Fibroblast Growth Factor 21 Levels Research Articles

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

838-P: Reversion of Nonalcoholic Steatohepatitis by Skeletal-Muscle Directed FGF21 Gene Therapy

Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease, which is driven by the global obesity and type 2 diabetes epidemic. NASH is characterized by liver inflammation and fibrosis that can progress to cirrhosis, liver failure, cancer and death. Currently, NASH is an unmet medical need. Recent studies revealed the therapeutic potential of fibroblast growth factor 21 (FGF21) analogues/mimetics against NASH in pre-clinical models and in human patients, although periodic administrations are required and immunological responses may raise due to the use of engineered, non-native, proteins. Here, we demonstrated that adeno-associated viral (AAV) vector-mediated-FGF21 genetic engineering of skeletal muscle of high-fat diet-fed obese and insulin-resistant mice resulted in increased circulating levels of native FGF21. AAV-FGF21-treatment normalized liver fat content, liver inflammatory and fibrotic markers and counteracted hepatocyte damage, consistent with NASH resolution. It also precluded progression from NASH to cirrhosis and hepato-cellular carcinoma. Moreover, circulating FGF21 reversed adipose tissue hypertrophy and inflammation, increased energy expenditure, normalized glycemia and insulinemia, and increased insulin sensitivity. Scale-up of muscular FGF21 gene transfer to large animals also successfully resulted in long-term secretion of biologically active FGF21 and therapeutic effects in key target tissues, in the absence of adverse events. All these results point out the potential of the AAV-FGF21-mediated gene therapy to treat NASH and support the clinical translation of the approach. Disclosure V. Jimenez: None. V. Sacristán: None. C. Jambrina: None. M. Jaén: None. S.A. Munoz: None. E. Casana: None. M. Garcia: None. I. Grass: None. X. Leon: None. I. Elias: None. A. Ribera: None. G. Elias: None. V. Sanchez: None. A. Casellas: None. T. Ferré: None. M. Molas: None. F. Bosch: None.

The potential effect of metformin on fibroblast growth factor 21 in type 2 diabetes mellitus (T2DM).

Fibroblast growth factor 21 (FGF21) is a peptide hormone mainly synthesized and released from the liver. FGF21 acts on FGF21 receptors(FGFRs) and β-Klotho, which is a transmembrane co-receptor. In type 2 diabetes mellitus (T2DM), inflammatory disorders stimulate the release of FGF21 to overcome insulin resistance (IR). FGF21 improves insulin sensitivity and glucose homeostasis. Metformin which is used in the management of T2DM may increase FGF21 expression. Accordingly, the objective of this review was to clarify the metformin effect on FGF21 in T2DM. FGF21 level and expression of FGF2Rs are dysregulated in T2DM due to the development of FGF21 resistance. Metformin stimulates the hepatic expression of FGF21/FGF2Rs by different signaling pathways. Besides, metformin improves the expression of β-Klotho which improves FGF21 sensitivity. In conclusion, metformin advances FGF21 signaling and decreases FGF21 resistance in T2DM, and this might be an innovative mechanism for metformin in the enhancement of glucose homeostasis and metabolic disorders in T2DM patients.

#5528 FIBROBLAST GROWTH FACTOR 21 PREDICTS ARTERIOVENOUS FISTULA FUNCTIONAL PATENCY LOSS AND MORTALITY IN PATIENTS UNDERGOING MAINTENANCE HEMODIALYSIS

Abstract Background and Aims Arteriovenous fistula (AVF) dysfunction is a common complication in patients undergoing maintenance hemodialysis (MHD). Elevated serum level of fibroblast growth factor 21 (FGF21) was associated with atherosclerosis and cardiovascular mortality. However, its association with vascular access outcomes remains elusive. In this study, we aimed to evaluate the relationship of serum FGF21 levels with AVF dysfunction and all-cause mortality in patients undergoing MHD. Method We performed a study of patients undergoing MHD who received AVF creation at a tertiary medical center in China from January 2018 to December 2019. Serum FGF21 concentration was detected by enzyme-linked immunosorbent assay (ELISA). Patients were followed-up to record two clinical outcomes, including AVF functional patency loss and all-cause mortality. The follow-up period ended at April 30, 2022. Kaplan-Meier curves were used to analyze AVF dysfunction events and mortality. Univariate and multivariate Cox proportional risk model analyses were used to calculate risk ratios (HR) and 95% CI and independent prognostic factors. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to analyze the predictive value of FGF21 in AVF functional patency loss and all-cause mortality. Results Among 147 patients, the mean age was 58.49±14.41 years, and 58.50% of them were males. The median serum level of FGF21 was 150.15 (70.57-318.01) pg/ml. During median follow-up period of 40.83 months, the serum level of FGF21 was an independent predictor for AVF functional patency loss (per 1 pg/mL increase, HR 1.002 [95% CI: 1.001-1.003, P = 0.003]. Besides, patients with higher serum level of FGF21 was 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 an AUC of 0.701 (95% CI 0.606-0.796, P = 0.001) and 0.677 (95% CI 0.566-0.788, P = 0.006), respectively. Conclusion Serum FGF21 level was an independent risk factor and predictor for AVF functional patency loss and all-cause mortality in patients undergoing MHD.

Fibroblast growth factor 21 attenuates ventilator-induced lung injury by inhibiting the NLRP3/caspase-1/GSDMD pyroptotic pathway

BackgroundVentilator-induced lung injury (VILI) is caused by overdistension of the alveoli by the repetitive recruitment and derecruitment of alveolar units. This study aims to investigate the potential role and mechanism of fibroblast growth factor 21 (FGF21), a metabolic regulator secreted by the liver, in VILI development.MethodsSerum FGF21 concentrations were determined in patients undergoing mechanical ventilation during general anesthesia and in a mouse VILI model. Lung injury was compared between FGF21-knockout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect.ResultsSerum FGF21 levels in patients and mice with VILI were significantly higher than in those without VILI. Additionally, the increment of serum FGF21 in anesthesia patients was positively correlated with the duration of ventilation. VILI was aggravated in FGF21-KO mice compared with WT mice. Conversely, the administration of FGF21 alleviated VILI in both mouse and cell models. FGF21 reduced Caspase-1 activity, suppressed the mRNA levels of Nlrp3, Asc, Il-1β, Il-18, Hmgb1 and Nf-κb, and decreased the protein levels of NLRP3, ASC, IL-1β, IL-18, HMGB1 and the cleaved form of GSDMD.ConclusionsOur findings reveal that endogenous FGF21 signaling is triggered in response to VILI, which protects against VILI by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These results suggest that boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for the treatment of VILI during anesthesia or critical care.

FGF21 modulates hippocampal cold-shock proteins and CA2-subregion proteins in neonatal mice with hypoxia-ischemia.

Fibroblast growth factor 21 (FGF21) is a neuroprotectant with cognitive enhancing effects but with poorly characterized mechanism(s) of action, particularly in females. Prior studies suggest that FGF21 may regulate cold-shock proteins (CSPs) and CA2-marker proteins in the hippocampus but empirical evidence is lacking. We assessed in normothermic postnatal day (PND) 10 female mice, if hypoxic-ischemic (HI) brain injury (25 min 8% O2/92% N2) altered endogenous levels of FGF21 in serum or in the hippocampus, or its receptor β-klotho. We also tested if systemic administration of FGF21 (1.5 mg/kg) modulated hippocampal CSPs or CA2 proteins. Finally, we measured if FGF21 therapy altered markers of acute hippocampal injury. HI increased endogenous serum FGF21 (24 h), hippocampal tissue FGF21 (4d), and decreased hippocampal β-klotho levels (4d). Exogenous FGF21 therapy modulated hippocampal CSP levels, and dynamically altered hippocampal CA2 marker expression (24 h and 4d). Finally, FGF21 ameliorated neuronal damage markers at 24 h but did not affect GFAP (astrogliosis) or Iba1 (microgliosis) levels at 4d. FGF21 therapy modulates CSP and CA2 protein levels in the injured hippocampus. These proteins serve different biological functions, but our findings suggest that FGF21 administration modulates them in a homeostatic manner after HI. Hypoxic-ischemic (HI) injury in female post-natal day (PND) 10 mice decreases hippocampal RNA binding motif 3 (RBM3) levels in the normothermic newborn brain. HI injury in normothermic newborn female mice alters serum and hippocampal fibroblast growth factor 21 (FGF21) levels 24 h post-injury. HI injury in normothermic newborn female mice alters hippocampal levels of N-terminal EF-hand calcium binding protein 2 (NECAB2) in a time-dependent manner. Exogenous FGF21 therapy ameliorates the HI-mediated loss of hippocampal cold-induced RNA-binding protein (CIRBP). Exogenous FGF21 therapy modulates hippocampal levels of CA2-marker proteins after HI.

Increased serum fibroblast growth factor 21 levels are associated with adverse clinical outcomes after intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the most prevalent cause of death. We sought to explore whether serum Fibroblast growth factor 21 (FGF21) is of substantial benefit in predicting poor prognosis in ICH patient. A prospective, multicenter cohort analysis of serum FGF21 levels in 418 ICH patients was carried out. At three months following ICH start, the primary endpoint was death or major disability, whereas the secondary endpoint was death. We investigated the association between serum FGF21 and clinical outcomes. We added FGF21 to the existing rating scale to assess whether it enhanced the prediction ability of the original model. Effectiveness was determined by calculating the C-statistic, net reclassification index (NRI), absolute integrated discrimination improvement (IDI) index. Among 418 enrolled patients, 217 (51.9%) of the all subjects had death or significant disability. Compared with patients in the lowest quartile group, those in the first quartile group had higher risk of the primary outcome (Odds ratio, 2.73 [95%CI,1.42-5.26, p < 0.05]) and second outcome (Hazard ratio, 4.28 [95%CI,1.61-11.42, p < 0.001]). The integration of FGF21 into many current ICH scales improved the discrimination and calibration quality for the integrated discrimination index's prediction of main and secondary findings (all p < 0.05). Elevated serum FGF21 is associated with increased risks of adverse clinical outcomes at 3 months in ICH patients, suggesting FGF21 may be a valuable prognostic factor.

Exploring the role of FXR signaling in maintaining ileal mucosa integrity in subjects with altered glucose tolerance conditions

Aim: Treatment with the FXR agonist obeticholic acid (OCA) has been found to improve glucose metabolism in type 2 diabetes (T2DM) subjects with mechanisms not completely elucidated. In the gut, FXR is mainly expressed in the ileum where promotes transcription of fibroblast growth factor-19 (FGF19) having positive effects on glucose homeostasis, and maintains gut barrier integrity by regulating tight-junction (TJ) proteins expression. Herein, we evaluate whether subjects with dysglycemic conditions exhibit a down-regulation of the intestinal FXR-FGF19-TJ axis and whether treatment with OCA may revert this aberration. Methods: Levels of FXR, FGF19 and TJ proteins and pro-inflammatory cytokines were assessed in ileal mucosa specimens collected during colonoscopy from 53 subjects subdivided according to their glucose tolerance in: NGT (n=26), prediabetes (n=12) and T2DM (n=15). Effects of OCA treatment was assessed on ileal mucosa specimens of subjects with prediabetes or T2DM cultured in absence or presence of OCA for 6h. Results: Ileal FXR protein and mRNA levels were progressively decreased in prediabetes (-26%) and T2DM (-34%) as compared to the NGT group (both P&lt;0.05). Ileal FXR downregulation was paralleled by lower FGF19 expression and circulating levels (both P&lt;0.05). Additionally, we observed a progressive decrease of proteins and mRNA levels of the TJ zonulin (ZO)-1, occludin and claudin-1 (P&lt;0.05 for all) with an activation of pro-inflammatory pathways in the ileal mucosa of subjects with prediabetes and T2DM as compared to the NGT group. OCA treatment resulted in an up-regulation of FGF19 expression and release (both P&lt;0.01), mRNA and protein levels of the TJ ZO-1, occludin and claudin-1 and in reduced pro-inflammatory cytokines synthesis and release (P&lt;0.05 for all). Conclusion: FXR stimulation by OCA treatment reverts the altered FGF-19/TJ axis in subjects with prediabetes and T2DM, indicating intestinal FXR signaling as a novel target for prevention and/or treatment of T2DM.

Effects of quercetin on hepatic fibroblast growth factor-21 (FGF-21) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) levels in rats fed with high fructose

Available studies show that quercetin reduces Metabolic Syndrome (MetS) and its complications, increases insulin sensitivity and improves glucose levels. It has been reported that the increase in hepatic gene expressions of fibroblast growth factor-21 (FGF-21), an important metabolic regulator of insulin sensitivity, glucose and energy homeostasis, and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which plays a central role in the regulation of cellular energy metabolism, eliminate the negative effects of fructose in fructose-fed rats. The main purpose of our study is to examine the effects of quercetin on hepatic FGF-21 and PGC-1α expressions and levels, as well as its protective and therapeutic role on MetS components in rats fed with fructose. In our study, 24 Sprague Dawley male rats were divided into 4 groups: control, fructose, quercetin, fructose+quercetin (n = 6). During the 10-week experiment, quercetin was administered at a daily dose of 15mg/kg body weight and fructose at a rate of 20%. Blood pressure and weights of all groups were measured and recorded. At the end of week 10, blood and liver tissue samples were taken. Serum insulin, glucose and triglyceride, total, HDL and VLDL cholesterol levels were determined from the samples. Insulin resistance was calculated using the HOMA-IR formula. Hepatic PGC-1α and FGF-21 protein levels and their mRNA expressions were determined. Criteria for metabolic syndrome were successfully established with fructose. It was observed that the administration of quercetin alone and in combination with fructose exerted positive effects and improved MetS criteria. It was determined that the administration of quercetin increased hepatic FGF-21 and PGC-1α protein levels and Messenger RNA (mRNA) expressions of them, which were decreased by fructose application. The results of our study showed that 10-week administration of quercetin at 15mg/kg exerted beneficial effects on lipid and carbohydrate metabolism in the fructose-mediated MetS model; therefore, quercetin may have great potential in the prevention and treatment of metabolic disorders.

Exercise-Induced Fibroblast Growth Factor-21: A Systematic Review and Meta-Analysis.

This systematic review aimed to synthesize and quantify the results of the studies investigating the changes in fibroblast growth factor-21 (FGF-21) induced by exercise. We searched for studies that did not differentiate between patients and healthy adults but compared them before and after exercise and with and without exercise. For quality assessment, the risk-of-bias assessment tool for nonrandomized studies and the Cochrane risk-of-bias tool were used. A quantitative analysis was performed using the standardized mean difference (SMD) and random-effects model in RevMan 5.4. A total of 94 studies were searched in international electronic databases, and after screening, 10 studies with 376 participants were analyzed. Compared with no exercise, there was a significant increase in the FGF-21 levels from before to after exercise (SMD = 1.05, 95% confidence interval (CI), 0.21 to 1.89). The changes in FGF-21 levels in the exercise group showed a significant difference from the levels in the controls. The results of the random-effects model were as follows: SMD = 1.12; 95% CI, -0.13 to 2.37. While the data on acute exercise were not synthesized in this study, FGF-21 levels generally increased after chronic exercise compared with no exercise.

High circulating fibroblast growth factor-21 levels as a screening marker in fatty pancreas patients.

The study aimed to detect the serum levels of fibroblast growth factor-21 (FGF-21) in fatty pancreas (FP) patients and to investigate their potential clinical value. We screened patients with FP using transabdominal ultrasound. The anthropometric, biochemical and serum levels of FGF-21 were compared between the FP group and the normal control (NC) group. A receiver operating characteristic (ROC) curve was used to evaluate the predictive value of serum FGF-21 for FP patients. Compared with the NC group, body mass index, fasting blood glucose levels, uric acid levels and cholesterol levels of the FP group were significantly higher, while the high-density lipoprotein level was lower. In addition, levels of serum FGF-21, resistin, leptin and tumor necrosis factor-α were significantly higher than those in the NC group, while the serum adiponectin level was lower. Pearson analysis showed serum FGF-21 levels in FP patients were negatively correlated with leptin. The ROC curve showed the best critical value of the serum FGF-21 level in FP patients was 171 pg/mL (AUC 0.744, P=0.002, 95% confidence intervals 0.636-0.852). Serum FGF-21 was closely related to fatty pancreas. Detecting serum FGF-21 levels may help identify the population susceptible to FP.

Modulation of GCN2/eIF2α/ATF4 Pathway in the Liver and Induction of FGF21 in Young Goats Fed a Protein- and/or Phosphorus-Reduced Diet.

Mammals respond to amino acid (AA) deficiency by initiating an AA response pathway (AAR) that involves the activation of general control nonderepressible 2 (GCN2), phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), and activation of transcription factor 4 (ATF4). In this study, the effects of protein (N) and/or phosphorus (P) restriction on the GCN2/eIF2α/ATF4 pathway in the liver and the induction of fibroblast growth factor 21 (FGF21) in young goats were investigated. An N-reduced diet resulted in a decrease in circulating essential AA (EAA) and an increase in non-essential AA (NEAA), as well as an increase in hepatic mRNA expression of GCN2 and ATF4 and protein expression of GCN2. Dietary N restriction robustly increased both hepatic FGF21 mRNA expression and circulating FGF21 levels. Accordingly, numerous significant correlations demonstrated the effects of the AA profile on the AAR pathway and confirmed an association. Furthermore, activation of the AAR pathway depended on the sufficient availability of P. When dietary P was restricted, the GCN2/eIF2α/ATF4 pathway was not initiated, and no increase in FGF21 was observed. These results illustrate how the AAR pathway responds to N- and/or P-reduced diets in ruminants, thus demonstrating the complexity of dietary component changes.

Fibroblast growth factor-21 is required for weight loss induced by the glucagon-like peptide-1 receptor agonist liraglutide in male mice fed high carbohydrate diets

ObjectiveGlucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RA) and fibroblast growth factor-21 (FGF21) confer similar metabolic benefits. GLP-1RA induce FGF21, leading us to investigate mechanisms engaged by the GLP-1RA liraglutide to increase FGF21 levels and the metabolic relevance of liraglutide-induced FGF21. MethodsCirculating FGF21 levels were measured in fasted male C57BL/6J, neuronal GLP-1R knockout, β-cell GLP-1R knockout, and liver peroxisome proliferator-activated receptor alpha knockout mice treated acutely with liraglutide. To test the metabolic relevance of liver FGF21 in response to liraglutide, chow-fed control and liver Fgf21 knockout (LivFgf21−/−) mice were treated with vehicle or liraglutide in metabolic chambers. Body weight and composition, food intake, and energy expenditure were measured. Since FGF21 reduces carbohydrate intake, we measured body weight in mice fed matched diets with low- (LC) or high-carbohydrate (HC) content and in mice fed a high-fat, high-sugar (HFHS) diet. This was done in control and LivFgf21−/− mice and in mice lacking neuronal β-klotho (Klb) expression to disrupt brain FGF21 signaling. ResultsLiraglutide increases FGF21 levels independently of decreased food intake via neuronal GLP-1R activation. Lack of liver Fgf21 expression confers resistance to liraglutide-induced weight loss due to attenuated reduction of food intake in chow-fed mice. Liraglutide-induced weight loss was impaired in LivFgf21−/− mice when fed HC and HFHS diets but not when fed a LC diet. Loss of neuronal Klb also attenuated liraglutide-induced weight loss in mice fed HC or HFHS diets. ConclusionsOur findings support a novel role for a GLP-1R-FGF21 axis in regulating body weight in a dietary carbohydrate-dependent manner.

Abstract 365: Targeting FGF21 inhibits tumor growth and attenuates cachexia in experimental colorectal cancer

Abstract Background: Colorectal cancer (CRC) is frequently accompanied by cachexia, an uncured multi-organ wasting syndrome, debilitating musculoskeletal health, physical function, and overall survival. Fibroblast growth factor 21 (FGF21) is a modulator of musculoskeletal health and metabolism and has been associated with CRC risk and progression. Here, we investigated the effects of tumor derived FGF21 on musculoskeletal health in CRC. Methods: Plasma from CRC patients and preclinical models of CRC (C26, MC38) were assessed for circulating FGF21 levels, and CRC cell lines (C26, MC38, HCT116) were screened for FGF21 expression. Using CRISPR/Cas9 technology, FGF21 was deleted from MC38 cells (KO-MC38). 8-week-old male C57BL/6J mice were subcutaneously injected (1.0x106) with wild-type (WT-MC38) or FGF21-/- (KO-MC38) MC38 tumor cells, while experimental control animals received saline (n = 10-13/group). Animals underwent electrophysiological testing to obtain motor unit number estimation (MUNE) 48 hours prior to euthanasia and were assessed for maximum plantarflexion torque 24 hours prior to euthanasia. At the time of euthanasia, plasma was collected for assessment of systemic FGF21, while tumors and skeletal muscles (gastrocnemius, quadriceps, and tibialis anterior) were excised and weighed. Femur bones were processed for microcomputed tomography (µCT) imaging and analysis. Results: CRC patients and MC38 tumor hosts demonstrated elevated circulating plasma FGF21 (p&amp;lt;0.05) compared to controls. Gene expression of CRC cells revealed an 11-fold increase of FGF21 in MC38 compared to C26 and HCT116 cells. WT-MC38 tumor hosts had elevated plasma FGF21 (4-fold; p&amp;lt;0.05) compared to control, which was unchanged in KO-MC38 hosts. In line with the development of cachexia, WT-MC38 hosts displayed reductions in muscle mass (gastrocnemius: -5%; p&amp;lt;0.05, quadriceps: -10%; p&amp;lt;0.01, tibialis anterior: -8%; p&amp;lt;0.01), MUNE (-31%; p&amp;lt;0.01), and plantarflexion torque (-10%; p&amp;lt;0.05). Meanwhile, µCT of femur bones demonstrated reductions in trabecular bone volume fraction (BV/TV: -30%; p&amp;lt;0.05) and cortical cross-sectional thickness (Cs.Th: -14%; p&amp;lt;0.05) in WT-MC38 hosts compared to experimental controls. Conversely, when compared to WT-MC38, KO-MC38 hosts had preserved skeletal muscle mass (gastrocnemius: +7%; p&amp;lt;0.01, quadriceps: +13%; p&amp;lt;0.001, tibialis anterior: +8%; p&amp;lt;0.001), MUNE (+47%; p&amp;lt;0.01), plantarflexion torque (+8%; p&amp;lt;0.05), and bone mass (BV/TV: +69%; p&amp;lt;0.001, Cs.Th: +23%; p&amp;lt;0.001). Strikingly, the mass of KO-MC38 tumors was reduced 75% (p&amp;lt;0.01) compared to WT-MC38 tumors. Conclusion: Our data suggest that targeting CRC-derived FGF21 halts tumor growth, resulting in preservation of musculoskeletal health and function. Thus, counteracting tumor-derived FGF21 may serve as a therapeutic intervention against the progression of cancer and cancer-associated cachexia. Citation Format: Fabrizio Pin, Anika Shimonty, Joshua Robert Huot. Targeting FGF21 inhibits tumor growth and attenuates cachexia in experimental colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 365.

Fibroblast growth factor 21 may be a strong biomarker for renal outcomes: a meta-analysis

Background Fibroblast growth factor 21 (FGF21) is deemed to play an important role in kidney outcomes, while the association between FGF21 and various kidney diseases remains largely unclear and inconsistent. Therefore, we conducted this meta-analysis to find out the role of FGF21 in various renal diseases. Methods The outcome indicator of our study was assessed by the pooled standard mean difference (SMD) with 95% confidence intervals (CIs) which were calculated by random-effect model analysis. The risk of bias was assessed by Non-Randomized Studies of Interventions (ROBINS-I) tool. Funnel plot combined with Egger’s and Begg’s tests was performed to estimate the publication bias that existed in the study. Results A total of 28 eligible studies with 19348 participants were included in our research. The agreement between authors reached a kappa-value of 0.88. Overall, the serum FGF21 level was strongly higher in CKD patients (SMD = 0.97 (ng/L); 95% CI, 0.70—1.24 (ng/L)) and the renal outcomes in T2DM patients (SMD = 0.54 (ng/L); 95% CI, 0.39–0.70 (ng/L)) compared with the control group. Consistent with this, the incidence of CKD (OR = 2.56; 95% CI, 1.72–3.81) and the incidence of renal outcomes (OR = 1.63; 95% CI, 1.31–2.01) in T2DM patients was significantly higher in the patients with high FGF21 concentration, indicating that high serum FGF21 level may predict the incidence of CKD and the renal outcomes in T2DM patients. Conclusion Serum FGF21 may be one of the strong predictors for various kidney diseases including the progression of CKD and the hard renal outcomes in type 2 diabetes patients, but more large-scale clinical research are needed to confirm this finding.

Serum Fibroblast Growth Factor-21 Discriminates Between Decompensated Alcohol-Associated Cirrhosis and Severe Alcohol-Associated Hepatitis.

We hypothesized that fibroblast growth factor-21 (FGF-21) would be highly expressed in patients with alcohol-associated hepatitis (AH) and could be a novel and biologically relevant predictive biomarker to reliably distinguish severe AH and decompensated alcohol-associated cirrhosis (AC). We identified a discovery cohort of 88 subjects with alcohol-associated liver disease (ALD) of varying disease severity from our ALD repository. Our validation cohort consisted of 37 patients with a biopsy-proven diagnosis of AH, AC, or absence of ALD with Model for End-Stage Liver Disease scores ≥10. Serum from both groups during index hospitalization was assayed for FGF-21 by ELISA. We performed receiver operating characteristic analysis and prediction modeling in both cohorts to discriminate between AH and AC in high Model for End-Stage Liver Disease (≥20) patients. In both cohorts, FGF-21 concentrations were highest in subjects with moderate to severe AH compared with those having alcohol use disorder or AC (mean: 2,609 pg/mL, P < 0.0001). The discovery cohort area under the curve of FGF-21 between AH and AC was 0.81 (95% confidence interval: 0.65-0.98, P < 0.01). In the validation cohort, FGF-21 levels were higher in severe AH compared with AC (3,052 vs 1,235 pg/mL, P = 0.03), and the area under the curve was 0.76 (95% confidence interval: 0.56-0.96, P < 0.03). A survival analysis showed that patients with FGF-21 serum levels in the second interquartile had the highest survival compared with all other quartiles. FGF-21 performs well as a predictive biomarker to distinguish severe AH from AC and may be helpful in the management and clinical investigation of patients with severe alcohol-associated liver diseases.

FGF21 via mitochondrial lipid oxidation promotes physiological vascularization in a mouse model of Phase I ROP

Hyperglycemia in early postnatal life of preterm infants with incompletely vascularized retinas is associated with increased risk of potentially blinding neovascular retinopathy of prematurity (ROP). Neovascular ROP (Phase II ROP) is a compensatory but ultimately pathological response to the suppression of physiological postnatal retinal vascular development (Phase I ROP). Hyperglycemia in neonatal mice which suppresses physiological retinal vascular growth is associated with decreased expression of systemic and retinal fibroblast growth factor 21 (FGF21). FGF21 administration promoted and FGF21 deficiency suppressed the physiological retinal vessel growth. FGF21 increased serum adiponectin (APN) levels and loss of APN abolished FGF21 promotion of physiological retinal vascular development. Blocking mitochondrial fatty acid oxidation also abolished FGF21 protection against delayed physiological retinal vessel growth. Clinically, preterm infants developing severe neovascular ROP (versus non-severe ROP) had a lower total lipid intake with more parenteral and less enteral during the first 4 weeks of life. Our data suggest that increasing FGF21 levels in the presence of adequate enteral lipids may help prevent Phase I retinopathy (and therefore prevent neovascular disease).

FGF-21 and GDF-15 are increased in migraine and associated with the severity of migraine-related disability

BackgroundMigraine is a prevalent disorder with significant socioeconomic impact. The impairment of metabolic homeostasis in migraine warrants further investigation. Changes in serum levels of Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15) are characteristic of some metabolic and mitochondrial diseases. This study aimed to assess whether the presence of migraine affects serum levels of FGF-21 and GDF-15, and taking metabolic disorders into account as potential confounding factors.MethodsWe collected serum samples from 221 migraine patients (153 episodic migraineurs and 68 chronic migraineurs) and 124 healthy controls. The serum concentrations of FGF-21 and GDF-15 were measured using an enzyme-linked immunosorbent assay (ELISA) based approach. Clinical variables, including monthly headache days, peak headache pain intensity, the 6-item Headache Impact Test (HIT-6), and the Migraine Disability Assessment (MIDAS), were also addressed. The associations between the clinical variables of migraine patients and serum levels of FGF-21 and GDF-15 were studied.ResultsIn the multiple regression that corrected for age, we found that the serum levels of FGF-21 and GDF-15 were significantly higher in migraine sufferers than in healthy controls. A significant elevation in serum concentration of FGF-21, but not GDF-15, was observed in patients with chronic migraine (CM) compared to those with episodic migraine (EM). Regarding migraine-related disability, higher scores on the HIT-6 and MIDAS were associated with higher levels of FGF-21 and GDF-15. For the receiver operating characteristic (ROC) analysis, the diagnosis of migraine using GDF-15 showed that the area under the ROC curve (AUC) was 0.801 and the AUC of chronic migraine was 0.880.ConclusionSerum GDF-15 and FGF-21 levels are increased in patients with migraine and associated with the severity of migraine-related disability.

The Interrelation Between Hypothyroidism and Non-alcoholic Fatty Liver Disease, a Cross-sectional Study

Thyroid hormones play an important role in the regulation of diverse metabolic processes and might play a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, their association remains controversial. Therefore, our aim is to clarify whether overt or subclinical hypothyroidism was associated with NAFLD. This cross-sectional study included 60 participants with a new diagnosis of hypothyroidism and 30 age- and gender-matched healthy participants with thyroid-stimulating hormone (TSH) level <4.5mIU/L. Anthropometric measurements, laboratory parameters, plasma fibroblast growth factor 21 (FGF21), and hepatic steatosis diagnosed via controlled attenuation parameter (CAP) using transient elastography between the hypothyroid groups and control group were analyzed. Participants with hypothyroidism displayed significantly higher serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, total cholestrol, triglycerides, low-density lipoprotein cholesterol, TSH, hemoglobin A1c, fasting insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) but significantly lower serum albumin, high-density lipoprotein cholesterol, and free thyroxine levels than the control group (P=<0.001). The CAP values were significantly higher in participants with overt and subclinical hypothyroidism than the control group (P=<0.001). The only significant independent predictors of steatosis in our study were free T4, body mass index, and HOMA-IR after using multivariate logistic regression. The mean serum FGF21 levels were increased in hypothyroid participants with hepatic steatosis than those without hepatic steatosis (126.9±272.6) pg/ml vs. (106.8±138.7) pg/ml, P=0.8). Receiver operating characteristic (ROC) curve showed that FGF21 was not a significant marker for hepatic steatosis in hypothyroid participants (area under curve (AUC)=0.44, P=0.54). Individuals with subclinical or overt hypothyroidism were more likely to have NAFLD than those with normal thyroid function. Serum FGF21 levels were increased in hypothyroid individuals and its role as a marker of hepatic steatosis in hypothyroid individuals needs further assessment.