, and elevated postprandial GLP-1 responses.

Fibroblast Growth Factor 21 in Chronic Hepatitis C: A Potential Non-Invasive Biomarker of Liver Status upon Viral Eradication.

Fibroblast growth factor 21 (FGF-21), previously recognized as a marker of liver damage and a potential drug target in non-alcoholic fatty liver disease (NAFLD), has unclear implications in hepatitis C virus (HCV) infections. This study aimed to investigate the relationship between FGF-21 levels and liver health in patients with HCV undergoing direct-acting antiviral (DAA) treatment. Forty-five patients were assessed for liver stiffness, blood chemistry, and other relevant metrics before and after achieving sustained viral response (SVR), defined as the absence of detectable HCV-RNA after 24 weeks of treatment. Post-treatment, all patients showed a decrease in liver stiffness and improved liver enzyme levels (AST and ALT), alongside an increase in FGF-21 levels. Interestingly, the increase in FGF-21 correlated negatively with liver stiffness but showed no correlation with hepatic steatosis. The observed elevation in FGF-21 levels at SVR following DAA therapy for chronic HCV infection can be attributed to the restoration of hepatic function, including its synthetic capabilities. Specifically, the mitigation of liver fibrosis post-HCV eradication is expected to lead to improvements in liver function, such as enhanced albumin and FGF-21 production. This improvement in synthetic function likely drives the increase in FGF-21 levels, rather than changes in liver fat content. We suggest a potential role of FGF-21 as a marker of fibrosis and hepatic cytotoxicity and as a drug target beyond NAFLD, to be confirmed by additional studies.

Long-term effects of a fat-directed FGF21 gene therapy in aged female mice.

Fibroblast growth factor 21 (FGF21) has been developed as a potential therapeutic agent for metabolic syndromes. Moreover, FGF21 is considered a pro-longevity hormone because transgenic mice overexpressing FGF21 display extended lifespan, raising the possibility of using FGF21 to promote healthy aging. We recently showed that visceral fat directed FGF21 gene therapy improves metabolic and immune health in insulin resistant BTBR mice. Here, we used a fat directed rAAV-FGF21 vector in 17-month-old female mice to investigate whether long-term FGF21 gene transfer could mitigate aging-related functional decline. Animals with FGF21 treatment displayed a steady, significant lower body weight over 7-month of the study compared to age-matched control mice. FGF21 treatment reduced adiposity and increased relative lean mass and energy expenditure associated with almost 100 folds higher serum level of FGF21. However, those changes were not translated into benefits on muscle function and did not affect metabolic function of liver. Overall, we have demonstrated that a single dose of fat-directed AAV-FGF21 treatment can provide a sustainable, high serum level of FGF21 over long period of time, and mostly influences adipose tissue homeostasis and energy expenditure. High levels of FGF21 alone in aged mice is not sufficient to improve liver or muscle functions.

Fibroblast growth factor 21 ameliorates cholestatic liver injury via a hepatic FGFR4-JNK pathway

Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequently leads to liver injury, inflammation, fibrosis, and liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver-secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury caused by α-naphthylisothiocyanate (ANIT) treatment and Mdr2 deficiency. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.

ECG changes and post-COVID arrhythmia incidence in patients with acute COVID-19 infection

Objective: During the COVID-19 pandemic, many patients have experienced cardiovascular complications, including a variety of arrhythmias. The aim of our study was to evaluate the acute electrocardiography (ECG) changes and post-COVID arrhythmia incidence in patients with acute COVID-19 infection. Patients and Methods: One hundred hospitalized COVID-19 patients were consecutively included. Patients were divided into two groups according to their troponin levels. Thirty subjects were included as controls. All patients underwent daily 12-lead ECG during hospitalization and were followed up for at least 12 months, by performing ECG and ambulatory ECG monitoring and questioning their symptoms at 3-month intervals. Results: Thirty-one patients had elevated high sensitive cardiac troponin I (hs-cTnI). These patients had significantly longer QT dispersion compared to COVID-19 patients with normal troponin levels and controls. Regardless of troponin elevation, COVID-19 patients had significantly longer Tp-e intervals and P wave (PW) durations compared to controls. During the follow-up period; palpitation, beta-blocker usage, and inappropriate sinus tachycardia were more common in the COVID-19 group with hs-cTnI than control group. Conclusion: Our study did not find any relation between serum fibroblast growth factor-21 levels and carotid intima-media thickness. Further researches with wider study population are needed.

Characterization of Circulating Cold Shock Proteins FGF21 and RBM3 in a Multi-Center Study of Pediatric Cardiac Arrest.

Fibroblast Growth Factor 21 (FGF21) is a neuroprotective hormone induced by cold exposure that targets the β-klotho co-receptor. β-klotho is abundant in the newborn brain but decreases rapidly with age. RNA-Binding Motif 3 (RBM3) is a potent neuroprotectant upregulated by FGF21 in hypothermic conditions. We characterized serum FGF21 and RBM3 levels in patients enrolled in a prospective multi-center study of pediatric cardiac arrest (CA) via a secondary analysis of samples collected to evaluate brain injury biomarkers. Patients (n = 111) with remnant serum samples available from at least two of three available timepoints (0-24, 24-48 or 48-72 hours post-resuscitation) were included. Serum samples from 20 healthy controls were used for comparison. FGF21 was measured by Luminex and internally validated enzyme-linked immunoassay (ELISA). RBM3 was measured by internally validated ELISA. Of postarrest patients, 98 were managed with normothermia, while 13 were treated with therapeutic hypothermia (TH). FGF21 increased >20-fold in the first 24 hours postarrest versus controls (681 pg/mL [200-1864] vs. 29 pg/mL [15-51], n = 99 vs. 19, respectively, p < 0.0001, median [interquartile range]) with no difference in RBM3. FGF21 did not differ by sex, while RBM3 was increased in females versus males at 48-72 hours postarrest (1866 pg/mL [873-5176] vs. 1045 pg/mL [535-2728], n = 40 vs. 54, respectively, p < 0.05). Patients requiring extracorporeal membrane oxygenation (ECMO) postresuscitation had increased FGF21 versus those who did not at 48-72 hours (6550 pg/mL [1455-66,781] vs. 1213 pg/mL [480-3117], n = 7 vs 74, respectively, p < 0.05). FGF21 and RBM3 did not correlate (Spearman's rho = 0.004, p = 0.97). We conclude that in a multi-center study of pediatric CA patients where normothermic targeted temperature management was largely used, FGF21 was markedly increased postarrest versus control and highest in patients requiring ECMO postresuscitation. RBM3 was sex-dependent. We provide a framework for future studies examining the effect of TH on FGF21 or use of FGF21 therapy after pediatric CA.

The association of FGF-21 with the risk of newly diagnosed type-2 diabetes mellitus: a cross-sectional study in Southern China

BackgroundThis study investigated the relationship between fibroblast growth factor 21 (FGF-21) and newly diagnosed type-2 diabetes mellitus (T2DM).MethodsIn this cross-sectional study, FGF-21 and T2DM risk were analyzed using restricted cubic splines with univariate or multivariate logistic regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via logistic regression analysis. Cluster and subgroup analyses were conducted to evaluate the associations between FGF-21 and diabetes in different subpopulations. Nomograms and ROC curves were used to explore the clinical utility of FGF-21 in the diabetes assessment model.ResultsHigh levels of FGF-21 were significantly associated with a high risk of T2DM after adjusting for confounding factors in both the total population and subpopulations (P for trend < 0.001). In the total population, the ORs of diabetes with increasing FGF-21 quartiles were 1.00 (reference), 1.24 (95% CI 0.56–2.80; quartile 2), 2.47 (95% CI 1.18–5.33; quartile 3), and 3.24 (95% CI 1.53–7.14; quartile 4) in Model 4 (P < 0.001), and the trend was consistent in different subpopulations. In addition, compared with the model constructed with conventional noninvasive indicators, the AUC of the model constructed by adding FGF-21 was increased from 0.668 (95% CI: 0.602–0.733) to 0.715 (95% CI: 0.654–0.777), indicating that FGF-21 could significantly improve the risk-assessment efficiency of type-2 diabetes.ConclusionThis study demonstrated that a high level of circulating FGF-21 was positively correlated with diabetes, and levels of FGF-21 could be an important biomarker for the assessment of diabetes risk.

Association of plasminogen activator inhibitor-1 and fibroblastic growth factor 21 in 3 groups of type 2 diabetes: Without overweight/obesity, free of insulin resistance, and without hepatosteatosis.

The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.

Maternal overweight and obesity modify the association of serum fibroblast growth factor 21 levels with gestational diabetes mellitus: A nested case-control study.

To examine the prospective association between fibroblast growth factor 21 (FGF21) and risk of gestational diabetes mellitus (GDM) and the modifying effect of overweight/obesity for this association. Serum FGF21 levels were measured at 6-15weeks of gestation among 332 GDM cases and 664 matched controls. Conditional logistic regression was used to evaluate its association with GDM risk. Interaction analyses on multiplicative and additive scales were conducted to investigate the modifying effect of overweight/obesity. Elevated FGF21 levels were associated with a higher risk of GDM in multivariable models, but the positive association was attenuated after further adjustment for pre-pregnancy body mass index (BMI). A significant multiplicative interaction was noted between FGF21 (both continuous and dichotomous) and pre-pregnancy BMI (p for interaction=0.049 and 0.03), and the association was only significant in participants with pre-pregnancy BMI ≥24kg/m2 . When participants were grouped based on pre-pregnancy BMI (≥24 and <24kg/m2 ) and FGF21 levels (≥median and <median), a significant association was observed in those with higher BMI and FGF21 levels (odds ratio, 2.12; 95% CI: 1.41, 3.20) but not in those with either higher BMI or higher FGF21, with a significant additive interaction (relative excess risk due to interaction=1.23; 95% CI: 0.27, 2.20). FGF21 was also correlated with unfavourable glucose and lipid biomarkers as well as adipokines. Elevated serum FGF21 levels in early pregnancy were associated with a higher risk of GDM, particularly among those with overweight/obesity.

Double knockout of FFAR4 and FGF21 aggravates metabolic disorders in mice

Several investigations have examined the involvement of free fatty acid receptor 4 (FFAR4) in metabolic disorders, but its action remains controversial. To investigate whether endogenous fibroblast growth factor 21 (FGF21)-mediated signaling controls the metabolic status in FFAR4-deficient mice, we generated FFAR4/FGF21 double knockout (DKO) mice. We also evaluated the role of FGF21 on glucose and lipid metabolism in FFAR4 KO mice fed a high-fat diet. Levels of FGF21 were significantly increased in FFAR4-deficient mice and double deletion of FGF21 and FFAR4 led to severe metabolic disorders. Additionally, FFAR4/FGF21 DKO mice displayed metabolic abnormalities that may be caused by decreased energy expenditure. Collectively, this study characterized the effects of endogenous FGF21, which acts as a master feedback regulator in the absence of FFAR4.

Cord Blood FGF-21 and GDF-15 Levels Are Affected by Maternal Exposure to Moderate to Severe Anemia and Malaria.

Anemia and malaria are global health problems affecting >50% of pregnant women in sub-Saharan Africa and are associated with intrauterine growth restriction. The hormones fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) are involved in metabolic regulation and are expressed in the placenta. No studies exist on FGF-21 and GDF-15 responses to exposures of malaria and anemia in pregnancy. Using a prospective, longitudinal pregnancy and birth cohort of women with an average age of 26 years from a rural region in northeastern Tanzania, we examined if FGF-21 and GDF-15 levels in maternal blood at week 33 ± 2 (n = 301) and in cord blood at birth (n = 353), were associated with anemia and malaria exposure at different time points in pregnancy and with neonatal anthropometry. Among mothers at gestation week 33 ± 2, lower FGF-21 levels were observed after exposure to malaria in the first trimester, but not anemia, whereas GDF-15 levels at week 33 ± 2 were not associated with malaria nor anemia. In cord blood, moderate to severe anemia at any time point in pregnancy was associated with higher levels of FGF-21, whereas malaria exposure in the third trimester was associated with lower FGF-21 levels in cord blood. Negative associations were observed between cord blood FGF-21 and GDF-15 levels and neonatal skinfold thicknesses and birthweight. Our results suggest that moderate to severe anemia throughout pregnancy associates with higher FGF-21 levels, and malaria in last trimester associates with lower FGF-21 levels, in the neonates, thereby potentially affecting the future cardiometabolic health of the child.

Insight to the association among fibroblast growth factor 21, non-alcoholic fatty liver disease and cardiovascular outcomes: A population-based study

ObjectiveWe aimed to investigate whether there was a joint effect of fibroblast growth factor 21 (FGF21) and non-alcoholic fatty liver disease (NAFLD) or interaction on the incidence of cardiovascular diseases based on a community-dwelling population. MethodsSerum FGF21 levels were determined using an enzyme-linked immunosorbent method. NAFLD was diagnosed via ultrasonography. Multivariable-adjusted cox proportional hazards models were used to assess the joint effects of FGF21 and NAFLD on the major adverse cardiovascular events (MACE). ResultsA total of 1194 participants were enrolled in the final analysis. The multivariable-adjusted hazard ratio (HR) of MACE was 1.84 (95% confidence interval (CI) 1.18–2.86) in participants with diagnosed NAFLD at baseline, compared with those without NAFLD at baseline. The multivariable-adjusted HRs of MACE across quintiles of serum FGF21 levels at baseline were 1.00, 1.48 (95%CI 0.68–3.21), 2.01 (95%CI 0.98–4.13), 1.94 (95%CI 0.94–4.02) and 2.14 (95%CI 1.03–4.44) respectively. Participants with high FGF21 levels and NAFLD at baseline showed the highest risk of MACE with a significant interaction between the presence of NAFLD and serum FGF21 levels. ConclusionsBoth FGF21 and NAFLD were associated with MACE, while the association between FGF21 and MACE may be interacted by the presence of NAFLD at baseline.

Alteration of BDNF, SPARC, FGF-21, and GDF-15 circulating levels after 1 year of anti-obesity treatments and their association with 1-year weight loss

PurposeEmerging evidence revealed that brain-derived neurotrophic factor (BDNF), secreted protein acidic and rich in cysteine (SPARC), fibroblast growth factor 21(FGF-21) and growth differentiation factor 15 (GDF-15) are involved in energy metabolism and body weight regulation. Our study aimed at examining their association with BMI, their alterations after anti-obesity treatments, and their association with 1-year weight loss.MethodsA prospective observational study of 171 participants with overweight and obesity and 46 lean controls was established. All participants received lifestyle educational intervention (LEI) with or without anti-obesity treatments (LEI + bariatric/metabolic surgery, n = 41; LEI + topiramate, n = 46; LEI + liraglutide, n = 31; LEI + orlistat, n = 12; and LEI alone, n = 41). Anthropometric and metabolic parameters, insulin sensitivity, C-reactive protein (CRP), fasting plasma levels of BDNF, SPARC, GDF-15, and FGF-21 were measured at baseline and 1 year.ResultsMultiple linear regression showed that fasting levels of SPARC, FGF-21, and GDF-15 were significantly associated with baseline BMI after adjustment for age and sex. At 1 year, the average weight loss was 4.8% in the entire cohort with a significant improvement in glycemia, insulin sensitivity, and CRP. Multiple linear regression adjusted for age, sex, baseline BMI, type of treatment, and presence of T2DM revealed that the decrease in log10FGF-21 and log10GDF-15 at 1 year from baseline was significantly associated with a greater percentage of weight loss at 1 year.ConclusionsThis study highlights the association of SPARC, FGF-21, and GDF-15 levels with BMI. Decreased circulating levels of GDF-15 and FGF-21 were associated with greater weight loss at 1 year, regardless of the types of anti-obesity modalities.

Dietary Protein Regulates Female Estrous Cyclicity Partially via Fibroblast Growth Factor 21.

Fibroblast growth factor 21 (FGF21), a hormone predominantly released in the liver, has emerged as a critical endocrine signal of dietary protein intake, but its role in the control of estrous cyclicity by dietary protein remains uncertain. To investigated the role of FGF21 and hypothalamic changes in the regulation of estrous cyclicity by dietary protein intake, female adult Sprague-Dawley rats with normal estrous cycles were fed diets with protein contents of 4% (P4), 8% (P8), 13% (P13), 18% (P18), and 23% (P23). FGF21 liver-specific knockout or wild-type mice were fed P18 or P4 diets to examine the role of liver FGF21 in the control of estrous cyclicity. Dietary protein restriction resulted in no negative effects on estrous cyclicity or ovarian follicular development when the protein content was greater than 8%. Protein restriction at 4% resulted in decreased bodyweight, compromised Kiss-1 expression in the hypothalamus, disturbed estrous cyclicity, and inhibited uterine and ovarian follicular development. The disturbed estrous cyclicity in rats that received the P4 diet was reversed after feeding with the P18 diet. Liver Fgf21 mRNA expressions and serum FGF21 levels were significantly increased as dietary protein content decreased, and loss of hepatic FGF21 delayed the onset of cyclicity disruption in rats fed with the P4 diet, possibly due to the regulation of insulin-like growth factor-1. Collectively, severe dietary protein restriction results in the cessation of estrous cyclicity and ovarian follicle development, and hepatic FGF21 and hypothalamic Kiss-1 were partially required for this process.

Hepatocellular carcinoma induced by hepatocyte Pten deletion reduces BAT UCP-1 and thermogenic capacity in mice, despite increasing serum FGF-21 and iWAT browning.

Hepatocellular carcinoma (HCC) markedly enhances liver secretion of fibroblast growth factor 21 (FGF-21), a hepatokine that increases brown and subcutaneous inguinal white adipose tissues (BAT and iWAT, respectively) uncoupling protein 1 (UCP-1) content, thermogenesis and energy expenditure. Herein, we tested the hypothesis that an enhanced BAT and iWAT UCP-1-mediated thermogenesis induced by high levels of FGF-21 is involved in HCC-associated catabolic state and fat mass reduction. For this, we evaluated body weight and composition, liver mass and morphology, serum and tissue levels of FGF-21, BAT and iWAT UCP-1 content, and thermogenic capacity in mice with Pten deletion in hepatocytes that display a well-defined progression from steatosis to steatohepatitis (NASH) and HCC upon aging. Hepatocyte Pten deficiency promoted a progressive increase in liver lipid deposition, mass, and inflammation, culminating with NASH at 24 weeks and hepatomegaly and HCC at 48 weeks of age. NASH and HCC were associated with elevated liver and serum FGF-21 content and iWAT UCP-1 expression (browning), but reduced serum insulin, leptin, and adiponectin levelsand BAT UCP-1 content and expression of sympathetically regulated gene glycerol kinase (GyK), lipoprotein lipase (LPL), and fatty acid transporter protein 1 (FATP-1), which altogether resulted in an impaired whole-body thermogenic capacity in response to CL-316,243. In conclusion, FGF-21 pro-thermogenic actions in BAT are context-dependent, not occurring in NASH and HCC, and UCP-1-mediated thermogenesis is not a major energy-expending process involved in the catabolic state associated with HCC induced by Pten deletion in hepatocytes.

Exploring the correlation between serum fibroblast growth factor-21 levels and Sarcopenia: a systematic review and meta-analysis

BackgroundFibroblast growth factor 21 (FGF-21) plays an important role in the growth and metabolism of skeletal muscle cells. This study aims to systemically review the evidence regarding the relationship between FGF-21 levels and Sarcopenia, as well as the related influential factors.MethodsThis review was conducted according to the PRISMA guidelines. We comprehensively searched PubMed, EMBASE, the Web of Science, Scopus, and Chinese Databases (CNKI, Wan Fang, VIP, and CBM) up to 1 May 2023. 3 investigators performed independent literature screening and data extraction of the included literature, and two investigators performed an independent quality assessment of case-control studies using the Joanna Briggs Institute (JBI) tool. Data analysis was performed using Review Manager 5.4 software. For continuous various outcomes, mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CIs) was applied for assessment by fixed-effect or random-effect model analysis. The heterogeneity test was performed by the Q-statistic and quantified using I2, and publication bias was evaluated using a funnel plot.ResultsFive studies with a total of 625 cases were included in the review. Meta-analysis showed lower BMI in the sarcopenia group [MD= -2.88 (95% CI, -3. 49, -2.27); P < 0.00001; I2 = 0%], significantly reduced grip strength in the sarcopenia group compared to the non-sarcopenia group [MD = -7.32(95% CI, -10.42,-4.23); P < 0.00001; I2 = 93%]. No statistically significant differences in serum FGF21 levels were found when comparing the two groups of subjects [SMD = 0.31(95% CI, -0.42, 1.04); P = 0.41; I2 = 94%], and no strong correlation was found between the onset of sarcopenia and serum FGF21 levels.ConclusionThe diagnosis of sarcopenia is followed by a more significant decrease in muscle mass and strength, but there is a lack of strong evidence to support a direct relationship between elevated organismal FGF21 and sarcopenia, and it is not convincing to use FGF21 as a biological or diagnostic marker for sarcopenia. The currently used diagnostic criteria for sarcopenia and setting of cut-off values for each evaluation parameter no longer seem to match clinical practice.

Fluctuations of serum fibroblast growth factor-21 levels in prolonged fasting in male adults

Fibroblast Growth Factor-21 (FGF21) is a significant protein in the process of adaptation to fasting. The aim of this cross-sectional study to examine the effects of fasting on serum FGF21 levels, nutritional status, and anthropometric measurements of adult males during prolonged Ramadan fasting. This study included a total of 12 healthy individuals with normal body mass index, between the ages of 18-35. All individuals fasted for 16h each day for 29 days of Ramadan. A questionnaire was administered to determine individuals' general characteristics and nutritional habits. Anthropometric measurements, 24-h dietary recall, and physical activities were recorded, and blood samples were collected four times in the following periods: before Ramadan, 1st week of Ramadan, 3rd week of Ramadan and 4 weeks after Ramadan. It was observed that serum FGF21 levels increased until the 1st week of fasting. Remarkably, FGF21 levels declined in most subjects during the late phase of fasting and continued to decrease until 4 weeks after fasting. There was a positive correlation between serum FGF21 levels and protein intake at the 3rd week of fasting. Individuals' PAL and energy expenditure increased during fasting and continued to increase until 4 weeks after fasting. Energy intake, on the other hand, decreased from baseline until 4 weeks after fasting. FGF21 serum levels may show an increase during fasting, however in long-term fasting periods like Ramadan it may decrease back to the beginning levels, therefore, FGF21 serum levels must be evaluated carefully.

Fibroblast growth factor 21 resistance is associated with body shape in patients with type 2 diabetes complicating hypertension.

Obesity, especially abdominal obesity, increases the prevalence of metabolic and cardiovascular disease (CVD). Fibroblast growth factor 21 (FGF21) has been identified as a critical regulator playing a therapeutic role in diabetes and its complications. This study aims to evaluate the relationship between serum FGF21 levels and body shape parameters in patients with hypertension (HP) and type 2 diabetes mellitus (T2DM). Serum FGF21 levels were determined in 1,003 subjects, including 745 patients with T2DM, and 258 individuals were selected as a healthy control in this cross-sectional study. Serum FGF21 levels were significantly higher in T2DM patients with HP than those without [534.9 (322.6-722.2) vs. 220.65 (142.8-347.55) pg/ml, p < 0.001], and levels in both of these two groups were significantly increased compared with that of healthy control [123.92 (67.23-219.32) pg/ml, all p < 0.001]. These differences were also observed in body shape parameters, including weight, waistline, body mass index (BMI), body shape index (ABSI), and the percentage of abdominal obesity. Serum FGF21 levels in T2DM patients were positively correlated with body shape parameters, including weight, waistline, neck circumference, BMI, ABSI, percent of abdominal obesity, and triglyceride, while negatively with estimated glomerular filtration rate (all p < 0.01). The significance remained stable when adjusted for age and T2DM duration. In addition, both serum FGF21 concentrations and waistline were independently associated with HP in T2DM patients after the adjustment for risk factors (all p < 0.05). ROC analysis for FGF21 levels of 745 patients with T2DM identified 411.33 pg/ml as an optimal cut-off point to predict HP, with a sensitivity and specificity of 66.0% and 84.9%, respectively. FGF21 resistance occurs in patients of HP in T2DM, and positively correlates with body shape parameters (especially waistline and BMI). High levels of FGF21 may be a compensatory reaction to offset HP.

1651-P: Elevated FGF21 Levels after Total Pancreatectomy and in Response to Single-Dose Glucagon Receptor Antagonism in Humans

Fibroblast growth factor 21 (FGF21) is a liver-secreted peptide hormone reportedly improving metabolic homeostasis, partly via reduced hunger for sugar, fat, protein and alcohol. Exogenous glucagon has been shown to increase circulating FGF21 levels, but the role of endogenous glucagon for the control of FGF21 secretion remains unknown. To elucidate the relationship between endogenous glucagon and FGF21 in humans, we investigated the effect of chronic pancreatic glucagon depletion and acute glucagon receptor antagonism, respectively, on FGF21 levels. Nine totally pancreatectomized subjects (7 men, 2 women, age 61.3 ± 10.3 years, BMI 22.6 ± 4.8 kg/m2) and 9 matched control subjects (6 men, 3 women, age 65.9 ± 8.8 years, BMI 23.9 ± 2.7 kg/m2) underwent two randomized, double-blinded test days 24 hours after single-dose oral administration of either the glucagon receptor antagonist LY2409021 (300 mg) or placebo. FGF21 levels were measured both in the fasting state and in response to an oral glucose tolerance test (OGTT). The pancreatectomized patients exhibited significantly increased mean fasting FGF21 levels compared to the control subjects (493 ± 429 vs 108 ± 58 pg/mL, P=0.02). In the control subjects, administration of LY2409021 significantly increased mean fasting levels of FGF21 (216 ± 117 vs 108 ± 58 pg/mL, P=0.004) whereas fasting FGF21 levels in the pancreatectomized patients were unaffected by LY2409021. In both groups, FGF21 levels increased in response to the OGTT, with no significant treatment effect of LY2409021. Our results suggest that both chronic glucagon depletion and acute antagonism of the glucagon receptor mediate an increase in FGF21 levels in humans, pointing to direct or indirect effects of glucagon as important regulators of FGF21 secretion. Disclosure M.F.G.Grøndahl: Speaker's Bureau; Novo Nordisk A/S. T.Vilsbøll: Consultant; AstraZeneca, Boehringer Ingelheim Inc., Gilead Sciences, Inc., Eli Lilly and Company, Mundipharma, Merck &amp; Co., Inc., Novo Nordisk A/S, Sanofi, Sun Pharmaceutical Industries Ltd., Bristol-Myers Squibb Company. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. C.T.Juel: None. A.Lund: Speaker's Bureau; Novo Nordisk. S.Haedersdal: Consultant; Novo Nordisk. M.M.Andersen: None. J.S.Svenningsen: None. M.Gillum: None. B.Hartmann: Stock/Shareholder; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk A/S, Eli Lilly and Company, Board Member; Bainan Biotech, Antag Therapeutics, Consultant; Alphasights, Eli Lilly and Company, ShouTi Pharma Inc., Zealand Pharma A/S, Other Relationship; Novo Nordisk, Novo Nordisk Pharma, Mayo Clinic, Boehringer-Ingelheim, Scohia Pharma Inc., Research Support; ARLA, European Union, Novo Nordisk Foundation. Funding Aase and Ejnar Danielsen's Foundation; Novo Nordisk Foundation (LY2409021); Eli Lilly and Company