Fibroblast Growth Factor 21 Levels Research Articles

Metabolic and Hepatic Profiles of Non-Obese and Obese Metabolic Dysfunction-Associated Steatotic Liver Disease in Adolescents: The Role of FibroScan Parameters,Fibroblast Growth Factor-21, and Cytokeratin-18.

Metabolic dysfunction-associated steatotic liver disease (MASLD) in adolescents, including non-obese phenotypes, is an increasingly important public health issue. The current study investigated the use of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) as non-invasive tools, along with fibroblast growth factor-21 (FGF-21) and cytokeratin-18 (CK-18), in non-obese MASLD, obese MASLD, and healthy control groups, exploring metabolic and hepatic profiles in these groups. This cross-sectional study recruited 195 adolescents aged 9-18 years, stratified into controls (n = 92), non-obese MASLD (n = 32), and obese MASLD (n = 39) groups according to FibroScan and MASLD diagnostic criteria. FibroScan measured LSM and CAP, while enzyme-linked immunosorbent assay kit (ELISA) was used to analyze serum FGF-21 and CK-18 levels. Anthropometric, metabolic, and liver enzyme parameters were assessed. Metabolic dysfunction-associated steatotic liver disease groups had higher LSM than controls. Fibroblast growth factor-21 levels were significantly higher in MASLD groups, especially in obese MASLD, while CK-18 levels showed variability without significant group differences. Obese MASLD adolescents had marked metabolic dysfunction with higher insulin, homeostasis model assessment for insulin resistance, triglycerides, and liver enzymes compared to non-obese MASLD and controls. Fibroblast growth factor-21 has emerged as a potential biomarker for assessing metabolic dysfunction in MASLD, while LSMs from FibroScan provide valuable insights into fibrosis risk. Elevated FGF-21 levels and FibroScan parameters reflect their potential usefulness in non-invasive assessment of MASLD severity, particularly in obese adolescents. However, further longitudinal studies are needed to establish their roles in predicting disease progression and guiding clinical management.

The Diagnostic Performance of Fibroblast Growth Factor-21 during Early Stage of Missed Miscarriage

Abstract Background: Missed miscarriages (MMs) occur when an embryo without a cardiac pulse or gestational sac is not expelled from the uterus. Fibroblast growth factor-21 (FGF-21), a member of the fibroblast growth factor family, plays an important regulatory role in metabolism, primarily in glucose and lipid metabolism. Objective: The aim of this study is to investigate whether serum levels of FGF-21 are associated with MM in 8–14 weeks of gestation. Materials and Methods: This case–control study consisted of 88 pregnant women; they were divided into two groups: healthy pregnant (HP), composed of 40 women with a normal viable pregnancy at 8–14 weeks of gestation with mean age (29.07 ± 6.96 years); and study group that included 40 women with MM diagnosed by ultrasound at the same gestational age (GA) with mean age (28.27 ± 7.74 years). Demographic criteria and maternal serum FGF-21 levels were recorded for comparison. ELISA technique was used to measure FGF-21 in circulation. Results: This study revealed a statistically significant increase in serum levels of FGF-21 in MMs (142.47 ± 48.036 pg/ml) compared to normal pregnant women (87.9 ± 30.86). The cutoff point was ≥149.97, with high sensitivity (73.2%) and specificity (97.9%). There was no significant correlation between FGF-21 levels and age, GA, body mass index, or gravidity. Conclusion: The MM group’s serum concentrations of FGF-21 were markedly elevated within a time frame of 8–14 weeks compared to the HP group, suggesting its involvement in the development of MM. Based on the findings, FGF21 demonstrates a remarkable capacity for diagnosing MM.

P0160 Vitamin D and FGF-19 in patients with Inflammatory Bowel Disease

Abstract Background Vitamin D (vit. D) has pleiotropic effects, and in recent years, its role in regulating the immune response has been widely discussed. Patients with IBD tend to have lower vit. D levels, and this may be associated with more frequent relapses, increased need for surgical interventions, and a slower response to antibody treatments. Methods An observational study was conducted at the Gastroenterology Department of UH "Saint Ivan Rilski," Sofia, Bulgaria, involving 47 patients with ulcerative colitis (UC) and 55 with Crohn’s disease (CD). We evaluated serum vit. D, laboratory markers, Fibroblast growth factor-19 (FGF-19) levels. Results Patients with IBD were equally distributed between females (49%) and males (51%). Subnormal vit. D levels were observed in 94% of patients with CD and in 98% of those with UC. This contrasts with the general Bulgarian population, where 76% have lower levels [1]. The mean serum value in patients with IBD was 40 nmol/L, which is insufficient. Vit. D was found to vary depending on treatment. IBD receiving corticosteroids or immunosuppressants had lower levels compared to those treated with biologic agents. The difference was a 13% decrease in CD and 10% in UC. This may be attributed to the inhibitory effects of corticosteroids on vit. D metabolism or the restricted sun exposure when taking azathioprine. The evaluated data revealed that vit. D had a statistically significant inverse correlation with laboratory markers such as C-reactive protein (CRP) (P = 0.0018, r = -0.351), leukocytes (P = 0.0069, r = -0.2661), erythrocyte sedimentation rate (P = 0.0022, r = -0.2992), thrombocytes (P = 0.0083, r = -0.2600), and the neutrophil-to-lymphocyte ratio (NLR) (P = 0.0011, r = -0.3175) and in UC fecal calprotectin (P= 0.0025, r= -0.4025) [2]. Serum FGF-19 levels were evaluated in all IBD and were lower in 8 patients with CD, with a mean level of 20 pg/mL. Six of them had ileocolitis and two had terminal ileitis, which is associated with probable bile acid malabsorption. In other studies was found that patients have bile acid diarrhea with levels of 60pg/mL [3,4]. Statistically significant correlation was observed between FGF-19 and vit. D levels (P = 0.232, r = 0.2836). Conclusion Patients with IBD tend to have insufficient levels of vit. D, due to corticosteroid treatment, reduced sun exposure while taking azathioprine. The role of vit. D in inflammation is worth discussing, as it may have a potential effect on inflammatory markers. In CD is a higher risk of bile acid diarrhea in terminal ileitis or ileocolitis. Serum FGF-19 concentrations in CD may be dependent on vit. D. It is also possible that bile acid diarrhea could be affected by vit. D status.

Investigation of the protective effects of dichloroacetic acid in a rat model of diabetic neuropathy

BackgroundDiabetic neuropathy (DN) is a heterogeneous condition characterized by complex pathophysiological changes affecting both autonomic and somatic components of the nervous system. Inflammation and oxidative stress are recognized contributors to the pathogenesis of DN. This study aims to evaluate the therapeutic potential of dichloroacetic acid (DCA) in alleviating DN symptoms, focusing on its anti-inflammatory and antioxidant properties.MethodsThirty-two adult male Sprague Dawley rats were divided into four groups: Control, Diabetic, and two DCA-treated groups receiving 5 mg/kg and 10 mg/kg of DCA, respectively. Diabetes was induced with streptozotocin (STZ) injections. Assessments included lipid peroxidation levels, plasma fibroblast growth factor-21 (FGF-21) and transforming growth factor-beta (TGF-β) levels, electrophysiological measurements, histological examination of the sciatic nerve, and motor function tests.ResultsTreatment with DCA significantly reduced malondialdehyde (MDA) levels, indicating decreased lipid peroxidation. Plasma TGF-β levels were also lower in the DCA-treated groups, suggesting diminished inflammation. Conversely, plasma FGF-21 levels were elevated. Electrophysiological assessments revealed enhanced compound muscle action potential (CMAP) amplitudes and reduced distal latencies in DCA-treated rats, indicative of improved nerve conduction. Histopathological examinations showed reduced perineural thickness in the sciatic nerves of DCA-treated rats, pointing to decreased fibrosis. Enhanced performance in motor function tests was observed in these rats, implying improved muscle strength and motor capacity.ConclusionsThe study demonstrates that DCA therapy significantly reduces oxidative stress and inflammation in a rat model of DN, thereby ameliorating neuropathic symptoms. These results support the potential of DCA as a promising therapeutic agent for DN treatment. Further research is warranted to explore its clinical applications and to provide more detailed insights.

Fibroblast growth factor 21: a novel link in the development and treatment of metabolic disorders

In recent years, fibroblast growth factor 21 (FGF21) has garnered increasing attention as a metabolic regulator. It plays a role in the development of tissue insulin sensitivity, exerts beneficial effects on carbohydrate and lipid metabolism, and exhibits antihyperglycemic and antilipidemic properties. Elevated FGF21 levels have been observed in patients with type 2 diabetes, obesity, non-alcoholic fatty liver disease, and a range of other conditions. This may indicate either resistance to FGF21 or a compensatory response to metabolic stress. Evidence suggests that FGF21 can be considered both a marker of several metabolic disorders and a potential therapeutic agent for the treatment of significant societal health issues. Objective. The objective of this review is to summarize the data published to date in the literature, including meta-analyses, reviews, and original studies, focusing on the diagnostic and potential therapeutic role of FGF21 in metabolic disorders.

METTL14 knockdown attenuates neuron injury and improves function recovery after spinal cord injury via regulating FGF21 in a m6A-IGF2BP1 dependent mechanism.

Fibroblast growth factor 21 (FGF21) and Methyltransferase-like 14 (METTL14) have been identified to be involved in spinal cord injury (SCI). However, whether FGF21 functioned in SCI via METTL14-induced N6-methyladenosine (m6A) modification remains unclear. PC12 cells were exposed to lipopolysaccharide (LPS) in vitro. qRT-PCR and western blotting analyses were applied to detect the mRNA and protein levels of METTL14, FGF21 and Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1). The CCK-8 assay, EdU assay, flow cytometry and ELISA analysis were used to conduct in vitro functional analyses. Cell ferroptosis was assessed by measuring the levels of Fe2+, reactive oxygen species, glutathione and related regulators. The N6-methyladenosine (m6A) modification profile was analyzed by methylated RNA immunoprecipitation (MeRIP) assay. The interaction between IGF2BP1 and FGF21 was validated using RIP assay. SCI animal models were constructed for in vivo analysis. Levels of FGF21 were decreased in LPS-induced PC12 cells. Functionally, FGF21 overexpression reversed LPS-induced proliferation inhibition, apoptosis, ferroptosis and inflammation in PC12 cells. Mechanistically, METTL14 induced FGF21 m6A modification in SCI cell models, and m6A-binding protein IGF2BP1 was involved in regulating FGF21 expression by METTL14. METTL14 silencing abolished LPS-induced neuronal apoptosis, inflammation and ferroptosis via regulating FGF21. Moreover, METTL14 silencing improved neuronal injury in SCI rat models by modulating FGF21 expression. METTL14 knockdown attenuates neuron injury and improves function recovery after SCI via up-regulating FGF21 in an m6A-IGF2BP1 dependent mechanism, suggesting a useful target for SCI recovery.

Circulating fibroblast growth factor 21 levels in gestational diabetes mellitus and preeclampsia: a systematic review and meta-analysis

BackgroundThe connection between fibroblast growth factor 21 (FGF21) and the likelihood of gestational diabetes mellitus (GDM) or preeclampsia (PE) has received more attention recently. Based on published articles, meta-analysis were conducted to explore the differences in FGF21 levels in GDM or PE compared to control groups.MethodsArticles published before April 5, 2024 were searched across four databases: PubMed, Web of Science, Embase, and Cochrane Library, and studies exploring the association of FGF21 levels and GDM or PE were collected. Additionally, ClinicalTrials.gov was also searched for completed and ongoing trials. (Prospero Registration CRD42024504738). The standardized mean differences (SMDs) and 95% confidence intervals (CIs) were utilized to determine FGF21 levels among different groups.ResultsThis analysis incorporated a total of 16 articles, with 714 GDM and 701 non-GDM in the control group. The GDM-affected pregnant women had greater levels of circulating FGF21 than the control group (SMD = 0.529, 95% CI: 0.168 ~ 0.890, p = 0.004). Moreover, the PE case group covered 120 while the control group contained 134. The findings indicated that pregnant women with PE had significantly greater levels of circulating FGF21 than healthy expectant mothers (SMD = 0.743, 95% CI: 0.527 ~ 0.958, p = 0.000).ConclusionsOur study found that FGF21 has the potential to serve as a diagnostic marker for GDM or PE. However, due to the limited number of studies and the fact that most data were from the second and third trimesters of pregnancy, more large-scale prospective studies are needed to validate these conclusions, investigate the potential of FGF21 in enabling early diagnosis, and further examine the role of FGF21 in the development and progression of GDM/PE.Trial registrationNot applicable.

Correlation between serum levels of fibroblast growth factor-21 and the severity of migraine headache in patients undergoing sodium valproate treatment

Background: Mitochondrial metabolism disruption increases neuron excitability and reduces migraine attack threshold. This study investigates whether serum fibroblast growth factor-21 (FGF-21) levels in chronic migraine relate to headache severity and response to sodium valproate treatment. Methods: This pilot study involved 30 patients with chronic migraine treated with sodium valproate. Serum FGF-21 levels were assessed at baseline and after 12 weeks of treatment. Pain severity and disability were evaluated using visual analogue scale (VAS) and Migraine Disability Assessment (MIDAS). Paired t-test was used for the quantitative variables. The qualitative variables were evaluated using Pearson’s chi-square test and Fisher’s exact test. Moreover, correlation coefficients were calculated. A P < 0.05 was considered statistically significant. Results: Mean age of the patients was 42.9 ± 11.3 years. There was a significant reduction in headache severity between baseline and the end of the study regarding VAS scores (8.50 ± 1.50 vs. 5.30 ± 2.20, P < 0.001). The same reduction was observed in MIDAS during the study (61.20 ± 33.20 vs. 20.31 ± 17.07, P < 0.001). However, there was no significant changes in serum levels of FGF-21 over three months (299.53 ± 479.80 vs. 491.33 ± 456.64, P = 0.810), nor any relationship between these levels and headache severity scores (MIDAS: P = 0.658, VAS: P = 0.708). Conclusion: The results of this study did not show a significant correlation between FGF-21 serum levels and changes in VAS and MIDAS throughout the study. Further research on various mitochondrial pathways can provide valuable insights into the migraine pathophysiology and help identify more effective biomarkers for monitoring therapeutic regimens.

The association between circulating irisin, osteocalcin and FGF21 levels with anthropometric characteristics and blood lipid profile in young obese male subjects.

Myokines secreted from skeletal muscle such as irisin, osteokines secreted from bone such as osteocalcin, and hepatokines secreted from the liver such as fibroblast growth factor 21 (FGF21) play a role in the regulation of metabolic homeostasis. However, the changes that occur in obesity and the interaction between them have not been fully explained. Therefore, this study aimed to compare irisin, osteocalcin and FGF21 levels in young obese males against individuals with normal body weight and to reveal the possible relationship between them and with anthropometric measurements and blood lipid profile. This single-center study included 28 Turkish young males aged 20-29 years: 14 obese participants with a body mass index (BMI) between 30.0-34.9 and 14 healthy controls with a BMI between 18.5-24.9. Anthropometric, and body composition parameters, blood lipid profile, and irisin, osteocalcin and FGF21 levels of groups were measured. Correlation analyses were performed between irisin, osteocalcin, and FGF21 and other measured parameters. Circulating irisin, osteocalcin and FGF21 levels were significantly higher in the obese group than in the control group (p < 0.05). Correlation analysis showed that irisin was positively correlated with total cholesterol, triglycerides and low density lipoprotein-cholesterol (LDL-C) and FGF21 was positively correlated with total cholesterol and LDL-C (p < 0.05). Positive correlation between irisin and osteocalcin, FGF21 and osteocalcin and FGF21 and irisin was observed (p < 0.05). Irisin, osteocalcin, and FGF21 have a potential role in the pathophysiology of obesity and related metabolic diseases due to their interactions.

Fibroblast Growth Factor 21 Confers Protection Against Asthma Through Inhibition of NLRP3 Inflammasome Activation.

Fibroblast growth factor 21 (FGF21) modulates the inflammatory response in a range of pathological conditions. However, whether FGF21 modulates asthma remains unexplored. This study sought to investigate its function in asthma using an ovalbumin (OVA)-induced mouse model. Levels of FGF21 were observed to be elevated in mice exhibiting asthmatic symptoms. FGF21 knockout (KO) mice exhibited exacerbated asthmatic pathologies, marked by heightened infiltration of inflammatory cells and elevated release of inflammatory cytokine, compared to wild-type (WT) mice with OVA challenge. Adeno-associated virus (AAV)-mediated overexpression of FGF21 significantly reversed asthmatic pathologies in both WT and FGF21 KO mice. Activated NLRP3 inflammasome was observed in WT mice following OVA challenge, and this response was intensified in FGF21 KO mice, manifested by an upregulation of NLRP3, ASC, cleaved Caspase-1, cleaved Gasdermin D (GSDMD), IL-1β, and IL-18. Pharmacological suppression of NLRP3 ameliorated the aggravated asthmatic pathologies observed in FGF21 KO mice after OVA challenge. Overall, the present work underscores the pivotal function of FGF21 in the pathogenesis of asthma and suggests that FGF21 could serve as a potential target for therapeutic interventions.

Sulfur Amino Acid Restriction Mitigates High-Fat Diet-Induced Molecular Alterations in Cardiac Remodeling Primarily via FGF21-Independent Mechanisms.

Background/Objectives: Dietary sulfur amino acid restriction (SAAR) elicits various health benefits, some mediated by fibroblast growth factor 21 (FGF21). However, research on SAAR's effects on the heart is limited and presents mixed findings. This study aimed to evaluate SAAR-induced molecular alterations associated with cardiac remodeling and their dependence on FGF21. Methods: Male C57BL/6J wild-type and FGF21 knockout mice were randomized into four dietary regimens, including normal fat and high-fat diets (HFDs) with and without SAAR, over five weeks. Results: SAAR significantly reduced body weight and visceral adiposity while increasing serum FGF21 levels. In the heart, SAAR-induced molecular metabolic alterations are indicative of enhanced lipid utilization, glucose uptake, and mitochondrial biogenesis. SAAR also elicited opposing effects on the cardiac gene expression of FGF21 and adiponectin. Regarding cellular stress responses, SAAR mitigated the HFD-induced increase in the cardiac expression of genes involved in oxidative stress, inflammation, and apoptosis, while upregulating antioxidative genes. Structurally, SAAR did not induce alterations indicative of cardiac hypertrophy and it counteracted HFD-induced fibrotic gene expression. Overall, most alterations induced by SAAR were FGF21-independent, except for those related to lipid utilization and glucose uptake. Conclusions: Altogether, SAAR promotes cardiac alterations indicative of physiological rather than pathological remodeling, primarily through FGF21-independent mechanisms.

Serum fibroblast growth factor 21: Lack of association with gestational diabetes and pregnancy outcomes

BACKGROUND The prevalence of gestational diabetes mellitus (GDM) has been increasing worldwide and is associated with multiple adverse pregnancy outcomes. Despite standard screening, some cases remain undiagnosed. Fibroblast growth factor 21 (FGF21) plays a role in modulating glucose metabolism. There is an ongoing controversy regarding the relevance of FGF21 to GDM. AIM To evaluate the association between early second trimester serum FGF21 levels and gestational diabetes, and its predictive potential for outcomes. METHODS This cross-sectional observational study was conducted at a tertiary medical center, Chiang Mai University, Thailand. It included 28 pregnant women diagnosed with GDM and 81 pregnant women with normal glucose status. Blood samples were collected according to the study schedule, and pregnancy outcomes were recorded meticulously. Descriptive analysis was employed to evaluate the data. RESULTS Most participants in our study had no risk factors for GDM (body mass index &lt; 24 kg/m2, no first-degree relatives with diabetes, no history of GDM), normal baseline glucose status (fasting glucose &lt; 110 mg/dL), and no insulin resistance (homeostatic model assessment of insulin resistance &lt; 2). There was a trend of increased FGF21 levels in the insulin-treated GDM group compared with dietary-treated GDM and non-GDM (73.58 pg/mL vs 62.94 pg/mL vs 63.59 pg/mL, respectively, P = 0.73). However, no significant association was found between FGF21 concentrations and pregnancy outcomes based on quintiles of FGF21 levels. CONCLUSION FGF21 was not associated with GDM or pregnancy outcomes; however, due to the small sample size, larger clinical trials with a diverse population are suggested to confirm these results.

Cross-sectional and Mendelian randomization study of fibroblast growth factor 19 reveals causal associations with metabolic diseases.

Fibroblast growth factor 19 (FGF19) is an intestinal-derived factor that plays a role in metabolic diseases. We performed a differential study of circulating FGF19 levels and investigated the causal effects of FGF19 on metabolic diseases using Mendelian randomization (MR). Firstly, 958 subjects were included in the physical examination center of affiliated hospital from January 2019 to January 2021. Dividing the subjects into different subgroups to compare FGF19 levels. We conducted a two-sample MR analysis of genetically predicted circulating FGF19 in relation to alcohol, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available genome-wide association study summary statistics data. The circulating FGF19 levels in nonalcoholic fatty liver disease (NAFLD) patients were lower than those without NAFLD (P<0.001). The FGF19 levels in participants with obese were lower than those without obese (P<0.001). In two-sample MR analyses, genetically predicted higher circulating FGF19 levels was significantly associated with lower aspartate aminotransferase, γ-glutamyltransferase, triglycerides, total cholesterol, low-density lipoprotein, and C-reactive protein concentrations (P<0.05) and a negative correlation with cardiovascular disease and cirrhosis whereas a positive association with type 2 diabetes mellitus (P<0.05). Our study found that circulating FGF19 levels were lower in NAFLD and obese populations. Additionally, our MR research results support the causal effects of FGF19 on improved liver function, lipids, and reduced the occurrence of inflammation, cardiovascular disease, and cirrhosis. We found a positive correlation with diabetes, which may indicate a compensatory increase in regulating above FGF19 resistance states in humans.

The role of the glucagon-FGF21 axis in improving beta cell function during glucose intolerance and SGLT2 inhibition.

Although primarily secreted by the liver, Fibroblast Growth Factor 21 (FGF21) is also expressed in the pancreas, where its function remains unclear. This study aims to elucidate the role of the glucagon-FGF21 interaction in the metabolic benefits of SGLT2 inhibition (SGLT2i) and hypothesizes it is key to enhancing glucose and lipid metabolism in individuals with glucose intolerance or type 2 diabetes (T2D). FGF21, FGF1R, and β-klotho expression in human pancreas was analysed by RNAscope, qPCR and immunofluorescent techniques. Glucose-stimulated insulin secretion (GSIS) assay was used to investigate the effects of recombinant FGF21 (rFGF21) on islets from donors with glucose intolerance or T2D. To explore the role of the glucagon-FGF21 axis in the benefits of SGLT2i, we used WT and Sglt2 knockout (KO) mice fed a chow diet (CD) or a high-fat diet (HFD) and chronically treated with vehicle or dapagliflozin. Chronic rFGF21 treatment enhanced GSIS in islets from donors with glucose intolerance, with increased FGFR1 expression, suggesting FGF21's greater efficacy in the early stages of disease. In diet-induced insulin-resistant mice, dapagliflozin reduced postprandial glycaemia and elevated plasma glucagon and FGF21 levels. Sglt2 KO mice on a CD showed increased fasting plasma glucagon without changes in FGF21. In diet-induced insulin-resistant Sglt2 KO mice, elevated glucagon and FGF21 levels paralleled chronic dapagliflozin treatment, indicating similar metabolic adaptations in both models. Our findings indicate FGF21 as a crucial mediator in liver-pancreas crosstalk, improving lipid and glucose metabolism, enhancing pancreatic function, and potentiating the therapeutic efficacy of SGLT2i, thereby representing a target for prediabetes treatment.

Plasma fibroblast growth factor 21 and risk of cognitive impairment among patients with ischemic stroke

Background and aimsPrevious study reported that plasma fibroblast growth factor 21 (FGF-21) was associated with poor prognosis in patients with ischemic stroke. The purpose of present study was to prospectively investigate the relationship between plasma FGF-21 and post-stroke cognitive impairment (PSCI). MethodsA total of 600 patients from 7 hospitals were included in this study and plasma FGF-21 levels were examined for all the participants. Cognitive impairment was evaluated using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at 3 months after ischemic stroke onset. Results323(53.8 %) or 419(69.8 %) participants had PSCI according to MMSE or MoCA at 3 months, respectively. After adjustment for age, National Institutes of Health stroke score, education, and other covariates, the odds ratio of PSCI defined by MMSE and MoCA for the highest vs lowest quartile of plasma FGF-21 was 1.77(1.05–2.98) and 2.40(1.35–4.29), respectively. Multiple-adjusted spline regression model showed a linear association between FGF-21 levels and PSCI (all P < 0.005 for linearity). Subgroup analyses further confirmed these results. ConclusionElevated plasma FGF-21 level was associated with PSCI at 3 months after stroke independently of established conventional risk factors, suggesting that plasma FGF-21 may have potential prognostic value in risk stratification of PSCI.

Intranasal administration of mesenchymal stem cells overexpressing FGF21 demonstrates therapeutic potential in experimental Parkinson's disease

Parkinson's disease (PD) is a prevalent movement disorder characterized by mitochondrial dysfunction and dopaminergic neuronal loss in the substantia nigra of the midbrain. Currently, there are no effective treatments to cure or slow the progression of PD, highlighting an urgent need for new therapeutic strategies. Emerging evidence suggests that mesenchymal stem cells (MSCs) and fibroblast growth factor 21 (FGF21) are potential candidates for PD treatment. This study investigates a therapeutic strategy involving FGF21 delivered via mouse MSCs in the PD model of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and dopaminergic SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+). FGF21-overexpressing MSCs were administered intranasally, either before or after MPTP treatment in mice. Intranasally delivered FGF21-overexpressing MSCs efficiently migrated to the injured substantia nigra, ameliorated MPTP-induced PD-like motor deficits, reinstated dopaminergic neurons in the substantia nigra and nerve terminals in the striatum, as well as normalized brain-derived neurotrophic factor (BDNF) and FGF21 levels. In contrast, MSCs not overexpressing FGF21 showed limited or no impact on these parameters. In a PD cellular model of MPP+-treated SH-SY5Y cells, FGF21-overexpressing MSCs showed enhanced PD cell viability. Treatment with conditioned medium from FGF21-overexpressing MSCs or exogenous FGF21 prevented cell death, reduced mitochondrial reactive oxygen species (ROS), and restored neuroprotective proteins, including phospho-Akt, BDNF, and Bcl-2. These findings indicate that intranasal delivery of FGF21-overexpressing MSCs holds promise as a potential PD therapy, likely through activating the Akt-BDNF-Bcl-2 pathway, normalizing mitochondrial dysfunction, and mitigating dopaminergic neurodegeneration. Further clinical investigations are essential to validate these promising findings.

The potential of fibroblast growth factor-21 and adiponectin as diagnostic biomarkers for type 2 diabetes mellitus: differential levels in response to treatments

BackgroundDiabetes mellitus (DM) is a global epidemic disease affecting millions each year. Recent studies have suggested novel biomarkers that are linked to DM. This study aimed to measure the levels of fibroblast growth factor-21 (FGF-21) and adiponectin in the blood of patients with type 2 DM and to assess the variations in their levels in response to the type of treatments. The possible correlations with several biochemical parameters and the diagnostic potential of FGF-21 and adiponectin as biomarkers for DM were also investigated. Eighty subjects were classified into control, Type 2 DM patients who were treated with metformin, Type 2 DM patients who were treated with metformin + oral hypoglycemic agents (OHAs), and Type 2 DM patients who were treated with insulin + metformin + OHAs.ResultsThe metformin + OHAs group and the insulin + metformin + OHAs group had higher levels of FGF-21 when compared to the control group. The metformin + OHAs also had significantly higher adiponectin levels when compared to the control or metformin groups. The serum levels of FGF-21 in the diabetic subjects were negatively correlated with LDL, direct bilirubin, albumin, and insulin levels and positively correlated with the duration of DM. However, the serum levels of adiponectin in the diabetic subjects were negatively correlated with weight while positively correlated with potassium levels. Remarkably, FGF-21 and adiponectin were effective biomarkers for diagnosing DM with a specificity of 100% and 90% and sensitivity of 52.3% and 64.5%, respectively.ConclusionThese findings suggest that FGF-21 and adiponectin play crucial roles in DM diagnosis and prognosis and that their levels change depending on the treatment type.

Activation of fibroblast growth factor 21 by Canagliflozin reduces high-fat diet associated obesity-related cardiac injury: a translational study from bench to bedside

Abstract Aims/hypothesis Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are indicated for the treatment of type 2 diabetes, and evidence shows that they may confer a cardioprotective effect to reduce the incidence of cardiovascular conditions in obese type 2 diabetes patients. The mechanisms underlying this effect remain unclear, but an SGLT2i, canagliflozin (CANA), has been reported to increase levels of fibroblast growth factor-21 (FGF21) and enhance activation of its downstream target proteins. We thus aimed to study whether the effect on FGF21 by CANA can reduce obesity-related cardiac injury. Methods 1) Animal study: Sixteen-week-old normal diet and high-fat diet male mice were treated with or without 30 mg/kg CANA once a day for 24 weeks, and were subsequently examined for body weight, blood glucose levels, adipose tissue changes, lipid accumulation in the liver, and cardiac function. 2) Cell study: An in vitro study that treated H9c2 cardiomyocyte cells cultured in a simulated high-lipid environment containing palmitic acid (PA) with FGF21 recombinant protein was also conducted to examine protein expression profiles. Furthermore, the effect of CANA on FGF21 expression. 3) Human clinical trial: A randomized double-blinded control trial (NCT 05764811) was performed to test effect of CANA on MRI liver fibrosis scores of obese type 2 diabetes patients (n = 40). Results 1) High-fat diet mice treated with CANA for 24 weeks had lower average body weight than untreated controls (34 g vs. 40 g, p &amp;lt; 0.001). In addition, CANA treatment stimulated FGF21 protein production in liver tissue and plasma at higher levels for both normal diet and high-fat diet mice, and reduced expression levels of proteins associated with fibrosis and apoptosis. 2) H9c2 cardiomyocyte culture studies suggested that a simulated high-lipid environment with PA caused higher expression of apoptotic proteins, but the addition of FGF21 recombinant protein significantly reduced apoptosis signalling. 3) MRI before and after 4 weeks of CANA treatment in obese type 2 diabetes patients showed a significant reduction in liver fibrosis scores for those receiving CANA treatment. Conclusion CANA treatment stimulated FGF21 protein expression and reduced fibrosis and apoptosis signalling protein expression. Moreover, reductions in liver fibrosis scores were observed in obese type 2 diabetes patients treated with CANA. Taken together, this suggests that CANA-induced FGF21 expression may exert a cardioprotective effect against fibrosis and apoptosis and can potentially reduce the risk of obesity-related cardiac injury.

Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy

The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation, and hepatocyte injury, which can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models. AAV1-FGF21 treatment also counteracted obesity, adiposity, and insulin resistance, which are significant drivers of MASH. Scale-up to large animals successfully resulted in safe skeletal muscle biodistribution and biological activity in key metabolic tissues. Moreover, as a step toward the clinic, circulating FGF21 levels were characterized in obese, insulin-resistant and MASH patients. Overall, these results underscore the potential of the muscle-directed AAV1-FGF21 gene therapy to treat MASH and support its clinical translation.

Low Serum Fibroblast Growth Factor 21 Level and Its Altered Regulation by Thyroid Hormones in Patients with Hashimoto's Thyroiditis on Levothyroxine Substitution.

Fibroblast growth factor 21 (FGF21) is a hormonal regulator of lipid and glucose metabolism exerting protection against atherosclerosis by multiple actions on the blood vessels, liver, and adipose tissues. We aimed to investigate serum FGF21 level and its relation to thyroid hormones and metabolic parameters among patients with Hashimoto's thyroiditis (HT). Eighty patients with HT on levothyroxine treatment and eighty-two age- and BMI-matched adults without thyroid disease serving as controls were enrolled. Serum FGF21 concentrations were determined with an enzyme-linked immunosorbent assay. Median serum FGF21 level was significantly lower in HT patients compared with controls (74.2 (33.4-148.3) pg/mL vs. 131.9 (44.8-236.3) pg/mL; p = 0.03). We found a positive correlation between FGF21 and age, triglyceride, total cholesterol, and low-density lipoprotein cholesterol in both groups, while thyroid stimulating hormone and C-reactive protein showed a positive correlation, and thyroxine had an inverse correlation with FGF21 only in control subjects. According to multiple regression analyses, thyroid status is the main predictor of FGF21 in healthy controls, while it is not a significant predictor of FGF21 among HT patients on levothyroxine supplementation therapy. Our results indicate that the physiological role of thyroid function in the regulation of FGF21 synthesis is impaired in HT patients, which may contribute to the metabolic alterations characteristic of HT patients.