Maternal High-Fat Diet Alters the Characteristics of Astrocytes and Worsens the Outcome of Stroke in Rat Offspring, Which Improves After FGF21 Administration

Background: Maternal high-fat diet (MHFD) has been shown to increase susceptibility to neurological disease in later offspring, but the underlying mechanism is not clear. Fibroblast growth factor 21 (FGF21) has been reported to have a neuroprotective effect in stroke, but its mechanism of action remains unknown. In this study, we investigated the mechanism of the effect of MHFD on stroke in offspring in adulthood and the mechanism by which FGF21 acts on stroke and restores neurological function.Methods: We performed transcriptome sequencing analysis on D21 neonatal rats. Bodyweight and blood indicators were recorded in the adult rats after MHFD. FGF21 was administered 7 h after photochemical modeling twice a day for three consecutive days.Results: We found numerous mRNA changes between the MHFD group and a normal maternal normal diet (MND) group at D21, including genes related to astrocyte and PI3K/Akt pathways. The body weight, blood glucose, and triglycerides of the MHFD offspring were higher, ischemic lesions were larger, the number of activated astrocytes was lower, and the neurological function score was worse than that of the MND group. After FGF21 administration, WB and qPCR analyses showed that astrocytes and the PI3K/Akt pathway were upregulated, while NF-κB and inflammatory cytokines expression were inhibited in stroke and peri-stroke regions.Conclusion: Taken together, we conclude that MHFD alters the characteristics of astrocytes and other transcriptome changes in their offspring, leading to a worse prognosis of stroke, while FGF21 plays a neuroprotective role by inhibiting NF-κB and inflammatory factors and activating the PI3K/Akt pathway and activating more astrocytes in the MND group than the MHFD group.

Fibroblast growth factor-21 improves insulin action in non-lactating ewes

During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g., growth hormone and TNFa) and others potentiating (e.g., adiponectin) insulin action. Fibroblast growth factor-21 (FGF21) was recently identified as a sensitizing hormone in rodent and primate models of defective insulin action. FGF21 administration, however, failed to improve insulin action in dairy cows during the naturally occurring insulin resistance of lactation, raising the possibility that ruminants as a class of animals or lactation as a physiological state are unresponsive to FGF21. To start addressing this question, we asked whether FGF21 could improve insulin action in non-lactating ewes. Gene expression studies showed that the ovine FGF21 system resembles that of other species, with liver as the major site of FGF21 expression and adipose tissue as a target tissue based on high expression of the FGF21 receptor complex and activation of p44/42 ERK1/2 following exogenous FGF21 administration. FGF21 treatment for 13 days reduced plasma glucose and insulin over the entire treatment period and improved glucose disposal during a glucose tolerance test. FGF21 increased plasma adiponectin by day 3 of treatment but had no effect on the plasma concentrations of total, C16:0-, or C18:0-ceramide. Overall, these data confirm that the insulin-sensitizing effects of FGF21 are conserved in ruminants and raise the possibility that lactation is an FGF21 resistant state.

Fibroblast growth factor 21 (FGF21) is increased in MDD and interacts with body mass index (BMI) to affect depression trajectory

Fibroblast growth factor 21 (FGF21) is a key regulator of metabolic function and nutrient preference. It also affects biological pathways associated with major depressive disorder (MDD), including corticotrophin-releasing hormone (CRH), leptin, and sympathetic activity. Lower levels of cerebrospinal fluid FGF21 have been associated with higher Beck Depression Inventory scores. FGF21 was examined as a metabolic marker that could be associated with MDD and evaluated as a biomarker of antidepressant treatment response in a large, randomized placebo-controlled trial in chronic, early-onset MDD participants. FGF21 levels at baseline and during treatment were determined for participants in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. FGF21 was analyzed by ELISA in individuals with chronic, early-onset MDD (first major depressive episode before 30 years) compared to healthy control participants. Participants with MDD had higher levels of FGF21 compared to healthy controls (HCs), even after controlling for baseline age, sex, race, Hispanic ethnicity, BMI, and site (β-coefficient = 1.20, p < 0.0001, Cohen’s d = 0.60). FGF21 did not change over time nor differ between treatment groups. Interestingly though, those with normal BMI and lower FGF21 levels showed a reduction in depression severity over time compared to all other groups. In conclusion, depression is associated with higher levels of FGF21 compared to healthy controls and those with lower levels of FGF21 (25th percentile of the sample) in the context of normal-weight BMI seem to have improved depression severity over time.

Elevated Serum Fibroblast Growth Factor 21 Is Relevant to Heart Failure Patients with Reduced Ejection Fraction

Objective. The aim of this study was to evaluate the roles of fibroblast growth factor 21 (FGF21) in heart failure patients with reduced ejection fraction and its association with Heart Failure with reduced Ejection Fraction (HFrEF). Methods. The level of FGF21 was measured by enzyme-linked immunosorbent assay (ELISA) in 199 subjects enrolled in this study, including 128 subjects with HFrEF and 71 control subjects. The mean follow-up time was 13.36 months. The left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) percentage were evaluated by the 2D echocardiography. Serum brain natriuretic peptide (BNP) was measured in the routine clinical laboratory. Results. The serum FGF21 level was evidently higher in patients with HFrEF than in the control group ( 228.72 ± 24.04 vs. 171.60 ± 12.98 , p < 0.001 ). After 1 year of follow-up, 61 patients (47.66%) with heart failure were readmitted to the hospital, including 8 deaths (13.11%). The AUC of the receiver operating characteristic (ROC) curve for the predictive value of FGF21 for prognosis was 0.964. Kaplan-Meier analysis results showed that there were significant differences in the 1-year mortality and heart failure readmission events between the grouped subjects. A poor prognosis was correlated with the serum level of FGF21, BNP, LVEDD, and LVEF, which was confirmed by the univariate Cox analysis. Conclusion. FGF21 was independently associated with an increased risk of mortality and readmission HFrEF patients. Therefore, FGF21 has the potential to be a biomarker for the progression of HFrEF in patients.

Fibroblast growth factor-21 as a novel metabolic factor for regulating thrombotic homeostasis

Fibroblast growth factor-21 (FGF-21) performs a wide range of biological functions in organisms. Here, we report for the first time that FGF-21 suppresses thrombus formation with no notable risk of bleeding. Prophylactic and therapeutic administration of FGF-21 significantly improved the degree of vascular stenosis and reduced the thrombus area, volume and burden. We determined the antithrombotic mechanism of FGF-21, demonstrating that FGF-21 exhibits an anticoagulant effect by inhibiting the expression and activity of factor VII (FVII). FGF-21 exerts an antiplatelet effect by inhibiting platelet activation. FGF-21 enhances fibrinolysis by promoting tissue plasminogen activator (tPA) expression and activation, while inhibiting plasminogen activator inhibitor 1 (PAI-1) expression and activation. We further found that FGF-21 mediated the expression and activation of tPA and PAI-1 by regulating the ERK1/2 and TGF-β/Smad2 pathways, respectively. In addition, we found that FGF-21 inhibits the expression of inflammatory factors in thrombosis by regulating the NF-κB pathway.

Phytochemicals from the Cocoa Shell Modulate Mitochondrial Function, Lipid and Glucose Metabolism in Hepatocytes via Activation of FGF21/ERK, AKT, and mTOR Pathways

The cocoa shell is a by-product that may be revalorized as a source of bioactive compounds to prevent chronic cardiometabolic diseases. This study aimed to investigate the phytochemicals from the cocoa shell as targeted compounds for activating fibroblast growth factor 21 (FGF21) signaling and regulating non-alcoholic fatty liver disease (NAFLD)-related biomarkers linked to oxidative stress, mitochondrial function, and metabolism in hepatocytes. HepG2 cells treated with palmitic acid (PA, 500 µmol L−1) were used in an NAFLD cell model. Phytochemicals from the cocoa shell (50 µmol L−1) and an aqueous extract (CAE, 100 µg mL−1) enhanced ERK1/2 phosphorylation (1.7- to 3.3-fold) and FGF21 release (1.4- to 3.4-fold) via PPARα activation. Oxidative stress markers were reduced though Nrf-2 regulation. Mitochondrial function (mitochondrial respiration and ATP production) was protected by the PGC-1α pathway modulation. Cocoa shell phytochemicals reduced lipid accumulation (53–115%) and fatty acid synthase activity (59–93%) and prompted CPT-1 activity. Glucose uptake and glucokinase activity were enhanced, whereas glucose production and phosphoenolpyruvate carboxykinase activity were diminished. The increase in the phosphorylation of the insulin receptor, AKT, AMPKα, mTOR, and ERK1/2 conduced to the regulation of hepatic mitochondrial function and energy metabolism. For the first time, the cocoa shell phytochemicals are proved to modulate FGF21 signaling. Results demonstrate the in vitro preventive effect of the phytochemicals from the cocoa shell on NAFLD.

The Nuanced Metabolic Functions of Endogenous FGF21 Depend on the Nature of the Stimulus, Tissue Source, and Experimental Model

Fibroblast growth factor 21 (FGF21) is a hormone that is involved in the regulation of lipid, glucose, and energy metabolism. Pharmacological FGF21 administration promotes weight loss and improves insulin sensitivity in rodents, non-human primates, and humans. However, pharmacologic effects of FGF21 likely differ from its physiological effects. Endogenous FGF21 is produced by many cell types, including hepatocytes, white and brown adipocytes, skeletal and cardiac myocytes, and pancreatic beta cells, and acts on a diverse array of effector tissues such as the brain, white and brown adipose tissue, heart, and skeletal muscle. Different receptor expression patterns dictate FGF21 function in these target tissues, with the primary effect to coordinate responses to nutritional stress. Moreover, different nutritional stimuli tend to promote FGF21 expression from different tissues; i.e., fasting induces hepatic-derived FGF21, while feeding promotes white adipocyte-derived FGF21. Target tissue effects of FGF21 also depend on its capacity to enter the systemic circulation, which varies widely from known FGF21 tissue sources in response to various stimuli. Due to its association with obesity and non-alcoholic fatty liver disease, the metabolic effects of endogenously produced FGF21 during the pathogenesis of these conditions are not well known. In this review, we will highlight what is known about endogenous tissue-specific FGF21 expression and organ cross-talk that dictate its diverse physiological functions, with particular attention given to FGF21 responses to nutritional stress. The importance of the particular experimental design, cellular and animal models, and nutritional status in deciphering the diverse metabolic functions of endogenous FGF21 cannot be overstated.

Associations of FGF21 and GDF15 with mitochondrial dysfunction in children living with perinatally-acquired HIV: A cross-sectional evaluation of pediatric AIDS clinical trials group 219/219C

Background In persons living with HIV, mitochondrial disease (MD) is difficult to diagnose, as clinical signs are non-specific with inconsistent patterns. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) are mitokines elevated in MD patients without HIV, and associated with cardiometabolic comorbidities in adults living with HIV. We assessed relationships of these biomarkers with MD in children living with perinatally-acquired HIV infection (CPHIV). Setting Cross-sectional study of CPHIV from Pediatric ACTG 219/219C classified by Mitochondrial Disease Criteria (MDC) that defines scores 2–4 as “possible” MD. Methods Each case with MDC equaling 4 (MDC4; n = 23) was matched to one randomly selected control displaying no MDC (MDC0; n = 23) based on calendar date. Unmatched cases with MDC equaling 3 (MDC3; n = 71) were also assessed. Plasma samples proximal to diagnoses were assayed by ELISA. Mitokine distributions were compared using Wilcoxon tests, Spearman correlations were calculated, and associations with MD status were assessed by conditional logistic regression. Results Median FGF21 and GDF15 concentrations, respectively, were highest in MDC4 (143.9 and 1441.1 pg/mL), then MDC3 (104.0 and 726.5 pg/mL), and lowest in controls (89.4 and 484.7 pg/mL). Distributions of FGF21 (paired Wilcoxon rank sum p = 0.002) and GDF15 (paired Wilcoxon rank sum p<0.001) differed in MDC4 vs MDC0. Mitokine concentrations were correlated across all participants (r = 0.33; p<0.001). Unadjusted odds ratios of being MDC4 vs MDC0 were 5.2 [95% confidence interval (CI): 1.06–25.92] for FGF21 and 3.5 (95%CI: 1.19–10.25) for GDF15. Relationships persisted after covariate adjustments. Conclusion FGF21 and GDF15 levels may be useful biomarkers to screen for CPHIV with mitochondrial dysfunction.