Fibroblast Growth Factor 21 Levels Research Articles

Brief Report: Increased Inflammation and Liver Disease in HIV/HBV-Coinfected Individuals.

HIV and hepatitis B virus (HBV) coinfection can accelerate morbidity and mortality, especially in sub-Saharan Africa where both infections are common. Although inflammation contributes to disease progression, more information is needed to better understand the pathology. This study compared markers of cirrhosis and inflammation in HIV/HBV-coinfected individuals compared with monoinfected and uninfected patients. The HIV/HBV-coinfected subjects from the Ugandan arm of the prospective African Cohort Study were selected for evaluation and matched by age and gender with HIV-monoinfected, HBV-monoinfected, and uninfected controls. Plasma samples were used to quantify markers of immune activation and inflammation. The FIB-4 (a simple index to predict significant liver fibrosis) score was used to estimate liver fibrosis. Demographic and laboratory characteristics were compared across the groups. Together, 31 HIV/HBV-coinfected participants were identified and compared with 62 HIV-monoinfected, 7 HBV-monoinfected, and 62 uninfected controls. The HIV/HBV-coinfected group had generally higher levels of inflammation. Most notably, matrix metalloproteinase-2, matrix metalloproteinase-9, and fibroblast growth factor-19 levels were dysregulated among the HIV/HBV-coinfected individuals. Furthermore, the FIB-4 score was higher in the HIV/HBV-coinfected group compared with the HIV-monoinfected group and revealed that 11% of HIV/HBV-coinfected individuals had evidence of undiagnosed advanced liver disease. Differences in levels of inflammation exist between individuals with HIV/HBV coinfection compared with monoinfected and uninfected controls. A distinct signature of inflammation was associated with HIV/HBV coinfection that could reflect the mechanism of liver fibrosis and increased risk for disease progression. Finally, there may be an underappreciated amount of undiagnosed advanced liver disease in sub-Saharan Africa.

Does FGF21 Mediate the Potential Decrease in Sweet Food Intake and Preference Following Bariatric Surgery?

The liver-derived hormone fibroblast growth factor 21 (FGF21) has recently been linked to preference for sweet-tasting food. We hypothesized, that surgery-induced changes in FGF21 could mediate the reduction in sweet food intake and preference following bariatric surgery. Forty participants (35 females) with severe obesity (BMI ≥ 35 kg/m2) scheduled for roux-en-y gastric bypass (n = 30) or sleeve gastrectomy (n = 10) were included. Pre- and postprandial responses of intact plasma FGF21 as well as intake of sweet-tasting food assessed at a buffet meal test, the hedonic evaluation of sweet taste assessed using an apple juice with added sucrose and visual analog scales, and sweet taste sensitivity were assessed before and 6 months after bariatric surgery. In a cross-sectional analysis pre-surgery, pre- and postprandial intact FGF21 levels were negatively associated with the hedonic evaluation of a high-sucrose juice sample (p = 0.03 and p = 0.02). However, no changes in pre- (p = 0.24) or postprandial intact FGF21 levels were found 6 months after surgery (p = 0.11), and individual pre- to postoperative changes in pre- and postprandial intact FGF21 levels were not found to be associated with changes in intake of sweet foods, the hedonic evaluation of sweet taste or sweet taste sensitivity (all p ≥ 0.10). In conclusion, we were not able to show an effect of bariatric surgery on circulating FGF21, and individual postoperative changes in FGF21 were not found to mediate an effect of surgery on sweet food intake and preference.

Circulating fibroblast growth factor 21 links hemodynamics with kidney function in middle-aged and older adults: A mediation analysis.

Altered hemodynamics are commonly observed in individuals with declining renal function; however, the pathophysiological mechanisms linking renal dysfunction and hemodynamics have not been fully elucidated. Fibroblast growth factor 21 (FGF21), which upregulates sympathetic nerve activity, can alter systemic hemodynamics, and its level can increase as renal function declines. This study aimed to determine the associations among circulating FGF21 levels, hemodynamics, and renal function in middle-aged and older adults. In a total of 272 middle-aged and older adults (age range: 46-83 years), estimated glomerular filtration rate (eGFR), hemodynamics (brachial and aortic blood pressure and aortic pulse wave velocity [PWV]), and serum FGF21 levels were measured. For mediation analysis, hemodynamic parameters were entered as outcomes. eGFR or log-transformed urinary albumin and creatinine ratio (UACR) and log-transformed serum FGF21 levels were set as the predictors and mediator, respectively. According to multivariable regression models after adjusting for potential covariates, serum FGF21 levels were significantly associated with brachial systolic blood pressure (β = 0.140), pulse pressure (β = 0.136), and aortic PWV (β = 0.144). Mediation analyses showed that serum FGF21 levels significantly mediated the relationship of eGFR with brachial systolic blood pressure (indirect effect [95% confidence interval]: -0.032 [-0.071, -0.002]), pulse pressure (-0.019 [-0.041, -0.001]), and aortic PWV (-0.457 [-1.053, -0.021]) and the relationship of UACR with aortic PWV (7.600 [0.011, 21.148]). These findings suggest that elevated circulating FGF21 levels partially mediate the association of elevated blood pressure and/or aortic stiffness with renal dysfunction in middle-aged and older adults.

Fibroblast growth factor 21 and adipose tissue distribution in young adult with abdominal obesity

Abstract Introduction Fibroblast growth factor 21 (FGF-21) is a hormone-like protein that is involved in the regulation of glucose and lipid homeostasis. Several studies have reported the association of FGF21 with visceral fat, epicardial fat, and pericardial fat. However, there is limited information about distribution of FGF21 levels in young adults with different metabolic status and its relationship to different body fat. Objective The main aim of study was to investigate the association between subcutaneous (SF), visceral (VF), periaortic (PF), epicardial (EF), perirenal (PRF), renal sinus (RSF) fat and fibroblast growth factor 21 (FGF21) in young adult with abdominal obesity (AO), or with metabolic syndrome (MS). Purpose To assess the level of FGF21 in blood serum in young people with AO and compare it with the distribution of adipose tissue. Methods There were 132 adult 18–45 y.o. in the study. We formed 3 groups: health (n=16, M - 43,8%, av.age 32 [27; 35]); AO plus 1 or less sing of MS (AO) (n=46, men (M) – 37,0%, av.age 40 [34; 43]), and MS (n=70, M – 81,4%, av.age 40 [35; 44]). Height, weight, BMI, waist circumference, blood tests (fast glucose (FG) and glucose tolerance (GT), lipid profile, insulin, adiponectin (ELISA, Mediagnost), leptin (ELISA, DBC), FGF21 (ELISA KIT, BCM Diagnostics) were measured. MS was defined as AO (cut-off of >80cm in women (W) and >94cm in M) plus >1 sign: HDL<1,30(w)/1,04(m)mmol/l; triglycerides>1,7mmol/l; FG>5,6mmol/l; violation GT; BP>140/90mmHg. SF, VF, PF, EF, PRF, RSF (range: −150 to −30 HU) was measured by computed tomography. We calculated ratio subcutaneous to visceral fat (RSV). 24-hour blood pressure monitoring was performed. Results The clinical characteristics of the groups are presented in table 1. We didn't find any difference of level FGF 21 between groups AO (294,4 pg / ml [110,0; 583,5]) and MS (245,7 pg/ml [129,2; 474,8]). But in health group (110,2 pg/ml [62,2; 221,9] it was significant lower (p=0,05). We found significant week relationship FGF 21 with VF (r=0,02, p<0,05) and SF (r=0,02, p<0,05), and insignificant association with PF (r=0,11 p>0,05), EF (r=0,04 p>0,05), PRF (r=−0,17 p>0,05), RSF (r=−0,02 p>0,05). Also, we checked association with other parameters (insulin (r=0,15 p>0,05), adiponectin (r=0,00 p>0,05), glucose (r=0,12 p>0,05)) and found a statistically significant association FGF21 with leptin (r=0,24, p<0,01). Conclusions Young adults with abdominal obesity had elevated level of FGF21. And it was associated with visceral, subcutaneous fat depots and leptin. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Health of Russian Federation Table 1. Clinical characteristics of the groups

Liraglutide Decreases Liver Fat Content and Serum Fibroblast Growth Factor 21 Levels in Newly Diagnosed Overweight Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease.

Purposes In this study, we aimed to verify plasma fibroblast growth factor 21 (FGF21) elevation in newly diagnosed overweight patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) and to evaluate the effectiveness of liraglutide on reducing liver fat content and serum (FGF21) levels in those patients. Methods A 12-week, single-center, prospective study was conducted. Twenty newly diagnosed overweight patients with T2DM and NAFLD were recruited. Twenty healthy age, sex, and body mass index (BMI) matched subjects were enrolled as the control group. Enzyme-linked immunosorbent assay was used to measure serum FGF21 levels. Liver fat content was determined using the 3.0 T whole-body MRI scanner. Results Those newly diagnosed overweight patients with T2DM and NAFLD had a BMI of 27.6 ± 0.5 kg/m2. They had higher levels of FGF21 (159.6 ± 35.7 vs. 124.1 ± 42.9 pg/ml, P < 0.001) and increased liver fat content (19.3 ± 9.4 vs. 4.5 ± 0.6%, P < 0.001) compared to the controls. Liraglutide treatment for 12 weeks induced a significant 4.9 kg weight loss (95% confidence interval (CI): -6.1, -3.7, P < 0.001), which was equivalent to a relative reduction of 6.8% (95% CI: 5.3%, 8.3%, P < 0.001). FGF21 levels decreased after the 12-week liraglutide treatment (159.6 ± 35.7 vs. 124.2 ± 27.8 pg/ml, P = 0.006). There was a positive correlation between relative changes of liver fat content and relative change of FGF21 (r = 0.645, P = 0.002). FGF21 levels significantly decreased in patients who had a significant decrease in liver fat content (≥29%) (95% CI: -262.8, -55.1, P = 0.006); however, there was no significant change in the patients without a significant decrease in liver fat content (<29%) (95% CI: -60.0, 54.1, P = 0.899). Conclusions Liraglutide treatment reduced both liver fat content and FGF21 levels in newly diagnosed overweight patients with T2DM and NAFLD. FGF21 may be a potential biomarker for evaluating the effects of liraglutide treatment on hepatic fat and glucose metabolism.

Fenofibrate ameliorates olanzapine's side effects without altering its central effect: emphasis on FGF-21-adiponectin axis.

The present work was designed to investigate whether fenofibrate could ameliorate olanzapine deleterious effect on insulin resistance via its effect on fibroblast growth factor-21 (FGF-21)-adiponectin axis without affecting olanzapine antipsychotic effect in postweaning socially isolated reared female rats. Treatment with olanzapine (6 mg/kg, intraperitoneally) or fenofibrate (100 mg/kg, orally) have been started 5 weeks after isolation, then behavioral tests, hippocampal content of neurotransmitters, and brain-derived neurotrophic factor (BDNF) were assessed. Moreover, insulin resistance, lipid profile, FGF-21, adiponectin, inflammatory, and oxidative stress markers of adipose tissue were assessed. Treatment of isolated-reared animals with olanzapine, or fenofibrate significantly ameliorated the behavioral and biochemical changes induced by postweaning social isolation. Co-treatment showed additive effects in improving hippocampal BDNF level. Besides, fenofibrate reduced the elevation in weight gain, adiposity index, insulin resistance, lipid profile, and FGF-21 level induced by olanzapine treatment. Also, fenofibrate increased adiponectin level which was reduced upon olanzapine treatment. Moreover, fenofibrate improved both adipose tissue oxidative stress and inflammatory markers elevation as a result of olanzapine treatment. Fenofibrate could ameliorate olanzapine-induced insulin resistance without affecting its central effect in isolated reared rats via its action on FGF-21-adiponectin axis.

Role of Fibroblast growth factor 21 (FGF-21) as a prognostic marker for fetal and maternal complications in patients with gestational diabetes mellitus

Abstract Background Gestational diabetes mellitus (GDM) defined as glucose intolerance with onset or first diagnosis during pregnancy. While GDM usually resolves following delivery, it can have long-lasting health consequences, including increased risk for type 2 diabetes (T2DM) and cardiovascular disease (CVD) in the mother, and future obesity, CVD, T2DM, and/or GDM in the child. This contributes to a vicious intergenerational cycle of obesity and diabetes that impacts the health of the population as a whole. Fibroblast growth factor 21 (FGF21) is a hormone that is expressed predominantly in the liver, but also in other metabolically active tissues such as pancreas, skeletal muscle and adipose tissue. An elevated FGF21 level is also an independent predictor of T2DM. GDM and T2DM are proposed to have similar underlying pathophysiologies, raising the question of whether a similar relationship exists between FGF21 and GDM as it does with T2DM. Objectives assess the role of Fibroblast growth factor 21 (FGF-21) as a prognostic marker for maternal and fetal complications in patients with gestational diabetes mellitus (GDM). Patients and Methods A case control study that was conducted on 50 patients diagnosed with Gestational Diabetes Mellitus and 50 control subjects at Diabetes and Obstetrics outpatient clinic and inpatient ward at Ain Shams university hospitals in the period between December 2018 and July 2019. Patients diagnosed with gestational diabetes mellitus (GDM) at 24-28 weeks of gestation were included in this study. Results FGF 21 levels varied significantly with blood sugar values where higher levels of FGF 21 levels were found in patients with GDM with study results showing that FGF 21 can be used as a diagnostic marker for GDM at levels above 121 pg/ml with sensitivity 84% and specificity 92%. Conclusion FGF 21 can be used as a diagnostic marker for gestational diabetes. Further studies needed for better correlation between FGF 21 levels during pregnancy and maternal outcome.

Elevated serum FGF21 predicts the major adverse cardiovascular events in STEMI patients after emergency percutaneous coronary intervention

BackgroundAlthough there have been several studies related to serum fibroblast growth factor 21 (FGF21) levels and acute myocardial infarction, the value of serum FGF21 levels in ST-segment elevation myocardial infarction (STEMI) patients after emergency percutaneous coronary intervention (PCI) has not been previously investigated.MethodsA total of 348 STEMI patients who underwent emergency PCI were enrolled from January 2016 to December 2018. The primary endpoint was the occurrence of major adverse cardiovascular events (MACEs), with a median follow-up of 24 months. Eighty patients with stable angina (SA) who underwent selective PCI served as the control group. Serum FGF21 levels were measured by ELISA.ResultsSerum FGF21 levels were significantly higher in the STEMI group than in the SA group (225.03 ± 37.98 vs. 135.51 ± 34.48, P < 0.001). Multiple linear regression analysis revealed that serum FGF21 levels were correlated with NT-proBNP (P < 0.001). According to receiver operating characteristic (ROC) analysis, the areas under the ROC curve (AUCs) of FGF21 and NT-proBNP were 0.812 and 0.865, respectively. The Kaplan-Meier curves showed that STEMI patients with lower FGF21 levels had an increased MACE-free survival rate. Cox analysis revealed that high FGF21 levels (HR: 2.011, 95% CI: [1.160–3.489]) proved to be a powerful tool in predicting the risk of MACEs among STEMI patients after emergency PCI.ConclusionElevated FGF21 levels on admission have been shown to be a powerful predictor of MACEs for STEMI patients after emergency PCI.

High FGF-21 level in a cohort of 22 patients with Dravet Syndrome-Possible relationship with the disease outcomes.

ObjectiveDravet syndrome (DS) is a severe and intractable form of epilepsy with prolonged seizures which may evolve to other seizure types and associated with mild‐to‐severe intellectual disabilities. Fibroblast growth factor 21 (FGF‐21) is a stress hormone mediating metabolic and oxidative stress and circulating level of FGF‐21 had been shown to increase in some patients with impairment of oxidative phosphorylation in muscles. In DS, FGF‐21 is of interest for further study as mitochondrial oxidative stress was identified previously in patients.MethodsPlasma FGF‐21 levels were compared between 22 DS patients and 22 normal controls, and their clinical characteristics of DS patients at the time of plasma sampling were studied retrospectively. Besides, the relationships of FGF‐21 level with intellectual development, seizure frequency, valproate treatment, and types of SCN1A mutations were analyzed. Logarithmic transformation of FGF‐21 levels was performed before comparison and statistical analysis.ResultsMean of log10 FGF‐21 level was significantly higher in DS patients when comparing with normal controls (P = .0042). Mean of log10 FGF‐21 level was significantly higher in DS patients with normal‐to‐mild ID versus mild‐to‐severe ID (P = .0193) and with valproate treatment versus without valproate treatment (P = .015). No significant difference was shown in FGF‐21 level in DS patients with missense versus truncating SCN1A variants, and no correlation could be demonstrated between seizure frequency and FGF‐21 level.SignificanceSignificantly higher level of plasma FGF‐21 was identified in DS patients. The high FGF‐21 levels were shown to be associated with developmental outcome and valproate treatment. These results support further investigation on the relationship of FGF‐21 with the clinical outcomes of DS and other related mechanism which is important for possible therapeutic development for this epileptic encephalopathy.

The stimulatory effects of glucagon on cortisol and GH secretion occur independently from FGF-21.

Glucagon stimulation test (GST) is used to assess the hypothalamo-pituitary-adrenal (HPA) and growth hormone (GH) axes with an incompletely defined mechanism. We aimed to assess if glucagon acted through fibroblast growth factor-21 (FGF-21) to stimulate cortisol and GH secretion. The secondary outcome was to determine the relationship of FGF-21 with variable GH responses to GST in obesity. A total of 26 healthy participants; 11 obese (body mass index (BMI) > 30 kg/m2) and 15 leans (BMI < 25 kg/m2) were included. Basal pituitary and target hormone levels were measured and GST was performed. During GST, glucose, insulin, cortisol, GH, and FGF-21 responses were measured. The mean age of the participants was 26.3±3.6 years. Glucagon resulted in significant increases in FGF-21, glucose, insulin, cortisol, and GH levels. The levels of basal cortisol, GH, FGF-21, and IGF-1 were similar in the two groups. The peak GH and area under the curve (AUC)(GH) responses to GST in the obese group were lower than those of the normal-weight group with a different pattern of response. There were no differences between the groups in terms of peak cortisol, AUC(cortisol), peak insulin, AUC(insulin), peak FGF-21, and AUC(FGF21). Obesity was associated with significantly increased glucose and insulin responses and slightly decreased FGF-21 response to glucagon. Obesity was associated with blunted and delayed GH, but preserved cortisol responses to GST. This is the first study showing that glucagon stimulates the HPA and GH axis independently from FGF-21. The delayed GH response to GST in obesity does not seem to be related to FGF-21.

Fibroblast Growth Factor 21 Ameliorates NaV1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes.

Infarcted myocardium is predisposed to cause lethal ventricular arrhythmias that remain the main cause of death in patients suffering myocardial ischemia. Liver-derived fibroblast growth factor 21 (FGF21) is an endocrine regulator, which exerts metabolic actions by favoring glucose and lipids metabolism. Emerging evidence has shown a beneficial effect of FGF21 on cardiovascular diseases, but the role of FGF21 on ventricular arrhythmias following myocardial infarction (MI) in humans has never been addressed. This study was conducted to investigate the pharmacological effects of FGF21 on cardiomyocytes after MI in humans. Patients with arrhythmia in acute MI and healthy volunteers were enrolled in this study. Serum samples were collected from these subjects on day 1 and days 7–10 after the onset of MI for measuring FGF21 levels using ELISA. Here, we found that the serum level of FGF21 was significantly increased on day 1 after the onset of MI and it returned to normal on days 7–10, relative to the Control samples. In order to clarify the regulation of FGF21 on arrhythmia, two kinds of arrhythmia animal models were established in this study, including ischemic arrhythmia model (MI rat model) and nonischemic arrhythmia model (ouabain-induced guinea pig arrhythmia model). The results showed that the incidence and duration time of ischemic arrhythmias in rhbFGF21-treated MI rats were significantly reduced at different time point after MI compared with normal saline-treated MI rats. Moreover, the onset of the first ventricular arrhythmias was delayed and the numbers of VF and maintenance were attenuated by FGF21 compared to the rhbFGF21-untreated group in the ouabain model. Consistently, in vitro study also demonstrated that FGF21 administration was able to shorten action potential duration (APD) in hydrogen peroxide-treated AC16 cells. Mechanically, FGF21 can ameliorate the electrophysiological function of AC16 cells, which is characterized by rescuing the expression and dysfunction of cardiac sodium current (I Na) and inward rectifier potassium (I k1) in AC16 cells induced by hydrogen peroxide. Moreover, the restorative effect of FGF21 on NaV1.5 and Kir2.1 was eliminated when FGF receptors were inhibited. Collectively, FGF21 has the potential role of ameliorating transmembrane ion channels remodeling through the NaV1.5/Kir2.1 pathway by FGF receptors and thus reducing life-threatening postinfarcted arrhythmias, which provides new strategies for antiarrhythmic therapy in clinics.

The Mitochondrial Biomarkers FGF-21 and GDF-15 in Patients with Episodic and Chronic Migraine.

Mitochondrial processes may play a role in the pathophysiology of migraine. Serum levels of two biomarkers, Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15), are typically elevated in patients with mitochondrial disorders. The study investigated whether the presence of migraine may influence FGF-21 and GDF-15 serum levels considering vascular and metabolic disorders as possible confounders. A cross-sectional study in two headache centers was conducted analyzing GDF-15 and FGF-21 serum concentration in 230 patients with episodic and chronic migraine compared to a control group. Key clinical features of headache were evaluated, as well as health-related life quality, anxiety and depression using SF-12 and HADS-questionnaires. Elevated GDF-15 values were detected in the migraine group compared to the control group (506.65 ± 275.87 pg/mL vs. 403.34 ± 173.29 pg/mL, p < 0.001, Mann–Whitney U test). A strong correlation between increasing age and higher GDF-15 levels was identified (p < 0.001, 95%-CI elevation of GDF-15 per year 5.246–10.850 pg/mL, multiple linear regression). Mean age was different between the groups, and this represents a confounding factor of the measurements. FGF-21 levels did not differ between migraine patients and controls (p = 0.635, Mann–Whitney U test) but were significantly influenced by increasing BMI (p = 0.030, multiple linear regression). Neither biomarker showed correlation with headache frequency. Higher FGF-21 levels were associated with a higher mean intensity of headache attacks, reduced health-related life quality and anxiety. When confounding factors were considered, increased serum levels of FGF-21 and GDF-15 were not detected in migraine patients. However, the results show an age-dependence of GDF-15 in migraine patients, and this should be considered in future studies. Similar findings apply to the relationship between FGF-21 and BMI. Previous studies that did not adjust for these factors should be interpreted with caution.

Is serum fibroblast growth factor 21 associated with the severity or presence of coronary artery disease?

BackgroundRecent studies have shown that increased circulating concentrations of fibroblast growth factor 21 (FGF21) are associated with obesity, metabolic disorder, and atherosclerosis. However the relationship between FGF21 and coronary artery disease (CAD) is controversial This study was planned to investigate the role of FGF21 in CAD development and CAD severity.MethodsSeventy-eight patients with stable angina pectoris (SAP) (lesion positive) and 40 control patients (lesion negative) with similar cardiovascular risk factors were included in the study. Serum FGF21 levels were measured by ELISA method. CAD severity was evaluated by using SYNTAX and GENSINI risk scores.ResultsFGF21 concentrations were found significantly higher in the SAP group than in the control group. [101.18 ± 141.62 vs. 47.93 ± 58.74 pg/mL; p = 0.03], no correlation was found between the SYNTAX (r = 0.146 and p = 0.134) and GENSINI (r = 0.211 and p = 0.084) scores with serum FGF21 levels. There was a negative relationship between serum FGF21 and serum HDL-C levels in correlation analysis (r = - 0.272; p = 0.026).ConclusionsThe serum FGF21 levels are different between SAP and control patients. FGF21 is a marker for CAD diagnosis, but not for the evaluation of CAD severity.

Lower melanoma pulmonary metastatic burden in obese mice: role of FGF-21.

Obesity is a risk factor for malignant melanoma. The lungs are main target organs for metastization and their immune response is a key modulator of this mechanism. The concept that the metastatic potential of some types of cancer is reduced or inhibited by obesity, known as the obesity paradox, drives major concerns on the prognosis of metastasized patients. The aim of this study was to investigate how high-fat diet (HFD)-induced obesity affects melanoma metastization. C57Bl6/J mice were fed with HFD or standard diet for 180 days and inoculated intravenously with B16F10 melanoma cells. Upon 21 days of inoculation, lung tissue of overweight and lean mice was assessed for histology and immunohistochemistry assays. Adipokine antibody arrays were performed in mice serum. In vitro RAW 264.7 macrophage cultures were established and incubated with FGF-21 and/or lipopolysaccharide (LPS). Conditioned media was added to B16F10 cells for viability quantification. HFD-fed mice presented a reduced number of metastases with lower proliferative rates. The high content of inflammatory foci observed in noninoculated obese mice was significantly decreased upon B16F10 inoculation, concurrent with a slight fibrosis reduction. Plasma levels of fibroblast growth factor-21 (FGF-21), an endocrine regulator, were elevated in noninoculated HFD mice and the expression of FGF receptor 1 (FGFR-1) was significantly upregulated after inoculation. FGF-21 reduced melanoma viability in LPS-stimulated macrophages. Altogether, these findings suggest that higher amounts of FGF-21 are able to counterbalance the proinflammatory effects associated with obesity, protecting the lungs from melanoma metastization.

The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease.

Background and AimsProtein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD.MethodsA total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn’s disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci [pQTL] analysis). Intestinal mucosal RNA sequencing and faecal metagenomic data were used for complementary analyses.ResultsThirty-two proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins were independent of active inflammation; 69 proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 [FUT2] gene [rs602662] and two independent cis-pQTLs of C-C motif chemokine 25 [CCL25] affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression [e]QTL-variant [rs3745387] of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of faecal butyrate-producing bacteria.ConclusionsThis study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD, and identifies disease-associated pathways that may help to improve disease management in the future.

Fibroblast Growth Factor 21 and Its Association With Oxidative Stress and Lipid Profile in Type 2 Diabetes Mellitus.

IntroductionCardiovascular diseases are the leading cause of mortality in diabetic patients. Oxidative stress and mitochondrial dysfunction lead to diabetic cardiomyopathy (DCM) characterized by impaired cardiac structure and function. Hyperglycemia causes oxidative stress, which can lead to microvascular complications, macrovascular complications, and atherosclerosis. Peripheral tissues produce fibroblast growth factor 21 (FGF-21), which has anti-inflammatory properties, increases oxidation of fatty acids, and improves insulin sensitivity. Its increased levels are found in metabolic syndrome and type 2 diabetes mellitus and may also lead to coronary heart disease. Our study sought to measure the serum FGF-21 levels and their associations with lipid profile parameters and oxidative stress in patients with type 2 diabetes mellitus.MethodologyOne-hundred fifty (150) patients of both genders with type 2 diabetes mellitus were recruited along with 150 controls. Simple random sampling was done. After taking relevant history and physical examination, we drew venous blood samples of each patient and sent them to the institutional laboratory for analysis of fasting blood sugar (FBS) levels, glycated hemoglobin (HbA1C), lipid profile, and FGF-21 serum levels. Oxidative stress parameter malondialdehyde (MDA) was estimated and the total antioxidant status by ferric reducing antioxidant power assay (FRAP) was assessed. Patients were followed up after three months to record the glycemic index, and the values were recorded. We used SPSS Software 25.0 (SPSS, Inc., Chicago, USA) to analyze the data. For consideration of results to be statistically significant, a 𝑃 value of < 0.05 was selected.ResultsThe levels of serum cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were increased in diabetics compared to controls and were statistically significant (p<0.05). High-density lipoprotein (HDL) cholesterol was lower in diabetic patients as compared to the controls (p<0.05). There was a statistically significant increase in the level of MDA in diabetics compared to controls (p˂0.005). Serum levels of total antioxidant status (FRAP) were decreased in diabetics in comparison with controls (p˂0.005). Serum FGF-21 level was statistically increased in diabetics compared to controls (p˂0.005). FGF-21 and MDA are positively correlated and FGF-21 and FRAP are negatively correlated. Serum FGF-21 is positively correlated with total cholesterol, triglycerides, serum LDL cholesterol, and HDL cholesterol.ConclusionOur study concludes that there is a significant correlation between fibroblast growth factor 21, oxidative stress, and abnormal lipid profile in type 2 diabetic patients. FGF-21 could be the target of certain medications used to treat metabolic disorders and obesity.

Acute sleep loss alters circulating fibroblast growth factor 21 levels in humans: A randomised crossover trial.

The hormone fibroblast growth factor 21 (FGF21) modulates tissue metabolism and circulates at higher levels in metabolic conditions associated with chronic sleep-wake disruption, such as type 2 diabetes and obesity. In the present study, we investigated whether acute sleep loss impacts circulating levels of FGF21 and tissue-specific production, and response pathways linked to FGF21. A total of 15 healthy normal-weight young men participated in a randomised crossover study with two conditions, sleep loss versus an 8.5-hr sleep window. The evening before each intervention, fasting blood was collected. Fasting, post-intervention morning skeletal muscle and adipose tissue samples underwent quantitative polymerase chain reaction and DNA methylation analyses, and serum FGF21 levels were measured before and after an oral glucose tolerance test. Serum levels of FGF21 were higher after sleep loss compared with sleep, both under fasting conditions and following glucose intake (~27%-30%, p=0.023). Fasting circulating levels of fibroblast activation protein, a protein which can degrade circulating FGF21, were not altered by sleep loss, whereas DNA methylation in the FGF21 promoter region increased only in adipose tissue. However, even though specifically the muscle exhibited transcriptional changes indicating adverse alterations to redox and metabolic homeostasis, no tissue-based changes were observed in expression of FGF21, its receptors, or selected signalling targets, in response to sleep loss. In summary, we found that acute sleep loss resulted in increased circulating levels of FGF21 in healthy young men, which may occur independent of a tissue-based stress response in metabolic peripheral tissues. Further studies may decipher whether changes in FGF21 signalling after sleep loss modulate metabolic outcomes associated with sleep or circadian disruption.

Elabela prevents angiotensin II-induced apoptosis and inflammation in rat aortic adventitial fibroblasts via the activation of FGF21-ACE2 signaling.

Apoptosis, inflammation, and fibrosis contribute to vascular remodeling and injury. Elabela (ELA) serves as a crucial regulator to maintain vascular function and has been implicated in the pathogenesis of hypertensive vascular remodeling. This study aims to explore regulatory roles and underlying mechanisms of ELA in rat aortic adventitial fibroblasts (AFs) in response to angiotensin II (ATII). In cultured AFs, exposure to ATII resulted in marked decreases in mRNA and protein levels of ELA, fibroblast growth factor 21 (FGF21), and angiotensin-converting enzyme 2 (ACE2) as well as increases in apoptosis, inflammation, oxidative stress, and cellular migration, which were partially blocked by the exogenous replenishment of ELA and recombinant FGF21, respectively. Moreover, treatment with ELA strikingly reversed ATII-mediated the loss of FGF21 and ACE2 levels in rat aortic AFs. FGF21 knockdown with small interfering RNA (siRNA) significantly counterbalanced protective effects of ELA on ATII-mediated the promotion of cell migration, apoptosis, inflammatory, and oxidative injury in rat aortic AFs. More importantly, pretreatment with recombinant FGF21 strikingly inhibited ATII-mediated the loss of ACE2 and the augmentation of cell apoptosis, oxidative stress, and inflammatory injury in rat aortic AFs, which were partially prevented by the knockdown of ACE2 with siRNA. In summary, ELA exerts its anti-apoptotic, anti-inflammatory, and anti-oxidant effects in rat aortic AFs via activation of the FGF21–ACE2 signaling. ELA may represent a potential candidate to predict vascular damage and targeting the FGF21–ACE2 signaling may be a promising therapeutic intervention for vascular adventitial remodeling and related disorders.

Increased Fibroblast Growth Factor 21 (FGF21) Concentration in Early Second Trimester Amniotic Fluid and Its Association with Fetal Growth.

Altered fetal growth, either reduced or exacerbated, is associated with adverse perinatal outcomes. The underlying pathogenetic mechanisms of altered growth remain unclear. Fibroblast growth factor 21 (FGF21) and insulin are both considered to be major regulators of tissue growth and metabolism. The aim of our study was to investigate the association of second trimester amniotic fluid FGF21 and insulin concentrations with fetal growth. The amniotic fluid concentrations of FGF21 and insulin were determined in 80 cases of different fetal growth patterns (SGA—small for gestational age, LGA—large for gestational age, and AGA—appropriate for gestational age fetuses). Both peptides were found to be increased in cases of abnormal fetal growth, reduced growth velocity (SGA), or macrosomia (LGA). Specifically, FGF21 was significantly increased, as higher FGF21 levels were observed in the amniotic fluid of SGA and LGA fetuses compared with AGA fetuses (p < 0.05). Furthermore, the more severe the fetal smallness, the higher the FGF21 levels (p < 0.05). Similarly, higher insulin levels were noted in the amniotic fluid of SGA and LGA fetuses compared with those in AGA fetuses, though this was not statistically significant (p > 0.05). Again, the more severe the reduced fetal growth, the higher the insulin levels.

Fibroblast Growth Factor 21 as a Potential Biomarker for Improved Locomotion and Olfaction Detection Ability after Weight Reduction in Obese Mice.

Obesity is one of the most challenging diseases of the 21st century and is accompanied by behavioural disorders. Exercise, dietary adjustments, or time-restricted feeding are the only successful long-term treatments to date. Fibroblast growth factor 21 (FGF21) plays a key role in dietary regulation, but FGF21 resistance is prevalent in obesity. The aim of this study was to investigate in obese mice whether weight reduction leads to improved behaviour and whether these behavioural changes are associated with decreased plasma FGF21 levels. After establishing a model for diet-induced obesity, mice were subjected to three different interventions for weight reduction, namely dietary change, treadmill exercise, or time-restricted feeding. In this study, we demonstrated that only the combination of dietary change and treadmill exercise affected all parameters leading to a reduction in weight, fat, and FGF21, as well as less anxious behaviour, higher overall activity, and improved olfactory detection abilities. To investigate the interrelationship between FGF21 and behavioural parameters, feature selection algorithms were applied designating FGF21 and body weight as one of five highly weighted features. In conclusion, we concluded from the complementary methods that FGF21 can be considered as a potential biomarker for improved behaviour in obese mice after weight reduction.