FGF21 Levels Research Articles

Identification of growth differentiation factor 15 as an early predictive biomarker for metabolic dysfunction-associated steatohepatitis: A nested case-control study of UK Biobank proteomic data.

This study aims to determine the predictive capability for metabolic dysfunction-associated steatohepatitis (MASH) long before its diagnosis by using six previously identified diagnostic biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) with proteomic data from the UK Biobank. A nested case-control study comprising a MASH group and three age- and sex-matched control groups (metabolic dysfunction-associated steatosis, viral hepatitis and normal liver controls) was conducted. Olink proteomics, anthropometric and biochemical data at baseline levels were obtained from the UK Biobank. The baseline levels of CDCP1, FABP4, FGF21, GDF15, IL-6 and THBS2 were analysed prospectively to determine their predictive accuracy for subsequent diagnosis with a mean lag time of over 10 years. At baseline, GDF15 demonstrated the best performance for predicting MASH occurrence at 5 and 10 years later, with AUCs of 0.90 at 5 years and 0.86 at 10 years. A predictive model based on four biomarkers (GDF15, FGF21, IL-6 and THBS2) showed AUCs of 0.88 at both 5 and 10 years. Furthermore, a protein-clinical model that included these four circulating protein biomarkers along with three clinical factors (BMI, ALT and TC) yielded AUCs of 0.92 at 5 years and 0.89 at 10 years. GDF15 at baseline levels outperformed other individual circulating protein biomarkers for the early prediction of MASH. Our data suggest that GDF15 and the GDF15-based model may be used as easy-to-implement tools to identify patients with high risks of developing MASH at a mean lag time of over 10 years.

Deletion of Arntl, a component of the molecular clock, in adipocytes leads to cellular hypertrophy by increasing insulin sensitivity via FGF21

Brain and muscle Arnt-like protein 1 (BMAL1), encoded by Aryl hydrocarbon receptor nuclear translocator like 1 (Arntl) gene, is a transcription factor that regulates the circadian rhythm of the expressions of several genes. The link between the loss of BMAL1 function in adipose tissue and obesity has been reported. Although these previous studies have suggested that dysregulation of lipolysis is a contributing factor, but the detailed mechanism has not been fully understood. This study aimed to elucidate the role of BMAL1 in adipocytes using adipocyte-specific Arntl deficient (AAKO) mice. Deletion of Arntl in adipocytes leads to increased cellular insulin sensitivity, which in turn, inhibited lipolysis in adipocytes and caused cellular hypertrophy. The expression levels of Fgf21 in adipose tissue were significantly elevated in AAKO mice compared to Arntlflox/flox mice. Double knockout of Arntl and Fgf21 in adipocytes abolished metabolic phenotypes such as decreased circulating non-esterified fatty acid levels, adipocyte hypertrophy, and increased insulin sensitivity in AAKO mice. These results indicated that BMAL1 regulates fat mobilization and insulin signaling in adipocytes via FGF21 during the stationary phase. This is the possible mechanism by which disruption of circadian rhythm induces obesity.

Separate and Combined Effects of Moderate-Intensity Exercise Training and Detraining with Protocatechuic Acid (PCA) on Myokines and Insulin-Signaling Pathways in Male Wistar Rats: A Preclinical Randomized Study

Background: Exercise training positively modulates myokine secretion and improves glucose metabolism. Herein, we analyzed the effect of moderate-intensity training, detraining, and Protocatechuic Acid (PCA) supplementation on myokine secretions and regulation of insulin-signaling pathways. Methods: A five-arm study was conducted on 47 healthy male Wistar rats, trained at a moderate intensity level for four weeks (T0-T4). Animals were randomly classified into groups according to PCA supplementation and exercise durations: four weeks of Aerobic Training with or without PCA (AT4, AT4-PCA), eight weeks of Aerobic Training with or without PCA (AT8, AT8-PCA), and PCA Vehicle Control (VC). The animals were followed up until week 12 (T12). We decapitated six rats at T0 and T4, four rats per group at T8, and three rats per group at T12. Myokines (IGF-1, IL-6, FGF-21, myostatin, and irisin) were analyzed with ELISA. Western blot analysis measured protein expression of insulin-signaling pathways and GLUT-4 in the gastrocnemius muscle. Results: The IL-6 levels increased significantly (p < 0.01) with 8-week training in AT8 by 34% and AT8-PCA by 32%, compared to groups trained for only 4 weeks (AT4 and AT4-PCA). Similarly, the PI3K, and GLUT-4 expression improved in AT8 and AT8-PCA at T8. Training for 4 weeks improved IGF-1 levels, but a further 14% improvement was observed with 8-week training in AT8 at T8. Myostatin level significantly dropped by 27% even with 4-week training (p < 0.001). However, detraining increased the myostatin levels in all groups, but in AT8-PCA with PCA dose, myostatin reduced by 11% compared to AT8 at T12. PCA supplementation reduced the FGF-21 levels by 54% during detraining at T12 in AT8-PCA compared to AT8. However, the irisin level did not change markedly in any group. Conclusions: Physical training (with and without PCA) modulates myokine production and improves glucose metabolism, but the benefits are lost after detraining.

Multiomics unravels the complexity of male obesity: a prospective observational study

BackgroundObesity is associated with varying degrees of metabolic dysfunction. In this study, we aimed to discover markers of the severity of metabolic impairment in men with obesity via a multiomics approach.MethodsThirty-two morbidly men with obesity who were candidates for Roux-en-Y gastric bypass (RYGB) surgery were prospectively followed. Nine healthy adults served as controls. Deep phenotyping, including targeted metabolomics, transcriptomics, and brain magnetic resonance imaging (MRI), was performed.ResultsTestosterone emerged as a key contributor to phenotypic variability via principal component analysis and was therefore used to further categorize obese patients as having or not having hypogonadotropic hypogonadism (HH). Despite having comparable body mass indices, obese individuals with HH presented with worse metabolic defects than obese individuals without HH, including higher insulin resistance, as well as MRI signs of hypothalamic inflammation and a specific blood transcriptomics signature. The upregulated genes were involved mainly in inflammation, mitochondrial function, and protein translation. Integration of gene expression and clinical data revealed high FGF21 and low cortisol levels as the top markers correlated with the transcriptomic signature of metabolic risk. Following RYGB-induced substantial weight loss, testosterone levels markedly increased in both obese individuals with and without HH, challenging the current definition of hypogonadism. A longitudinal study in a subset of men with obesity following bariatric surgery revealed a unique FGF21 trajectory with a sharp peak at one month post-RYGB that correlated with metabolic and reproductive improvements.ConclusionsCombining clinical, biochemical, and molecular markers allows adequate stratification of metabolic risk in men with obesity and provides novel tools for personalized care.

Increased FGF-19 levels following explantation in women with breast implant illness

Breast Implant Illness (BII) is characterized by a cluster of systemic and local symptoms affecting a subset of women with silicone breast implants. While symptom improvement is frequently observed following implant removal, the underlying mechanisms remain poorly understood, and the absence of reliable biomarkers complicates clinical decision-making. Here, we investigate inflammatory protein profiles in 43 women with BII, comparing pre- and post-explantation levels using the Olink Target 96 Inflammation panel and Meso Scale Discovery technology for absolute quantification. Sixteen inflammatory proteins, including MCP-1, CD8A, and CCL11, were elevated post-explantation, with FGF-19 showing the most pronounced increase (64%). FGF-19 levels increased from a median of 136 pg/mL to 195 pg/mL (p = 0.001), comparable to levels in women with silicone breast implants but no BII. We propose that explantation may alleviate FGF-19 signaling disruption, restoring its metabolic benefits. These findings suggest FGF-19 as a potential diagnostic and therapeutic marker for BII, warranting further investigation.

Effects of exercise intensity and diet on cardiac tissue structure and FGF21/β-Klotho signaling in type 2 diabetic mice: a comparative study of HFD and HFD + STZ induced type 2 diabetes models in mice

BackgroundStructural heart disease is one of the leading causes of death in people with type 2 diabetes (T2D), which is not known to have an effect on exercise training. The aim of this study was to compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on heart tissue structure, the serum level of FGF21 and the heart tissue level of β-Klotho, an FGF21 coreceptor, in HFD and HFD + STZ-induced diabetic mice.MethodsThirty-six male C57BL/6J mice were divided into high-fat diet (HFD) and normal chow diet (ND) groups. After 20 weeks of diet, the HFD mice were divided into HFD and HFD + STZ groups, and the latter group was injected with STZ. Then, the mice in the ND, HFD and HFD + STZ groups were divided into three subgroups of control (C), HIIT and MICT, and mice were placed in one of nine groups ND-C, ND-HIIT, ND-MICT, HFD-C, HFD-HIIT, HFD-MICT, HFD + STZ-C, HFD + STZ-HIIT, and HFD + STZ-MICT. The mice in the exercise training (ET) groups were run on a treadmill for eight weeks. Finally, the tissue and serum samples were collected and analyzed by two-way ANOVA.ResultsStatistical analyses showed that the main effect of diabetes inducing model (DIM) was significant for all variables (p < 0.05), except vascular density (p = 0.055); the main effect of ET type on fasting blood glucose and FGF21 was significant (p < 0.001); and the interaction was significant for fasting blood glucose, heart weight and FGF21 (p < 0.001). Post hoc and subgroup analysis showed a superior effect of MICT over HIIT in decreasing fasting blood glucose and serum level of FGF21 (p < 0.001). Additionally, the results of the myocardial tissue qualitative analyses differed between the diabetic mouse models and the ET groups.ConclusionsIn a mouse model, type 2 diabetes can negatively affect heart tissue structure and FGF21 signaling in cardiac tissue, and both HIIT and MICT can prevent this effect. However, MICT likely more effective that HIIT in reducing circulating FGF21.

Effects of fibroblast growth factor 21 serum level on clinicopathological findings in papillary thyroid carcinoma.

This research examined the connection between circulating FGF21 and clinicopathological findings in papillary thyroid carcinoma. This analytical cross-sectional research was conducted on patients with papillary thyroid cancer at the Seyyed Shirazi Endocrinology Clinic in Gorgan, Iran. Laboratory data, including demographics, ultrasonography and pathology reports, and FGF21 levels, were collected. The data was analyzed with SPSS 25. Normal distribution was evaluated by using Kolmogorov-Smirnov and Shapiro-Wilk tests. Group differences were evaluated with Chi-square, independent sample t-test and Mann-Whitney U tests. A p-value less than 0.05 was considered significant. In this research, 83% of patients were female, and the mean±SD age was 42.51±13.28 years old. The mean±SD and FGF21 concentrations in 49 patients were 716.41±458.7, the median was 489 pg/ml, and 24 (49%) patients were in the high FGF21 group. There was no statistically significant relation between FGF21 level and age (P=0.95), sex (P=>0.99), tumor size (P=0.68), tumor stage (P=>0.99), lymphadenopathy (P=>0.99), lymph node metastasis (P=0.24), triglycerides (P=0.93), total cholesterol (P=0.47), LDL (P=0.08), and HDL (P=0.08). However, FGF21 levels were significantly associated with fasting blood glucose (P=0.03), body mass index (BMI) (P=<0.0001), capsular invasion (P=0.001), lymphovascular involvement (P=0.0001) and Thyroid Imaging Reporting and Data System (TIRADS) score (P=0.02). In addition, high levels of FGF21 were found to be 78.95% sensitive and 70% specific for capsular invasion. Our study demonstrated that FGF21 is associated with more severe papillary thyroid cancer clinicopathological features such as capsular invasion, lymphovascular involvement, TIRADS score, and BMI.

Reduction of Hepatic Fat Content by Dulaglutide for the Treatment of Diabetes Mellitus: A Two-Centre Open, Single-Arm Trial.

With the elevated level of NAFLD prevalence, the incidence of diabetes, hypertension, metabolic syndrome and other diseases is also significantly elevated. GLP-1RA can exert weight loss, glucose-lowering effects and various nonglycaemic effects. However, the relationship between quantitative reduction in hepatic fat content and improvement of pancreatic islet function by GLP-1RA is unclear. This trial was a single-arm open cohort study. A total of 38 patients with T2DM and NAFLD were enrolled in the GLP-1RA treatment group. The included patients were tested for biochemical and blood glucose levels, adiponectin and FGF21 levels, and liver fat content was measured using MRI. Measure the above indicators again after at least 3 months of GLP-1RA treatment. Divided into Q1 (average decrease of 0.37%) and Q2 (average decrease of 8.6%) groups based on the degree of reduction in liver fat content. Q2 group showed an average reduction in liver fat content of 8.6%, a decrease in glycated haemoglobin of 18.17%, a weight loss of 7.29% and an increase in fasting c-peptide release by 1.03%, 1-h and 2-h postprandial c-peptide release by 28.86% and 18.28% respectively. In contrast, Q1 group had an average reduction in liver fat content of 0.37%, a decrease in glycated haemoglobin of only 6.53%, a weight loss of 3.41%, a decrease in fasting c-peptide release by 1.91% and an increase in 1-h and 2-h postprandial c-peptide release by 19.18% and 11.66% respectively. Reduction in liver fat content effectively improves pancreatic islet function secretion, particularly postprandial c-peptide secretion, especially in the first hour after a meal. This improvement leads to a decrease in glycated haemoglobin levels and promotes better compliance with blood glucose control.

FGF21 and its underlying adipose tissue-liver axis inform cardiometabolic burden and improvement in obesity after metabolic surgery

This research investigates the determinants of circulating FGF21 levels in a cohort reflecting metabolic disease progression, examining the associations of circulating FGF21 with morphology and function of adipose tissue (AT), and with metabolic adjustments following metabolic surgery. We measured serum FGF21 in 678 individuals cross-sectionally and in 189 undergoing metabolic surgery longitudinally. Relationships between FGF21 levels, AT histology, transcriptomes and proteomes, cardiometabolic risk factors, and post-surgery metabolic adjustments were assessed using univariate and multivariate analyses, causal mediation analysis, and network integration of AT transcriptomes and proteomes. FGF21 levels were linked to central adiposity, subclinical inflammation, insulin resistance, and cardiometabolic risk, and were driven by circulating leptin and liver enzymes. Higher FGF21 were linked with AT dysfunction reflected in fibro-inflammatory and lipid dysmetabolism pathways. Specifically, visceral AT inflammation was tied to both FGF21 elevation and liver dysfunction. Post-surgery, FGF21 peaked transitorily at three months. Mediation analysis highlighted an underlying increased AT catabolic state with elevated free fatty acids (FFA), contributing to higher liver stress and FGF21 levels (total effect of free fatty acids on FGF21 levels: 0.38, p<0.01; proportion mediation via liver 32%, p<0.01). In line with this, histological AT fibrosis linked with less pronounced FGF21 responses and reduced fat loss post-surgery (FFA and visceral AT fibrosis: rho=-0.31, p=0.030; FFA and fat-mass loss: rho=0.17, p=0.020). FGF21 reflects the liver's disproportionate metabolic stress response in both central adiposity and after metabolic surgery, with its dynamics reflecting an AT-liver crosstalk. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through CRC 1052, project number 209933838, CRC1382 and a Walther-Benjamin Fellowship and by a junior research grant by the Medical Faculty, University of Leipzig, and by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501. Part of this work was supported by the European Union's Seventh Framework Program for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 and by the CRC1382 and the Novo Nordisk Foundation and by the Deutsche Forschungsgemeinschaft (DFG, German Research foundation) project number 530364326.

10045: The serum Level of adiponectin, FGF-21, and GDF-15 in Acute Myocardial Infarction in Bandung, Indonesia

10045: The serum Level of adiponectin, FGF-21, and GDF-15 in Acute Myocardial Infarction in Bandung, Indonesia

Liver-gut axis signaling regulates circadian energy metabolism in shift workers.

Circadian rhythm is critical to maintaining the whole-body metabolic homeostasis of an organism. Chronic disruption of circadian rhythm by shift work is an important risk factor for metabolic diseases. Fibroblast growth factor 15/19 (FGF15/19), a key component in the liver-gut axis, potently suppresses bile acid (BA) synthesis and improves insulin sensitivity. FGF15/19 emerges as a novel pharmaceutical target for prevention and treatment of metabolic diseases. The nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin 1 (SIRT1) deacetylase plays an important role in the maintenance of hepatic homeostasis by linking hepatic metabolism to circadian rhythm. Here, our clinical study identified that circadian rhythmicity and levels of plasma FGF19 and BA profiling, and cellular NAD+-dependent SIRT1 signaling were disturbed in night shift (NS, n = 10) compared to day shift (DS, n = 12) nurses. Our invitro data showed that recombinant FGF19 protein rescued cellular circadian rhythm disrupted by SIRT1 inhibitors. Furthermore, we determined the effect of FGF15 on circadian rhythm and hepatic metabolism in wild-type (WT), Fgf15 knockout (KO), and Fgf15 transgenic (TG) mice. The expressions of circadian-controlled genes (CCGs) involved in SIRT1 signaling, BA and lipid metabolism, and inflammation were disrupted in Fgf15 KO compared to WT and/or Fgf15 TG mice. Moreover, systemic FGF15 deficiency led to the circadian disturbance of NAD+-dependent SIRT1 signaling and significant reduction during nighttime in mice. These findings suggest that FGF15/19 regulates the circadian energy metabolism, which warrants further studies as a putative prognostic biomarker and pharmaceutical target for preventing against metabolic diseases associated with chronic shift work.

Gut Microbiota Modulates Fgf21 Expression and Metabolic Phenotypes Induced by Ketogenic Diet.

The ketogenic diet (KD) is a widely used intervention for obesity and diabetes, effectively reducing body weight and blood glucose levels. However, the molecular mechanisms by which the KD influences body weight and glucose metabolism are not fully understood. While previous research has shown that the KD affects the gut microbiota, the exact role of microbiota in mediating its metabolic effects remains unclear. In this study, we used antibiotics to eliminate the gut microbiota, confirming its necessity for the KD's impact on weight loss and glucose metabolism. We also demonstrated the significant role of FGF21 in these processes, through antibiotics intervention in Fgf21-deficient mice. Furthermore, we revealed that the KD alters serum valine levels via the gut microbiota, which in turn regulates hepatic Fgf21 expression and circulating FGF21 levels through the GCN2-eIF2α-ATF5 signaling pathway. Additionally, we demonstrated that valine supplementation inhibits the elevated expression of FGF21, leading to the reduced body weight and improved glucose metabolism of the KD-fed mice. Overall, we found that the gut microbiota from the KD regulates Fgf21 transcription via the GCN2-eIF2α-ATF5 signaling pathway. ultimately affecting body weight and glucose metabolism. Our findings highlight a complex regulatory network linking the KD, Fgf21 expression, and gut microbiota, offering a theoretical foundation for targeted therapies to enhance the metabolic benefits of the KD.

Predictive Value of NT-proBNP, FGF21, Galectin-3 and Copeptin in Advanced Heart Failure in Patients with Preserved and Mildly Reduced Ejection Fraction and Type 2 Diabetes Mellitus.

Background and Objectives: Heart failure (HF) is one of the most common initial presentations of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). There are different cardiac biomarkers related to the pathophysiological mechanisms of HF in T2DM. The current research aims to identify additional biomarkers that could improve the diagnosis and prognosis of HFpEF, which is currently assessed using NT pro-BNP levels. NT pro-BNP is a valuable tool for diagnosing heart failure but may not always correlate with clinical symptom severity or can present normal levels in certain cases, such as obesity. Biomarkers like FGF-21 and galectin-3 could provide greater insight into heart failure severity, especially in diabetic patients. The main objective of the current study is to assess the performance of NT-proBNP, FGF21, Galectin-3 and Copeptin to discriminate between advanced and mild HF. Materials and Methods: A total of 117 patients were enrolled in this study and divided into two groups: 67 patients in NYHA functional class I-II (mild HF) and 50 patients in NYHA III-IV (advanced HF). NT-pro BNP, FGF21, Galectin 3 and Copeptin serum levels were determined with the ELISA method. Receiver operating characteristic (ROC) analysis and binomial logistic regression analysis were used to measure the ability of the studied biomarkers to distinguish between advanced and mild HF patients. Results: In patients with T2DM with advanced HF, serum FGF21 level was significantly positively correlated with eGFR (ρ = 0.35, p = 0.0125) and triglycerides (ρ = 0.28, p = 0.0465) and significantly negatively correlated with serum levels of HDL cholesterol (ρ = -0.29, p = 0.0386) and with RV-RA gradient (ρ = -0.30, p = 0.0358). In patients with mild HF, serum FGF21 level was significantly negatively correlated with NT-proBNP levels (ρ = -0.37, p = 0.0022), E/e' ratio (ρ = -0.29, p = 0.0182), TR velocity (ρ = -0.24, p = 0.0470) and RV-RA gradient (ρ = -0.24, p = 0.0472). FGF21 (AUC = 0.70, 95% CI: 0.60-0.79) and NT-proBNP (AUC = 0.73, 95% CI: 0.63-0.82) demonstrated significant predictive value to discriminate T2DM patients with advanced HF from those with mild HF. Elevated values for FGF21 (≥377.50 ng/mL) or NTproBNP (≥2379 pg/mL) were significantly associated with increased odds of advanced HF after adjusting for demographic and clinical covariates. Conclusions: NTpro-BNP and FGF21 have a similar ability to discriminate T2DM patients with advanced HF from those with mild HF. Univariable and multivariable logistic models showed that, FGF21 and NTproBNP were independent predictors for advanced HF in patients with preserved and mildly reduced ejection fraction and T2DM.

Herbo-vitamin medicine Livogrit Vital ameliorates isoniazid induced liver injury (IILI) in human liver (HepG2) cells by decreasing isoniazid accumulation and oxidative stress driven hepatotoxicity

BackgroundTuberculosis (TB) is a leading cause of infection related mortality. Isoniazid is one of the frontline drugs for anti-TB therapy. Hepatotoxicity induced by isoniazid is a major cause of drug-discontinuation which may lead to development of resistant TB or increased mortality.PurposeTo characterize pharmacological properties of plant-based prescription medicine, Livogrit Vital (LVV) against isoniazid-induced liver injury (IILI) using HepG2 cells.MethodPhytometabolite characterization of LVV was performed by High-performance liquid chromatography (HPLC). The effects of LVV on cytosafety, IC50 shift, oxidative stress, ER stress, apoptosis, liver injury markers, and accumulation of isoniazid and hydrazine was performed on HepG2 cells induced with isoniazid. Silymarin was used as the positive control.ResultsHPLC based phytometabolite characterization of LVV revealed the presence of several anti-oxidant, anti-apoptotic, and hepatoprotective compounds. In isoniazid-induced HepG2 cells, LVV reduced cytotoxicity of isoniazid and shifted its IC50 value. Treatment with LVV reduced ROS generation and lipid peroxidation; enhanced GSH enzyme levels in isoniazid-induced HepG2 cells. As per the mechanistic evaluation, LVV modulated gene expression level of Caspase-3, FGF21, and IRE-1α. LVV treatment also normalized isoniazid-induced elevated Caspase-3 activity and cPARP1 protein levels, indicating its potentials to regulate liver cell apoptosis. Concomitantly, biomarkers of hepatotoxicity, ALT and GGT, also decreased by LVV treatment. Interestingly, LVV treatment reduced intracellular accumulation of isoniazid and its toxic metabolite hydrazine, in isoniazid-stimulated HepG2 cells.ConclusionTreatment of hepatic cells with the herbo-vitamin medicine, Livogrit Vital, regulates IILI by modulation of oxidative and ER stress, apoptosis, and bioaccumulation of isoniazid and hydrazine. Collectively, Livogrit Vital could well be explored as an adjuvant hepatoprotective agent alongwith anti-TB medicines.

Non-fermented and fermented milk intake in relation to risk of ischemic heart disease and to circulating cardiometabolic proteins in swedish women and men: Two prospective longitudinal cohort studies with 100,775 participants

BackgroundThe effect of milk on the risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) is unclear. We aimed to examine the association between non-fermented and fermented milk consumption on these endpoints and investigate the relationship between milk intake and cardiometabolic-related proteins in plasma.MethodsOur study is based on two Swedish prospective cohort studies that included 59,998 women and 40,777 men without IHD or cancer at baseline who provided repeated measures of diet and lifestyle factors and plasma proteomics data in two subcohorts. Through registry linkage, 17,896 cases with IHD were documented during up to 33 years of follow-up, including 10,714 with MI. We used time-updated multivariable Cox regression analysis to examine non-fermented or fermented milk intake with time to IHD or MI. Using high-throughput multiplex immunoassays, 276 cardiometabolic plasma proteins were measured in two subcohorts. We applied multivariable-adjusted regression models using a discovery-replication design to examine protein associations with increasing consumption of non-fermented or fermented milk.ResultsThe results for non-fermented milk differed by sex (p-value for interaction = 0.01). In women, we found a pattern of successively greater risk of IHD and MI at non-fermented milk intake levels higher than 1.5 glasses/day. Compared with an intake of 0.5 glass/day (100 mL/day), non-fermented milk intake of 2 glasses/day in women conferred a multivariable-adjusted hazard ratio (HR) of 1.05 (95% CI 1.01–1.08) for IHD, an intake of 3 glasses/day an HR of 1.12 (95% CI 1.06–1.19), and an intake of 4 glasses/day an HR of 1.21 (95% CI 1.10–1.32). Findings were similar for whole, medium-fat, and low-fat milk. We did not detect higher risks of IHD with increasing milk intakes in men. Fermented milk intake was unrelated to the risk of IHD or MI in either sex. Increasing non-fermented milk intake in women was robustly associated with a higher concentration of plasma ACE2 and a lower concentration of FGF21.ConclusionsWe show a positive association between high amounts of non-fermented milk intake and IHD in women but not men. We suggest metabolic pathways related to ACE2 and FGF21 potentially underlie the association.Graphical abstractOur analysis of two large cohort studies involving 100,775 participants and 17,896 clinically confirmed IHD events supports a dose–response positive association between non-fermented milk intake higher than 300 mL/day with higher rates of IHD (and acute MI specifically) in women, but not in men. The higher risk of IHD with high milk intake in women was evident, irrespective of the fat content of the milk. Fermented milk intake was unrelated to the risk of IHD in both women and men. Non-fermented milk intake was associated in different directions with circulating levels of ACE2 and FGF21 in women—two essential cardiometabolic proteins, also related to IHD in women in our study.

Clinical significance of serum FGF21 levels in diagnosing nonalcoholic fatty liver disease early

The endogenous FGF21 level is a potential target for diagnosing NAFLD. This study aimed to assess the clinical utility of FGF21 in diagnosing NAFLD and provide new ideas for predicting and preventing NAFLD. A total of 193 patients diagnosed with NAFLD based on diagnostic criteria and 64 healthy individuals were included in the NAFLD and non-NAFLD groups, respectively. Data on the participant names, sex, age, height, weight, blood pressure, serum FGF21 levels, liver function enzyme (AST, ALT, ALP, and GGT) levels, lipid profile (TC, TG, HDL-C, and LDL-C) indicators, and blood glucose levels were collected. The data were statistically analyzed to assess the correlations between serum FGF21 levels and related biochemical markers in NAFLD patients. The areas under the receiver operating characteristic curves (AUCs) of serum FGF21, lipids (TG + TC + HDL + LDL), and FGF21 combined with lipids for the diagnosis of NAFLD were compared. Compared with the non-NAFLD group, the NAFLD group presented significantly higher levels of FGF21. Serum FGF21 levels in the NAFLD group were positively correlated with the TG, TC, and LDL-C levels (P < 0.05). The area under the receiver operating characteristic curve (AUC) of serum FGF21 for the diagnosis of NAFLD was 0.832 (95% CI: 0.77–0.886, P < 0.001). The AUC of FGF21 combined with lipids (TG + TC + HDL + LDL) for the diagnosis of NAFLD was 0.910 (95% CI: 0.874–0.946, P < 0.001). There is a close association between elevated FGF21 levels and the development of NAFLD. The progression of NAFLD is complex and varied, and its pathogenesis is unclear. Early detection, prevention, and intervention may help slow NAFLD development or even reverse the disease. In this study, we found that the FGF21 level could be used as an auxiliary biological indicator for predicting NAFLD, and the role of FGF21 in the progression of NAFLD deserves to be investigated in the future.

Genetic aspects of taste formation

The article discusses the molecular genetic basis of taste development which determines the peculiarity of perception of sweet, salty, sour, bitter and high-protein food (umami). The genes TAS1R3, FTO, GLUT2, FGF21, GNAT3 are responsible for individual perception of sugar volume. Serum FGF21 levels are significantly elevated in obese patients and in patients with type 2 diabetes mellitus which presumably indicates a state of resistance to FGF21. Given the role of refined sugars in the development of diseases, the use of foods with a reduced content or complete absence of added sugar is a worldwide trend, especially necessary in the nutrition of children. During genome-wide sequencing for 39 patients aged 15-18 years, FGF21 gene polymorphism was detected in 27 adolescents (69 %) without gender identity. Almost all patients with FGF21 gene polymorphism showed a high addiction to sweet foods. Currently, the existence of a sixth taste is being debated, it is ammonium chloride, whose receptors are regulated by the Otop1 gene which is also responsible for the identification of sour taste.

Hepatocyte-specific GDF15 overexpression improves high-fat diet-induced obesity and hepatic steatosis in mice via hepatic FGF21 induction

GDF15 and FGF21, stress-responsive cytokines primarily secreted from the liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effects of hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21, respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. In addition, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, whereas FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and XBP1 splicing, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids (FFAs), GDF15 overexpression upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Overall, continuous exposure to excess FFAs resulted in a gradual increase of β-oxidation-derived reactive oxygen species and endoplasmic reticulum stress, suggesting that GDF15 enhanced this pathway and induced FGF21 expression. GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.

Role of Maternal Serum Fibroblast Growth Factor 21 Level in Prediction of Preeclampsia

Abstract Background Pregnancy complications resulting from hypertensive disorders are a serious problem that impact 2-10% of all pregnancies globally. Preeclampsia is defined as new onset hypertension and proteinuria after 20 weeks of gestation which may be associated with other maternal organ dysfunction, such as liver or renal insufficiency, hematological or neurological complications, uteroplacental dysfunction and fetal growth restriction. Aim of the Work To establish the relationship between maternal serum fibroblast growth factor 21 levels and preeclampsia as a predictor for preeclampsia. Patients and Methods This was a Nested case-control study that was conducted on 90 primigravidas at Ain Shams University maternity hospital from April 2021 to April 2022. Results our study showed that there was a significant difference in FGF21 levels between the groups, patients with preeclampsia having higher levels than controls, 15.9% of patients with preeclampsia experienced maternal complications compared to none in the control group. Meanwhile, 18.2% of patients with preeclampsia experienced fetal complications compared to 0% in the control group. Conclusion Serum FGF-21 levels are significantly higher in preeclamptic pregnant women compared to healthy normotensive pregnant women. So, it can be used as a predictor for preclampsia and maternal complications

Exploring the Wound Healing Potential of Hispidin.

Hispidin, a polyphenol component mainly derived from the medicinal mushroom species Phellinus and Inonotus, shows promise for biomedical applications, yet its potential in wound healing remains largely unexplored. This research investigates the wound healing effects of hispidin through in vitro and in vivo experiments, while also evaluating its antimicrobial properties and safety profile. In vitro scratch assays were conducted to evaluate the impact of hispidin on the migration of NIH-3T3 cells. The wound healing potential of hispidin was assessed in rats using excision wounds, dead space wounds, and linear incisions, treated with various topical ointments including a simple ointment, 2.5% (w/w) and a 5% (w/w) hispidin ointment, and a 0.2% (w/w) nitrofurazone ointment, administered at 0.2 g daily for 14 days. Hispidin demonstrated antimicrobial properties and was particularly effective against Staphylococcus epidermidis. Hispidin enhanced NIH-3T3 cell viability, and promoted wound closure in scratch assays, correlating with increased levels of FGF21, TGF-β1, EGF, and VEGF. In excision wound models, the 5% (w/w) hispidin ointment improved wound contraction, epithelialization, tissue regeneration, fibroblast activity, and angiogenesis. In the granulation tissue from dead space wound models, hispidin reduced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and lipid peroxidation, while increasing anti-inflammatory cytokines (IL-10) and antioxidant activities (SOD, GPx, CAT), along with connective tissue markers like hydroxyproline, hexosamine, and hexuronic acid. Hispidin also enhanced wound breaking strength in incision models. Acute dermal toxicity studies indicated no adverse effects at 2000 mg/kg. These findings highlight hispidin's potential in wound care, demonstrating its antimicrobial, regenerative, and safety properties.