FGF21 Concentrations Research Articles

Systemic and transcriptional response to intermittent fasting and fasting-mimicking diet in mice

BackgroundDietary restriction (DR) has multiple beneficial effects on health and longevity and can also improve the efficacy of certain therapies. Diets used to instigate DR are diverse and the corresponding response is not uniformly measured. We compared the systemic and liver-specific transcriptional response to intermittent fasting (IF) and commercially available fasting-mimicking diet (FMD) after short- and long-term use in C57BL/6 J mice.ResultsWe show that neither DR regimen causes observable adverse effects in mice. The weight loss was limited to 20% and was quickly compensated during refeeding days. The slightly higher weight loss upon FMD versus IF correlated with stronger fasting response assessed by lower glucose levels and higher ketone body, free fatty acids and especially FGF21 concentrations in blood. RNA sequencing demonstrated similar transcriptional programs in the liver after both regimens, with PPARα signalling as top enriched pathway, while on individual gene level FMD more potently increased gluconeogenesis-related, and PPARα and p53 target gene expression compared to IF. Repeated IF induced similar transcriptional responses as acute IF. However, repeated cycles of FMD resulted in blunted expression of genes involved in ketogenesis and fatty acid oxidation.ConclusionsShort-term FMD causes more pronounced changes in blood parameters and slightly higher weight loss than IF, while both activate similar pathways (particularly PPARα signalling) in the liver. On individual gene level FMD induces a stronger transcriptional response, whereas cyclic application blunts transcriptional upregulation of fatty acid oxidation and ketogenesis only in FMD. Hence, our comparative characterization of IF and FMD protocols renders both as effective DR regimens and serves as resource in the fasting research field.

Effect of Fibroblast Growth Factor (FGF) 19 and 21 on Hip Geometry and Strength in Post-menopausal Osteoporosis (PMO)

Fibroblast Growth Factor (FGF) receptor signalling is important for skeletal development. The FGF19 subfamily which includes FGF19 and FGF21 are involved in bone metabolism, although their effects on bone mineral density (BMD) and bone strength remain unclear. To further characterise the influence of these two factors on the skeleton, we studied the association between circulating concentrations of FGF19 and 21 with BMD and parameters of hip geometry and strength in post-menopausal osteoporosis (PMO). The study cohort consisted of 374 women aged (mean [SD]) 68.7[12.3] years with PMO. FGF19 and FGF21 were measured in serum by ELISA. BMD was measured at the lumbar spine (LS), total hip (TH) and femoral neck (FN) (n = 277) by dual energy X-ray absorptiometry (DXA) and hip structural analysis (HSA) parameters (n = 263) at the narrow neck of the femur (NN), Intertrochanter (IT) and Femoral shaft (FS) were derived from DXA scans. FGF19 and 21 were not associated with prevalent fractures or BMD when corrected for covariates; age, BMI, smoking habits and alcohol intake. Log-transformed FGF 21 was negatively associated with HSA parameters including Outer Diameter (OD) (p = 0.019), Cross-sectional area (CSA) (p = 0.01), cross-sectional moment of inertia (CSMI) (p = 0.011), Section modulus (Z) (p = 0.002) and cortical thickness (Co Th) (p = 0.026) at the IT only. CSA, CSMI, Z and Co Th were significantly lower (p < 0.05) in women with FGF21 concentrations greater than the median (> 103.5 pg/ml). Our data suggest that FGF 21 may have potentially adverse effects on the skeleton. Further characterisation is needed, particularly as FGF 21 analogues or agonists may be used to treat obesity-related metabolic disorders.

Predictive Value of Serum microRNA-29b-3p in Recurrence of Atrial Fibrillation After Radiofrequency Catheter Ablation.

Atrial fibrillation (AF) is a common arrhythmia. This study explored serum miR-29b-3p expression in AF patients and its value in predicting AF recurrence after radiofrequency catheter ablation (RFCA). Totally 100 AF patients who underwent RFCA were enrolled, with 100 individuals without AF as controls. Serum miR-29b-3p expression in participants was determined using RT-qPCR. The correlation between miR-29b-3p and atrial fibrosis markers (FGF-21/FGF-23) was assessed by Pearson analysis. The diagnostic efficacy of serum miR-29b-3p and FGF-21/FGF-23 in predicting AF recurrence after RFCA was analyzed by the receiver operating characteristic (ROC) curves. The Kaplan-Meier method was adopted to evaluate the effect of miR-29b-3p expression on the incidence of AF recurrence after RFCA. The independent risk factors for AF recurrence after RFCA were analyzed by logistic regression analysis. Serum miR-29b-3p was poorly expressed in AF patients. After RFCA, AF patients showed elevated serum miR-29b-3p expression. Serum miR-29b-3p expression in AF patients negatively correlated with serum FGF-21 and FGF-23 concentrations. The cut-off values of serum miR-29b-3p, FGF-21, and FGF-23 in identifying AF recurrence were 0.860 (sensitivity: 100.00%, specificity: 39.71%), 222.2 pg/mL (sensitivity: 96.88%, specificity: 32.35%) and 216.3 ng/mL (sensitivity: 53.13%, specificity: 70.59%), respectively. Patients with low miR-29b-3p expression had a significantly higher incidence of AF recurrence than patients with high miR-29b-3p expression. Serum miR-29b-3p expression was one of the independent risk factors for AF recurrence after RFCA. Low miR-29b-3p expression in AF patients has certain predictive values and is one of the independent risk factors for AF recurrence after RFCA.

New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study

Background and aims: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol.Methods: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot.Results: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in sham-operated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet.Conclusions: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.

Association of circulating inflammatory proteins with type 2 diabetes mellitus and its complications: a bidirectional Mendelian randomization study.

Increasing evidence indicates that immune response underlies the pathology of type 2 diabetes (T2D). Nevertheless, the specific inflammatory regulators involved in this pathogenesis remain unclear. We systematically explored circulating inflammatory proteins that are causally associated with T2D via a bidirectional Mendelian randomization (MR) study and further investigated them in prevalent complications of T2D. Genetic instruments for 91 circulating inflammatory proteins were derived from a genome-wide association study (GWAS) that enrolled 14,824 predominantly European participants. Regarding the summary-level GWASs of type 2 diabetes, we adopted the largest meta-analysis of European population (74,124 cases vs. 824,006 controls) and a prospective nested case-cohort study in Europe (9,978 cases vs. 12,348 controls). Summary statistics for five complications of T2D were acquired from the FinnGen R9 repository. The inverse variance-weighted method was applied as the primary method for causal inference. MR-Egger, weighted median and maximum likelihood methods were employed as supplementary analyses. Results from the two T2D studies were combined in a meta-analysis. Sensitivity analyses and phenotype-wide association studies (PheWAS) were performed to detect heterogeneity and potential horizontal pleiotropy in the study. Genetic evidence indicated that elevated levels of TGF-α (OR = 1.16, 95% CI = 1.15-1.17) and CX3CL1 (OR = 1.30, 95% CI = 1.04-1.63) promoted the occurrence of T2D, and increased concentrations of FGF-21 (OR = 0.87, 95% CI = 0.81-0.93) and hGDNF (OR = 0.96, 95% CI = 0.95-0.98) mitigated the risk of developing T2D, while type 2 diabetes did not exert a significant influence on said proteins. Elevated levels of TGF-α were associated with an increased risk of ketoacidosis, neurological complications, and ocular complications in patients with T2D, and increased concentrations of FGF-21 were potentially correlated with a diminished risk of T2D with neurological complications. Higher levels of hGDNF were associated with an increased risk of T2D with peripheral vascular complications, while CX3CL1 did not demonstrate a significant association with T2D complications. Sensitivity analyses and PheWAS further ensure the robustness of our findings. This study determined four circulating inflammatory proteins that affected the occurrence of T2D, providing opportunities for the early prevention and innovative therapy of type 2 diabetes and its complications.

Docosahexaenoic and Eicosapentaenoic Acids Promote the Accumulation of Browning-Related Myokines via Calcium Signaling in Insulin-Resistant Mice

BackgroundMyokines have a prominent effect on improving insulin resistance (IR) by inducing browning of white adipose tissue (WAT). Although docosahexaenoic acids (DHA) and eicosapentaenoic acids (EPA) play roles in improving IR and stimulating browning, whether they mediate myokines directly remains unknown. ObjectiveThis study aims to investigate the effects of DHA and EPA on browning-related myokines under IR and clarify the mechanism via Ca2+ signaling. MethodsThe expression and secretion levels of myokines in IR mice and IR myotubes were detected after DHA/EPA treatment. The crosstalk between myotubes and adipocytes was evaluated through a method in which IR adipocytes were treated with the culture medium supernatant of myotubes treated with DHA/EPA. The expression of browning markers in the WAT of IR mice and adipocytes was determined. A calcium chelator was used to determine whether DHA and EPA regulate myokine production through a calcium ion-dependent pathway. ResultsIn vivo experiments: 3:1 and 1:3 DHA/EPA promoted the mRNA levels of Irisin, IL-6, IL-15, and FGF21 in skeletal muscle, stimulated WAT browning, reduced lipid accumulation; 3:1 DHA/EPA upregulated the serum concentration of Irisin; 1:3 DHA/EPA upregulated the serum concentrations of Irisin, IL-6, and FGF21. In vitro experiments: the levels of Irisin and IL-6 in C2C12 myotubes and their medium supernatant were significantly elevated in the 3:1 and 1:3 groups and the upregulation of browning markers and reduction in fat accumulation were observed in adipocytes treated with the medium supernatant of C2C12 myotubes in the 3:1 and 1:3 groups. However, the above phenomena disappeared when Ca2+ signaling was inhibited. ConclusionsTreatment with DHA and EPA at composition ratios of 3:1 and 1:3 induces browning of WAT in IR mice, which is likely related to the promotion of the accumulation of myokines, especially Irisin and IL-6, via Ca2+ signaling.

Predictive value of serum fibroblast growth factor 19 and liver stiffness for intestinal failure associated liver disease-cholestasis

BackgroundIntestinal failure associated liver disease (IFALD)-cholestasis is a common complication of long-term parenteral nutrition (PN) in patients with intestinal failure (IF). The lack of effective early identification indicators often results in poor clinical outcomes. The objective of this study was to evaluate the predictive value of serum FGF19 and liver stiffness in IFALD-cholestasis. MethodsEligible adults diagnosed with IF were identified from Jinling Hospital in China. Diagnostic criteria for IFALD-cholestasis: total bilirubin >1 mg/dL and conjugated bilirubin >0.3 mg/dL for ≥6 months. Fasting blood specimens were prospectively collected and serum FGF19 concentrations were determined using ELISA and liver stiffness was measured by Two-dimensional shear wave elastography. Binary logistic regression analysis identified predictors of IFALD-cholestasis. Receiver operating characteristic (ROC) curves and areas under the ROC curves (AUROC) were used to evaluate the accuracy of serum FGF19 and liver stiffness in identifying IFALD-cholestasis. ResultsOf 203 study patients with IF, 70 (34.5%) were diagnosed with IFALD-cholestasis. The serum FGF19 levels in those with IFALD-cholestasis were significantly decreased compared with those in patients without, and liver stiffness was significantly increased (p<0.001). Multivariate logistic regression analyses suggested that intestinal discontinuity, dependence on PN, liver stiffness >6.5 kPa, and serum FGF19 ≤107 pg/mL were independent risk factors for IFALD-cholestasis. The AUROC for serum FGF19 and liver stiffness, which indicate the occurrence of IFALD-cholestasis, were 0.810 and 0.714, respectively. Serum FGF19 had a superior predictive performance than liver stiffness (p<0.05). ConclusionBoth low circulating serum FGF19 concentration and increased liver stiffness are excellent predictors of IFALD-cholestasis, but serum FGF19 is superior to increased liver stiffness in predicting IFALD-cholestasis.

Differential effects of heart failure with reduced ejection fraction on locomotor and respiratory muscles

Abstract Background Muscle weakness impairs quality-of-life, exercise capacity, and survival in patients with heart failure and reduced left ventricular ejection fraction (HFrEF). However, the effects on systemic concentrations and local expression of inflammatory cytokines and myokines as well as metabolic markers might differ between locomotor and respiratory muscles. Purpose We prospectively evaluated clinical, functional, and molecular alterations of the diaphragm and the M. vastus lateralis (MVL) from HFrEF patients receiving a left ventricular assist device compared to patients without heart failure undergoing elective coronary bypass grafting (control). Methods Participants (Controls=21, HFrEF=18) underwent cardiopulmonary exercise and respiratory and leg muscle testing. Serum concentrations and local expression of inflammatory cytokines and myokines as well as key enzymes of metabolic pathways were examined in biopsies of the diaphragm and MVL. Results Exercise capacity, respiratory muscle function and endurance force of locomotor muscles were significantly reduced in HFrEF compared with controls (all p&amp;lt;0.05). The serum concentration of Il-6, Il-1beta and TNF-alpha were significantly higher or solely detectable in HFrEF compared with controls. Local mRNA expression of Il-6 was not different in MVL but 2.2-fold higher in the diaphragm of HFrEF compared with controls (p=0.013). In contrast, mRNA expression of Il-6 receptor was significantly reduced by 38% (p=0.004) in MVL of HFrEF compared with controls but comparable in the diaphragm. Serum concentrations of FGF-21 and Musclin were significantly higher in HFrEF compared with controls (all p&amp;lt;0.05). Local mRNA expression of FGF-21 was significantly lower in both MVL and diaphragm of HFrEF compared with controls. FGF-21 receptor 1 mRNA expression was reduced by 18% in the MVL of HFrEF (p=0.02), whereas co-receptor klotho was comparable to controls. In the diaphragm, FGF-21 receptor 1 mRNA expression was comparable between HFrEF and controls, but the co-receptor klotho had a 5-fold higher mRNA expression in HFrEF (p=0.002). We examined the activity of key enzymes of glucose, lipid and ketone metabolism as well as key enzymes of the Krebs cycle. The main differences were found for ß-hydroxyacyl-CoA Dehydrogenase in the diaphragm with a 1.6-fold higher activity in HFrEF compared with controls (p=0.01) and for succinyl-CoA: 3-ketoacid-coenzyme A transferase in the MVL with a 2-fold higher activity in HFrEF compared with controls (p&amp;lt;0.01) indicating a main utilization of lipids in the diaphragm and of ketones in the MVL for energy supply. Conclusions HFrEF induced divergent effects on inflammatory markers, myokine expression and metabolic parameters in locomotor and respiratory muscles in HFrEF patients compared with controls. This indicates that different molecular alterations contribute to locomotor/respiratory muscle dysfunction and reduced whole-body exercise capacity.

Epigenetic regulation of GABA catabolism in iPSC-derived neurons: The molecular links between FGF21 and histone methylation

ObjectiveFibroblast growth factor 21 (FGF21) analogs have been tested as potential therapeutics for substance use disorders. Prior research suggests that FGF21 administration might affect alcohol consumption and reward behaviors. Our recent report showed that plasma FGF21 levels were positively correlated with alcohol use in patients with alcohol use disorder (AUD). FGF21 has a short half-life (0.5–2 h) and crosses the blood–brain barrier. Therefore, we set out to identify molecular mechanisms for both the naïve form of FGF21 and a long-acting FGF21 molecule (PF-05231023) in induced pluripotent stem cell (iPSC)-derived forebrain neurons. MethodsWe performed RNA-seq in iPSC-derived forebrain neurons treated with naïve FGF21 or PF-05231023 at physiologically relevant concentrations. We obtained plasma levels of FGF21 and GABA from our previous AUD clinical trial (n = 442). We performed ELISA for FGF21 in both iPSC-derived forebrain neurons and forebrain organoids. We determined protein interactions using co-immunoprecipitation. Finally, we applied ChIP assays to confirm the occupancy of REST, EZH2 and H3K27me3 by FGF21 using iPSC-derived forebrain neurons with and without drug exposure. ResultsWe identified 4701 and 1956 differentially expressed genes in response to naïve FGF21 or PF-05231023, respectively (FDR < 0.05). Notably, 974 differentially expressed genes overlapped between treatment with naïve FGF21 and PF-05231023. REST was the most important upstream regulator of differentially expressed genes. The GABAergic synapse pathway was the most significant pathway identified using the overlapping genes. We also observed a significant positive correlation between plasma FGF21 and GABA concentrations in AUD patients. In parallel, FGF21 and PF-05231023 significantly induced GABA levels in iPSC-derived neurons. Finally, functional genomics studies showed a drug-dependent occupancy of REST, EZH2, and H3K27me3 in the promoter regions of genes involved in GABA catabolism which resulted in transcriptional repression. ConclusionsOur results highlight a significant role in the epigenetic regulation of genes involved in GABA catabolism related to FGF21 action.(The ClinicalTrials.gov Identifier: NCT00662571)

Role of FGF21 in Gestational Diabetes Mellitus in a Sample of Egyptian Population

Abstract Background Gestational diabetes (GDM) is defined as carbohydrate intolerance that begins or is first recognized during pregnancy. Gestational diabetes mellitus (GDM) affects approximately 5 to 7% of pregnancies and is associated with increased risk for fetal overgrowth, cesarean delivery, birth trauma, and pre-eclampsia. Objective To investigate serum FGF21 concentrations in a sample of Egyptian patients with GDM as compared with healthy pregnant controls matched for gestational age And its correlation to clinical and biochemical changes (Glucose, insulin, lipids) and fetal wellbeing using obstetric ultrasound to assess fetal size and development of congenital malformation. Methods This cross-sectional study was conducted on 80 participants collected from Obstetrics and Gynecology clinic at Ain Shams University Hospital during the period from November 2019 to March 2021. Results Shows that there is statistically significant increase in FGF21 in female pregnants with GDM as compared to female pregnants without GDM. The high FGF21 level didn’t affect fetal wellbeing. And both groups had normal fetal development with absence of macrosomia and congenital malformation as shown on results of obstetric ultrasound. In addition, there is statistically significant positive correlation between fasting FGF21 level and each of total cholesterol, LDL, HDL and TG (R +ve, P.&amp;lt; 0.05). Conclusion This high level of FGF21 may be FGF21 resistance or compensatory response to the underlying metabolic stress. FGF21 may have reduced an even higher level of blood glucose than the measured one, blood glucose level could have been in the Range of 400-500 mg/dl instead the measured range 200-300 mg/dl. Obstetric ultrasound results revealed normal fetal wellbeing and no change in fetal size nor development of congenital malformation between both groups.

Decreased FGF19 and FGF21: possible underlying common pathogenic mechanism of metabolic and cognitive dysregulation in depression.

Accumulating studies suggested that major depressive disorder (MDD) was closely related to metabolic syndrome (MetS). Important endogenous regulators fibroblast growth factors (FGFs) 19 and 21 were also reported to participate in psychiatric disorders. This study aimed to investigate the role of FGF19 and FGF21 in MDD and to explore the possible pathogenic mechanism of metabolic and cognitive dysregulation in depression. A total of 59 MDD patients and 55 healthy control participants were recruited. The serum levels of FGF19 and FGF21 and lipid profiles were measured by means of enzymatic methods. Cognitive function was measured by repeatable battery for the assessment of neuropsychological status (RBANS) scores. The gene expression of PGC-1α and FNDC5 was determined by quantitative polymerase chain reaction (PCR). We found that plasma FGF19 and FGF21 levels were significantly decreased in patients with MDD. Meanwhile, triglyceride (TG) was significantly elevated and PGC-1α was significantly downregulated in MDD patients. Correlation analyses showed negative associations between TG and FGF19 levels. As for cognitive performance, both FGF19 and FGF21 levels were positively correlated with immediate memory. However, FGF19 levels were negatively correlated with language, and FGF21 levels were also negatively correlated with attention and delayed memory. Additionally, negative associations were found between FGF19 levels and PGC-1α. FGF21 levels were positively associated with PGC-1α and negatively associated with FNDC5. This study elucidated the role of FGF19 and FGF21 in MDD. MDD patients were confirmed to have metabolic and cognitive dysregulation, and this abnormality was linked to the decreased concentrations of FGF19 and FGF21 through the PGC-1α/FNDC5 pathway. Our results showed that the alterations of FGF19 and FGF21 levels may be a common pathogenic mechanism of metabolic and cognitive disturbances in patients with MDD.

Fibroblast Growth Factor-21 as a Potential Therapeutic Target of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease without any approved treatment to-date despite intensive research efforts by researchers and pharmaceutical industry. Fibroblast growth factor (FGF)-21 has been gaining increasing attention as a possible contributing factor and thus therapeutic target for obesity-related metabolic disorders, including NAFLD, mainly due to its effects on lipid and carbohydrate metabolism. Most animal and human observational studies have shown higher FGF-21 concentrations in NAFLD than non-NAFLD, implying that FGF-21 may be increased to counteract hepatic steatosis and inflammation. However, although Mendelian Randomization studies have revealed that variations of FGF-21 levels within the physiological range may have effects in hyperlipidemia and possibly nonalcoholic steatohepatitis, they also indicate that FGF-21, in physiological concentrations, may fail to reverse NAFLD and may not be able to control obesity and other diseases, indicating a state of FGF-21 resistance or insensitivity that could not respond to administration of FGF-21 in supraphysiological concentrations. Interventional studies with FGF-21 analogs (eg, pegbelfermin, efruxifermin, BOS-580) in humans have provided some favorable results in Phase 1 and Phase 2 studies. However, the definite effect of FGF-21 on NAFLD may be clarified after the completion of the ongoing clinical trials with paired liver biopsies and histological endpoints. The aim of this review is to critically summarize experimental and clinical data of FGF-21 in NAFLD, in an attempt to highlight existing knowledge and areas of uncertainty, and subsequently, to focus on the potential therapeutic effects of FGF-21 and its analogs in NAFLD.

The New Markers of Early Obesity-Related Organ and Metabolic Abnormalities.

The objective of our study was to identify new markers related to excessive body adiposity and its early consequences. For this purpose we determined serum FGF-19 and FGF-21 concentrations in obese rats, whose role in the pathogenesis of obesity is not yet established. In addition, a total reflection X-ray fluorescence technique was applied to determine the elemental chemistry of certain tissues affected by obesity. Next, the new biochemical and molecular parameters were correlated with well-known obesity-related markers of metabolic abnormalities. Our obese rats were characterized by increased calorie consumption and body adiposity, hypercholesterolemia, elevated levels of liver enzymes and FGF-21, while the level of FGF-19 was reduced. Strong relationships between new hormones and established metabolic parameters were observed. Furthermore, we demonstrated that obesity had the greatest effect on elemental composition in the adipose tissue and liver and that rubidium (Rb) had the highest importance in distinguishing the studied groups of animals. Tissue Rb strongly correlated with both well-known and new markers of obesity. In conclusion, we confirmed serum FGF-19 and FGF-21 as useful new markers of obesity-related metabolic alternations and we robustly propose Rb as a novel indicator of excessive body adiposity and its early consequences. However, further investigations are encouraged to address this clinical issue.

Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH

BackgroundFibroblast growth factor 21 (FGF21) is a hepatokine that produces metabolic benefits, such as improvements of lipid profile. We performed a genome-wide association study (GWAS) to identify genetic variants associated with circulating FGF21 and investigated the causal effects of FGF21 on pertinent outcomes using Mendelian randomization (MR). MethodsWe conducted a GWAS testing ∼7.8 million DNA sequence variants with circulating FGF21 in a discovery cohort of 6259 Swedish adults with replication in 4483 Swedish women. We then performed two-sample MR analyses of genetically predicted circulating FGF21 in relation to alcohol and nutrient intake, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available GWAS summary statistics data. ResultsOur GWAS identified multiple single-nucleotide polymorphisms with genome-wide significant associations (P < 5 × 10−8) with circulating FGF21 on chromosomes 2 and 19 in or near the GCKR and FGF21 genes, respectively. The strongest signal at the FGF21 locus (rs2548957, β = 0.181, P < 2.18 × 10−42) displayed in two-sample MR analyses robust associations with lower alcohol intake, lower circulating low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, gamma-glutamyl transferase, and galectin-3 concentrations, and higher circulating insulin-like growth factor-I and alkaline phosphatase concentrations after correcting for multiple testing (P < 0.0018) whereas associations with fat mass, type 2 diabetes, and cardiovascular disease were largely null. ConclusionsWe identified robust associations of certain genetic variants in or near the GCKR and FGF21 genes with circulating FGF21 concentrations. Furthermore, our results support a strong causal effect of FGF21 on improved lipid profile, reduced alcohol consumption and C-reactive protein concentrations, and liver function biomarkers including fibrosis. We found largely null or weak positive associations with fat mass, diabetes, and cardiovascular disease as well as higher insulin-like growth factor-I concentrations, which could indicate a compensatory increase to regulate the above FGF21 resistant states in humans.

Exercise Induced-Cytokines Response in Marathon Runners: Role of ACE I/D and BDKRB2 +9/-9 Polymorphisms.

Renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) have a different site of interaction and modulate vascular tone and inflammatory response as well on exercise adaptation, which is modulated by exercise-induced cytokines. The aim of the study was to evaluate the role of ACE I/D and BDKRB2 +9/−9 polymorphism on exercise-induced cytokine response. Seventy-four male marathon finishers, aged 30 to 55 years, participated in this study. Plasma levels of exercise-induced cytokines were determined 24 h before, immediately after, and 24 h and 72 h after the São Paulo International Marathon. Plasma concentrations of MCP-1, IL-6 and FGF-21 increased after marathon in all genotypes of BDKRB2. IL-10, FSTL and BDNF increased significantly after marathon in the genotypes with the presence of the −9 allele. FSTL and BDNF concentrations were higher in the −9/−9 genotype compared to the +9/+9 genotype before (p = 0.006) and after the race (p = 0.023), respectively. Apelin, IL-15, musclin and myostatin concentrations were significantly reduced after the race only in the presence of −9 allele. Marathon increased plasma concentrations of MCP1, IL-6, BDNF and FGF-21 in all genotypes of ACE I/D polymorphism. Plasma concentrations of IL-8 and MIP-1alpha before the race (p = 0.015 and p = 0.031, respectively), of MIP-1alpha and IL-10 after the race (p = 0.033 and p = 0.047, respectively) and VEGF 72 h after the race (p = 0.018) were lower in II homozygotes compared to runners with the presence of D allele. One day after the race we also observed lower levels of MIP-1alpha in runners with II homozygotes compared to DD homozygotes (p = 0.026). Before the marathon race myostatin concentrations were higher in DD compared to II genotypes (p = 0.009). Myostatin, musclin, IL-15, IL-6 and apelin levels decreased after race in genotypes with the presence of D allele. After the race ACE activity was negatively correlated with MCP1 (r = −56, p < 0.016) and positively correlated with IL-8, IL-10 and MIP1-alpha (r = 0.72, p < 0.0007, r = 0.72, p < 0.0007, r = 0.47, p < 0.048, respectively). The runners with the −9/−9 genotype have greater response in exercise-induced cytokines related to muscle repair and cardioprotection indicating that BDKRB2 participate on exercise adaptations and runners with DD genotype have greater inflammatory response as well as ACE activity was positively correlated with inflammatory mediators. DD homozygotes also had higher myostatin levels which modulates protein homeostasis.

Circulating Fibroblast Growth Factor 21 and Total Testosterone in Type 2 Diabetes Mellitus Men With Coronary Heart Disease.

BackgroundFibroblast growth factor 21 increased in population with type 2 diabetes mellitus (T2DM), while serum total testosterone often decreased in men with T2DM. This study aimed to investigate the relationship between the prevalence of coronary artery disease (CAD) and circulating FGF21 concentrations and serum testosterone in T2DM men.Methods490 men with T2DM from January 2021 to December 2021 were recruited from the Renmin Hospital of Wuhan University, and they were divided into CAD group (n=248) and control group (n=242). FGF21 were determined based on ELISA principle and serum total testosterone was measured in a liquid chromatography mass spectrometer LC/MS-8050 (Shimadzu, Japan). Logistic and restricted cubic spline analyses were performed to examine the association between the prevalence of CAD and circulating FGF21 concentrations and serum testosterone in T2DM men. The receiver operating curve (ROC) analysis was used to explore the predictive performance.ResultsCirculating FGF21 levels were higher in T2DM men with CAD compared with those without CAD [214.63 (121.82, 348.64) pg/ml vs 166.55 (94.81,254.48) pg/ml, p<0.001], while serum total testosterone was lower [3.08 ± 0.07 ng/ml vs 3.76 ± 0.09 ng/ml, p<0.001]. The fully adjusted odds ratio (OR) and 95% confidence intervals (95%CI) was 2.956(1.409,6.201) for those in quartile 4 of FGF21 versus quartile 1 and the fully adjusted OR (95%CI) was 0.346(0.174,0.686) for those in quartile 4 of testosterone versus quartile 1. The receiver operating curve (ROC) analysis showed that the area under the curve (AUC) of combination of FGF21 and testosterone for predicting the occurrence of CAD in men with T2DM was 0.702 (95% CI: 0.667-0.741).ConclusionCirculating FGF21 levels were positively associated with CAD in men with T2DM, whereas serum total testosterone levels showed an inverse correlation with CAD in diabetic men.

MO697: FGF-21 Correlates with Overhydration: Is There a Role for Peritoneal GLUT-1?

Abstract BACKGROUND AND AIMS FGF-21 is a hepatokine that stimulates glucose uptake through GLUT-1. The presence of this glucose transporter in peritoneal fibroblasts is driven by peritoneal glucose exposure and is related to impaired ultrafiltration, predisposing to overhydration. The study was designed to determine FGF-21 levels in peritoneal effluent and serum, and its possible association with overhydration. METHOD Prevalent and incident peritoneal dialysis (PD) patients without diabetes were included. FGF-21 (dialysate and serum) was obtained during a 3.86% glucose peritoneal equilibration test. Peritoneal glucose load was calculated. The presence or absence of local peritoneal production was assessed by comparing the dialysate to plasma (D/P) ratio of FGF-21 (MW 32 kD) with that of albumin (MW 67 kD). Hydration status was assessed by bioimpedance. Spearman's correlations were performed. RESULTS A total of 58 patients (38 incident, 20 prevalent) were included, mean age 54 years, 67% males, PD duration from 1 to 75 months, mean 10.4. Residual GFR was 6.4 ± 3.5 mL/min/1.73 m2 and D/P creatinine 0.65 ± 0.12. Peritoneal glucose load was 110.5 g/day (range 40.8–226.9). Dialysate FGF-21 was 42.5 ± 47.0 pg/mL and serum FGF-21 943.9 ± 1164.8 pg/mL, giving a D/P ratio of 0.07. D/P albumin was 0.009, indicating that dialysate FGF-21 concentrations can be explained by transport from the circulation, without local peritoneal production. Serum FGF-21 was positively correlated with dialysate FGF-21, extracellular water excess and total peritoneal glucose load (all P &amp;lt; 0.01). Some association was present with PD duration (P &amp;lt; 0.05). No relationship was found between plasma FGF-21 and plasma insulin, D/P creatinine, or residual kidney function. CONCLUSION FGF-21 in peritoneal effluent is likely not locally produced, but caused by transport from the circulation. The associations between plasma FGF-21 levels with PD duration, peritoneal glucose load and overhydration, all indicate an effect of peritoneal glucose absorption from the peritoneal cavity into the interstitium with an insulin-independent storage into interstitial adipocytes, where it may stimulate the expression of GLUT-1.

Assessment of fibroblast growth factor 19 as a non-invasive serum marker for hepatocellular carcinoma.

BACKGROUNDFibroblast growth factor 19 (FGF-19) is one of the founding members of the endocrine FGF subfamily. Recently, it has been the subject of much interest owing to its role in various physiological processes affecting glucose and lipid metabolism and the regulation of bile acid secretion as well as cell proliferation, differentiation, and motility. Additionally, FGF-19 secretion in an autocrine style has reportedly contributed to cancer progression in various types of malignancies including hepatocellular carcinoma (HCC). AIMTo estimate the serum FGF-19 concentrations in HCC cases and assess its diagnostic performance for the detection of HCC.METHODSWe recruited 90 adult participants and divided them into three equal groups: Healthy controls, cirrhosis patients, and HCC patients. Serum FGF-19 concentrations were measured using the Human FGF-19 ELISA kit. RESULTSWe detected a high statistically significant difference in serum FGF-19 levels among the three groups. The highest level was observed in the HCC group, followed by the cirrhosis and control groups (236.44 ± 40.94 vs 125.63 ± 31.54 vs 69.60 ± 20.90 pg/mL, respectively, P ≤ 0.001). FGF-19 was positively correlated with alpha fetoprotein (AFP; r = 0.383, P = 0.003) and international normalised ratio (r = 0.357, P = 0.005), while it was negatively correlated with albumin (r = -0.500, P ≤ 0.001). For the detection of HCC, receiver operating characteristic curve analysis showed that the best cut-off point of AFP was > 8.2 ng/mL with an area under the curve (AUC) of 0.78, sensitivity of 63.33%, specificity of 83.33%, positive predictive value (PPV) of 79.2%, negative predictive value (NPV) of 69.4%, and total accuracy of 78%. However, FGF-19 at a cut-off point > 180 pg/mL had an AUC of 0.98, sensitivity of 100%, specificity of 90.0%, PPV of 90.0%, NPV of 100%, and total accuracy of 98%.CONCLUSIONFGF-19 represents a possible novel non-invasive marker for HCC. It may improve the prognosis of HCC patients due to its utility in several aspects of HCC detection and management.

Association of serum fibroblast growth factor 21 with diabetic complications and insulin dose in patients with type 1 diabetes mellitus.

IntroductionFibroblast growth factor (FGF) 21 is an important regulator of glycemic control, but the association between circulating FGF21 and diabetic complications is poorly understood. Moreover, basal FGF21 secretion, especially in response to insulin dose, in patients with type 1 diabetes mellitus (T1DM), has not been well examined. Therefore, this study aimed to determine the association of circulating FGF21 levels with diabetic complications and insulin dosage in middle-aged and elderly patients with T1DM.Materials and methodsA total of 127 middle-aged and elderly patients with T1DM, including 68 patients with diabetic complications, and 106 non-diabetic individuals were analyzed in this cross-sectional study. Information on demographic characteristics and T1DM was extracted from their electronic medical records. Serum FGF21 levels were determined using ELISA.ResultsSerum FGF21 levels were significantly lower in T1DM patients (75.2 [37.4–135.1] pg/mL) than in non-diabetic participants (151.6 [92.0–224.6] pg/mL; P < 0.001). No diabetic complications were associated with serum FGF21 concentrations. Both basal and bolus insulin doses were significantly and positively correlated with serum FGF21 levels (P < 0.05). Stepwise multiple regression analysis showed that FGF21 level was associated with age and body mass index (P < 0.05), while the basal insulin dose was an independent positive predictor of serum FGF21 levels (β = 0.197, P = 0.032).ConclusionsCirculating FGF21 levels are reduced in patients with T1DM; however, they are not associated with diabetic complications. In addition, aging, obesity, and insulin dosage are positive determinants of circulating FGF21.

Plasma FGF21 concentrations and spontaneous self-selection of protein suggest that 15% protein in the diet may not be enough for male adult rats

Protein requirement has been determined at 10%-15% energy. Under dietary self-selection, rats ingest 25%-30% energy as protein and regulate FGF21 (a hormone signaling protein deficiency) to levels lower than those measured with a 15% protein (15P) diet. Our hypothesis is that if a 15P diet was indeed sufficient to ensure protein homeostasis, it is probably a too low protein level to ensure optimal energy homeostasis. Adult male Wistar rats were used in this study. The first objective was to determine the changes in food intake, body composition, and plasma FGF21, IGF-1, and PYY concentrations in rats fed 8P, 15P, 30P, 40P, or 50P diets. The second was to determine whether the FGF21 levels measured in the rats were related to spontaneous protein intake. Rats were fed a 15P diet and then allowed to choose between a protein diet and a protein-free diet. Food intake and body weight were measured throughout the experiments. Body composition was determined at different experimental stages. Plasma samples were collected to measure FGF21, IGF-1, and PYY concentrations. A 15P diet appears to result in higher growth than that observed with the 30P, 40P, and 50P diets. However, the 15P diet probably does not provide optimal progression of body composition owing to a tendency of 15P rats to fix more fat and energy in the body. The variable and higher concentrations of FGF21 in the 15P diet suggest a deficit in protein intake, but this does not appear to be a parameter reflecting the adequacy of protein intake relative to individual protein requirements.NEW & NOTEWORTHY Under dietary self-selection, rats choose to ingest 25%-30% of energy as protein, a value higher than the protein requirement (10%-15%). According to our results, this higher spontaneous intake reflects the fact that rats fed a 15% protein diet, compared with high-protein diets, tend to bind more fat and have higher concentrations of FGF21, a hormone signaling protein deficiency. A 15% protein diet appears to be sufficient for protein homeostasis but not for optimal energy homeostasis.