Serum Fibroblast Growth Factor 23 Levels Research Articles

Fibroblast growth factor 21 (FGF21) is a sensitive marker of osteoporosis in haemodialysis patients: a cross-sectional observational study

IntroductionOsteoporosis is one of the important bone abnormalities in chronic kidney disease-mineral and bone disorder (CKD-MBD) and still lacks a sensitive biomarker to diagnose. Fibroblast growth factor 21 (FGF21) can stimulate bone loss in patients with diabetes and increase in CKD patients. In this study, we investigated whether FGF21 could serve as a biomarker to predict osteoporosis in a haemodialysis cohort.MethodsWe recorded demographic information, biochemical data, and serum FGF21 and FGF23 levels and measured the CT attenuation values of 339 haemodialysis patients from two large medical centres. We assessed the correlation of CT attenuation values with serum FGF21 and FGF23 levels and tested whether they were independent factors for osteoporosis. ROC curves were constructed to compare the prognostic value of FGF21 and FGF23 for osteoporosis.ResultsBased on the CT attenuation value, serum FGF21 levels were higher in our osteoporosis group (median 640.86 pg/ml vs. 245.46 pg/ml, P ˂ 0.01). Meanwhile, FGF21 (r = -0.136, P < 0.05) and FGF23 (r = -0.151, P < 0.05) were both negatively associated with osteoporosis. Moreover, FGF21 (β = -0.067, P < 0.05) was an independent factor for osteoporosis. Furthermore, FGF21 combined with age yielded a marked specificity (90.5 %) and sensitivity (61.8 %) in predicting osteoporosis of haemodialysis patients with less residual renal function.ConclusionsFGF21 has a positive relationship with the incidence of osteoporosis in patients on haemodialysis. FGF21 combined with age is a good predictive biomarker for osteoporosis in patients on haemodialysis, especially those with less residual renal function.

Spinal Cord Injury Reduces Serum Levels of Fibroblast Growth Factor-21 and Impairs Its Signaling Pathways in Liver and Adipose Tissue in Mice.

Spinal cord injury (SCI) results in dysregulation of carbohydrate and lipid metabolism; the underlying cellular and physiological mechanisms remain unclear. Fibroblast growth factor 21 (FGF21) is a circulating protein primarily secreted by the liver that lowers blood glucose levels, corrects abnormal lipid profiles, and mitigates non-alcoholic fatty liver disease. FGF21 acts via activating FGF receptor 1 and ß-klotho in adipose tissue and stimulating release of adiponectin from adipose tissue which in turn signals in the liver and skeletal muscle. We examined FGF21/adiponectin signaling after spinal cord transection in mice fed a high fat diet (HFD) or a standard mouse chow. Tissues were collected at 84 days after spinal cord transection or a sham SCI surgery. SCI reduced serum FGF21 levels and hepatic FGF21 expression, as well as β-klotho and FGF receptor-1 (FGFR1) mRNA expression in adipose tissue. SCI also reduced serum levels and adipose tissue mRNA expression of adiponectin and leptin, two major adipokines. In addition, SCI suppressed hepatic type 2 adiponectin receptor (AdipoR2) mRNA expression and PPARα activation in the liver. Post-SCI mice fed a HFD had further suppression of serum FGF21 levels and hepatic FGF21 expression. Elevated serum free fatty acid (FFA) levels after HFD feeding were observed in post-SCI mice but not in sham-mice, suggesting defective FFA uptake after SCI. Moreover, after SCI several genes that are implicated in insulin’s action had reduced expression in tissues of interest. These findings suggest that downregulated FGF21/adiponectin signaling and impaired responsiveness of adipose tissues to FGF21 may, at least in part, contribute to the overall picture of metabolic dysfunction after SCI.

Sternal Phosphaturic Mesenchymal Tumor-Induced Osteomalacia, Diagnosis and Management: A Case Report

Background: Tumor induced osteomalacia (TIO) is a rare paraneoplastic disorder in which overproduction of fibroblast growth factor-23 (FGF-23) by mesenchymal tumor results in decreased renal phosphorus reabsorption and low to inappropriately normal 1,25-dihydroxyvitamin D, leading to hypophosphatemia and osteomalacia. Patients often present with bone pain, fractures, muscle weakness, and progressive decline in mobility. Due to the nonspecific nature of presenting symptoms of TIO diagnosis is often delayed. Clinical Case: A 55-year-old male presented with complaints of chest pain, shortness of breath, and generalized weakness following a ground level fall. Patient also reported a 10-year history of osteoarthritis with chronic back pain and 1-year history of generalized weakness, resulting in significant decline in functional status. On work-up, the initial CT scan of chest revealed multiple fractures including ribs, manubrium, scapula, and pubic rami. Subsequent biochemical evaluation was remarkable for hypophosphatemia to low of 1.3 mg/dL (2.4 - 5.0 mg/dL), low of 1,25-dihydroxyvitamin D of 13.1 pg/ml (19.9 - 79.3 pg/mL), reduced tubular phosphate reabsorption rate of 28% (normal > 80%) ratifying for renal phosphate wasting, normal iPTH level, and elevated serum FGF-23 level of 460 (normal < 180). Then, localization imaging for TIO was performed. After PET/CT scan showing increased uptake at the sternal area suggestive of lytic metastasis, subsequent CT angiogram of the chest identified mottled, irregular, mildly expansile appearance of the sternal manubrium. Sternal biopsy revealed phosphaturic mesenchymal tumor with positive FGF 23 mRNA expression. Surgical resection was delayed due to poor functional status and concurrent discovery of an EBV-positive nasopharyngeal carcinoma. Prior to surgery patient was treated with phosphorus and calcitriol supplements. Post-operatively serum phosphorus and FGF-23 levels were normalized. Patient also improved clinically. Patients treatment course was complicated by secondary hyperparathyroidism; however, this improved following surgery. Conclusion: Diagnosis of TIO can be delayed due to its nonspecific symptoms. Thus, in patients with chronic bone pain, muscle weakness, and atraumatic fractures, TIO should be kept on the differential and these patients should undergo thorough biochemical and imaging evaluation. Tumor localization could be challenging. Patients should be managed with supplements of active vitamin D and phosphorus with goal to normalize phosphorus level to prevent further bone demineralization prior to surgery. However, surgical intervention remains the mainstay of management as this is curative of TIO.

Favorable Effects of Burosumab on Fibroblast Growth Factor 23-Related Osteomalacia: A Case Report

Background: Fibroblast growth factor 23 (FGF23) decreases serum phosphate levels by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption by decreasing serum 1,25-dihydroxyvitamin D level, thereby regulating phosphate metabolism. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by FGF23 overproduction by tumor tissue. Resecting the responsible tumor is a radical treatment for TIO. When the responsible tumor is undetectable, phosphate and active vitamin D administration is recommended. However, supplementation alone is frequently insufficient to maintain phosphate levels and it is difficult to prevent the complications associated with medical therapy, including hypercalciuria and nephrocalcinosis. Recently, burosumab, a human monoclonal anti-FGF23 antibody, has been approved in Japan as a therapeutic agent for FGF23-related hypophosphatemia. Here, we present a patient with TIO effectively treated with burosumab in the absence of identification of tumour location. Clinical case: A 47-year-old female developed pain and edema of the feet; however, the cause could not be determined at local hospitals. Afterwards, she developed marked bone atrophy in the feet and was referred to our hospital. Her age at symptom onset, hypophosphatemia (serum P, 1.9 mg/dl, 2.7 mg/dl < n < 4.6 mg/dl), high serum FGF23 level (630 pg/ml, 16 pg/ml < n < 69 pg/ml), and decreased 1,25-dihydroxyvitamin D level (12.9 pg/ml, 20 pg/ml < n < 60 pg/ml) indicated FGF23-related osteomalacia. She was not having any medication at the time of diagnosis, including saccharified iron oxide or iron polymaltose. Urinary phosphate excretion increased without renal tubular defect; therefore, hypophosphatemic osteomalacia was diagnosed. MRI showed high signal intensity in the talus, sacral, and L5 vertebral regions, indicating multiple pseudofractures. Comprehensive imaging studies, including systemic CT scan and 111In-pentetreotide scintigraphy, did not reveal any tumors despite the suspicion of TIO. Next, we performed systemic venous sampling, which revealed high FGF23 level in the left external iliac vein. Second venous sampling limited to the left lower limb exhibited high FGF23 level in the posterior tibial vein. However, an additional imaging study limited to the left foot could not identify any tumors. Genetic variation was negative for potentially responsible genes, including PHEX and FGF23. We decided to administer burosumab to normalize serum phosphate level without phosphate supplementation. Within 2 months, pain was relieved and the visual analog scale scores also improved from 10 to 6. Moreover, bone MRI showed improved pseudofractures. Conclusion: Burosumab administration was effective for TIO of unknown origin, and it improved not only laboratory findings but also clinical symptoms in this case.

Circulating fibroblast growth factor 21, renal function, and aortic hemodynamics in middle‐aged and older adults: a mediation analysis

Introduction A decline in renal function is associated with aortic stiffening and hypertension. However, the pathophysiological mechanisms behind the relation between renal dysfunction and altered aortic hemodynamics have not been fully elucidated. Fibroblast growth factor 21 (FGF21), which is an endocrine substance that is mainly secreted from the liver, has been reported to alter aortic hemodynamics via upregulation of sympathetic nerve activity. On the other hand, it has been demonstrated that circulating FGF21 levels were increased with decline of renal function. These findings have led us to hypothesize that elevated circulating levels of FGF21 may mediate the link between renal dysfunction, advanced aortic stiffness, and elevated blood pressure. Therefore, this study aimed to determine whether circulating FGF21 levels may mediate altered aortic hemodynamics in middle-aged and older adults with declined renal function. Methods Two-hundred ninety-nine middle-aged and older adults (age range: 46-83 years, percentage of men: 36%) were included in this study. To assess renal function, the estimated glomerular filtration rate (eGFR) was measured. The range of eGFR was 18 to 145 mL/min/1.73m2. Aortic blood pressure was measured by applanation tonometry. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV) using a standard procedure. Serum FGF21 levels were measured by ELISA. In the mediation analysis, aortic blood pressure and stiffness (cfPWV) were entered as outcomes respectively. The predictor and mediator were set for eGFR and log-transformed serum FGF21 levels respectively. Results Serum FGF21 levels were significantly correlated with aortic pulse pressure (r = 0.200) and cfPWV (r = 0.326). Moreover, eGFR was negatively correlated with aortic pulse pressure (r = −0.188) and cfPWV (r = −0.390). In multivariable regression models adjusting for the potential covariates including age, sex, body mass index, heart rate, current smoking status, anti-hypertensive, lipid lowering, and hypoglycemic medication use, serum FGF21 level was independently associated with aortic pulse pressure (β = 0.132) and cfPWV (β = 0.173). The mediation analysis demonstrated that serum FGF21 significantly mediates the relations of eGFR with aortic pulse pressure (indirect effect [95% CI]: −0.018 [−0.036, −0.003]) and cfPWV (−0.592 [−1.122, −0.184]). The percentages of these indirect effects were 33% and 34% of the total effect respectively. Conclusion The present study showed that circulating FGF21 level is independently associated with aortic hemodynamic parameters in middle-aged and older adults. Also, mediation analysis demonstrated that circulating FGF21 level mediated the association of renal function with aortic pulse pressure and stiffness. These findings suggest that elevated blood pressure and advanced aortic stiffness with decreased renal function may be partly mediated by the elevated circulating level of FGF21 in middle-aged and older adults.

Hyperphosphatemia Contributes to Skeletal Muscle Atrophy in Chronic Kidney Disease

Alterations in mineral metabolism involve changes in serum levels of phosphate as well as its key regulators, fibroblast growth factor 23 (FGF23), vitamin D, parathyroid hormone and klotho. Chronic Kidney Disease (CKD) is a public health epidemic that affects an estimated 37 million Americans, and is associated with elevated serum levels of phosphate (hyperphosphatemia) and FGF23 as well as various pathologies, such vascular calcification, cardiac hypertrophy, and skeletal muscle atrophy. We previously found that elevated FGF23 directly targets cardiac myocytes and contributes to cardiac hypertrophy. Furthermore, elevated phosphate has direct effects on smooth muscle cells and induces vascular calcification. In order to determine whether FGF23 and/or phosphate might also contribute to CKD-associated skeletal muscle atrophy, we tested if skeletal muscle cells can respond to elevations of FGF23 or phosphate. Since the skeletal muscle phenotype in CKD is not well characterized, we analyzed skeletal muscle on a functional, histological, and molecular level in two established mouse models of CKD. We studied the C2C12 skeletal muscle cell line during the differentiation process from myoblasts to myotubes as well as fully differentiated myotubes. Myoblast differentiation was induced with horse serum; cells were co-treated with 25 ng/ml FGF23 or 5 mM phosphate for 5 days, followed by the expression analysis of differentiation markers by qPCR. In a separate study, differentiated C2C12 myotubes were treated with FGF23 or phosphate for 24 hours, followed by the qPCR analysis of atrophy genes (atrogenes), including MT1, Murf1, and Fbox32. Furthermore, we studied mice with global deletion of collagen 4a3 (Col4a3-/-) and wildtype littermates at 10 weeks of age, as well as C57Bl/6 mice receiving an adenine-rich (0.2%) diet or regular chow for 12 weeks. In all mice we studied grip strength, hindlimb circumference by MRI, cross-sectional area of individual muscle fibers that were immuno-labeled with anti-laminin by fluorescence microscopy, and expression levels of atrogenes by qPCR. Phosphate but not FGF23 affected the differentiation process of C2C12 myoblasts and differentiated C2C12 myotubes. Phosphate treatments significantly reduced expression levels of MyoD and MyoG and increased expression of MT1. In both mouse models, grip strength and areas of hindlimb and myotubes were significantly reduced, and expression levels of MT1 and Murf1 were significantly elevated when compared to their controls. FGF23 does not target skeletal muscle cells suggesting that it cannot directly contribute to skeletal muscle atrophy. Elevated phosphate impairs myoblast differentiation and induces atrophy in vitro. We have characterized two CKD mouse models with associated skeletal muscle atrophy, where we will now determine the contribution of hyperphosphatemia to the injury process. Pharmacological approaches targeting phosphate uptake or excretion, or phosphate's direct actions on tissues might alleviate various CKD-associated pathologies.

FGF21 Serum Levels in the Early Second Trimester Are Positively Correlated With the Risk of Subsequent Gestational Diabetes Mellitus: A Propensity-Matched Nested Case-Control Study

BackgroundAs an important endocrine hormone regulating glucose metabolism, fibroblast growth factor 21 (FGF21) is increased in individuals with gestational diabetes mellitus (GDM) after 24 gestational weeks. However, it is unknown whether the increase in FGF21 precedes the diagnosis of GDM.MethodsIn this nested case-control study, 133 pregnant women with GDM and 133 pregnant women with normal glucose tolerance (NGT) were identified through propensity score matching, and serum FGF21 levels were measured at 14 to 21 gestational weeks, before GDM is routinely identified. The differences in FGF21 levels were compared. The association between FGF21 and the occurrence of GDM was evaluated using logistic regression models with adjustment for confounders.ResultsThe serum FGF21 levels of the GDM group at 14 to 21 gestational weeks were significantly higher than those of the NGT group overall (P < 0.001), with similar results observed between the corresponding BMI subgroups (P < 0.05). The 2nd (OR 1.224, 95% CI 0.603–2.485), 3rd (OR 2.478, 1.229–5.000), and 4th (OR 3.419, 95% CI 1.626–7.188) FGF21 quartiles were associated with greater odds of GDM occurrence than the 1st quartile after multivariable adjustments.ConclusionsThe serum FGF21 levels in GDM groups increased in the early second trimester, regardless of whether participants were stratified according to BMI. After adjusting for confounding factors, the FGF21 levels in the highest quartile were associated with more than three times higher probability of the diagnosis of GDM in the pregnancy as compared to levels in the first quartile.

The Effect of FGF21 and Its Genetic Variants on Food and Drug Cravings, Adipokines and Metabolic Traits.

Fibroblast growth factor 21 (FGF21) is a regulator of addictive behavior. Increasing evidence suggests an impact of FGF21 on eating behavior, food and drug cravings and on other adipokines like insulin-like growth factor 1 (IGF-1) or adiponectin. We investigated the association of serum FGF21 and genetic variants with aspects of food and drug craving and obesity related metabolic parameters including serum adipokine levels. Standardized questionnaires, blood samples and anthropometric data of the Sorbs cohort (n = 1046) were analyzed using SPSS. For genetic analyses, the FGF21-locus ±10 kb was genotyped and analyzed using PLINK. Validation was conducted in a second independent cohort (n = 704). FGF21 was significantly associated with alcohol and coffee consumption, smoking and eating behavior (disinhibition). We confirmed correlations of FGF21 serum levels with IGF-1, adiponectin, pro-enkephalin, adipocyte fatty-acid-binding protein, chemerin and progranulin. FGF21 genetic variants were associated with anthropometric and metabolic parameters, adipokines, food and drug craving while strongest evidence was seen with low-density lipoprotein cholesterol (LDL-C). We highlight the potential role of FGF21 in food and drug cravings and provide new insights regarding the link of FGF21 with other adipokines as well as with metabolic traits, in particular those related to lipid metabolism (LDL-C).

Serum Levels of Fibroblast Growth Factor 21 Are Positively Associated with Aortic Stiffness in Patients with Type 2 Diabetes Mellitus.

Aortic stiffness (AS), assessed using carotid–femoral pulse wave velocity (cfPWV), is associated with cardiovascular disease in type 2 diabetes mellitus (T2DM). The relationship between serum fibroblast growth factor 21 (FGF-21) and AS in T2DM patients was evaluated. Fasting serum FGF-21 levels of 130 T2DM patients were measured using an enzyme immunoassay kit. A validated tonometry system was used to measure cfPWV (>10 m/s indicated AS). Of these T2DM patients, 34.6% were defined as the AS group. T2DM patients with AS were older; exhibited higher systolic blood pressure, diastolic blood pressure, and body fat mass; higher triglyceride, fasting glucose, glycosylated hemoglobin, and creatinine levels; higher urine albumin-to-creatinine ratios and serum FGF-21 levels; and lower estimated glomerular filtration rates. The FGF-21 level (odds ratio = 1.005, 95% confidence interval: 1.002–1.009, p = 0.002) as well as systolic blood pressure was an independent predictor of AS and positively correlated to cfPWV values (β = 0.369, p < 0.001) in T2DM patients. For T2DM patients, serum FGF-21 level could be a predictor for AS.

Effect of selected elastic band resistance training on serum levels of fibroblast growth factor 23, TNF-α and hsCRP in overweight elderly women

ntroduction: Chronic inflammation can be the main cause of many common diseases in old age. Elevated level of CRP and proinflammatory cytokines such as TNF-α is positively associated with fibroblast growth factor 23 (FGF23). Therefore, considering the potentially beneficial effect of elastic band resistance training (EBRT) on these variables, this study was performed with aim to investigate the effect of 12 weeks of selected EBRT on serum levels of FGF23, TNF-α and hsCRP in overweight elderly women. Methods: This clinical trial study was performed in 2017 on 28 elderly women in Shahrekord. The subjects were randomly divided into experimental and control groups. EBRT was performed for 12 weeks. Fasting blood samples were taken 24 hours before the first training session and 48 hours after the last training session to measure serum levels of FGF23, TNF-α and hsCRP. Data were analyzed by SPSS software (version 25) and repeated measure two-way ANOVA test. P<0.05 was considered statistically significant. Results: EBRT had no significant effect on serum FGF23 levels, BMI, and Waist-to-hip ratio in elderly women (P>0.05); but serum levels of TNF-α (P=0.046), hsCRP (P=0.037), and also body fat percentage (P=0.023) significantly decreased after EBRT. Conclusion: Regardless to no significant changes in FGF23 levels, it seems that 12 weeks of EBRT can have a significant effect on reducing chronic inflammation in the elderly by reducing the levels of hsCRP and proinflammatory cytokine TNF-α.

Association between serum fibroblast growth factor 21 level and sight-threatening diabetic retinopathy in Chinese patients with type 2 diabetes

IntroductionWe conducted this cross-sectional study to explore the relationship between serum fibroblast growth factor 21 (FGF21) level and sight-threatening diabetic retinopathy (STDR).Research design and methodsA total of 654 patients with...

Retrospective analysis of factors associated with serum levels of fibroblast growth factor-21 in patients with diabetes.

Fibroblast growth factor-21 (FGF-21) plays multiple roles in pathophysiological processes of the human body. Previous studies have evidenced FGF-21 to be an inhibitor of vascular calcification through a variety of mechanisms. Increased levels of serum FGF-21 are known to be associated with an elevated risk of coronary heart disease; however, the factors affecting the expression of FGF-21 are currently unclear. This study aimed to observe the effects of some medications and other factors on serum FGF-21 levels in patients with diabetes. Baseline characteristics of patients with diabetes, including body mass index (BMI), medication, level of exercise, and other information, were collected and analyzed, and their baseline levels of serum FGF-21 were tested. The relationship of serum FGF-21 levels with these characteristics was analyzed. A total of 2118 patients were enrolled in the final analysis. Results revealed that the serum levels of FGF-21 in patients with a high BMI were elevated compared to those in patients with a normal or low BMI. Furthermore, the serum levels of FGF-21 in patients who engaged in regular exercise were higher than those in patients who exercised intermittently or not at all. No significant differences existed between patients who received different anti-diabetic drugs, or between patients treated with different antihyperlipidemic drugs. Also, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had no obvious effects on serum levels of FGF-21 in patients with diabetes. Drugs used in the treatment of patients with diabetes have no significant effects on serum levels of FGF-21. Obese patients had higher serum levels of FGF-21 than did non-obese patients. Participating in sports might increase the levels of FGF-21 in patients with diabetes.

Decreased serum fibroblast growth factor 19 level is a risk factor for type 1 diabetes.

BackgroundIncreasing evidence suggests that fibroblast growth factor 19 (FGF19) is a regulator of glucose metabolism and may provide a new therapeutic target for type 1 diabetes (T1D). However, the clinical relevance of FGF19 in T1D remains unclear. In this study, we examined the relationship between the serum FGF19 concentration and T1D.MethodsThis study included 81 newly diagnosed T1D patients and 80 sex- and age-matched healthy controls. The correlation between the FGF19 concentration and clinical characteristics of T1D patients and healthy controls was investigated. Logistic regression analysis was performed to determine whether levels of FGF19 were independently associated with T1D.ResultsThe fasting serum FGF19 levels in the T1D group were significantly lower than those in the control group [159.9 (100.0–272.7) vs. 205.0 (126.9–307.9) pg/mL, P=0.008]. In all subjects, serum FGF19 levels were negatively correlated with fasting blood glucose (FBG) (r=−0.192, P=0.015). In the control group, serum FGF19 levels were positively correlated with total cholesterol (TC) (r=0.338, P=0.002) and low-density lipoprotein cholesterol (LDL-c) (r=0.300, P=0.007). In addition to sex and body mass index (BMI), FGF19 was an independent impact factor for T1D [odds ratio (OR) =0.541, P=0.023; adjusted for sex, age, BMI, presence of hypertension, and presence of dyslipidemia].ConclusionsLow serum FGF19 level is associated with T1D, which could serve as a risk factor for T1D.

Effects of increased physical activity and/or weight loss diet on serum myokine and adipokine levels in overweight adults with impaired glucose metabolism.

The purpose of this study was to investigate the changes in serum irisin, fibroblast growth factor-21 (FGF21), visfatin, follistatin like protein-1 (FSTL1), and meteorin-like protein (Metrnl) levels in response to increased physical activity and/or diet interventions in overweight subjects with impaired glucose metabolism (IGM). A total of 60 subjects (BMI > 25.0 kg/m2) with IGM were recruited in this single-centered interventional study. Twelve subjects dropped out during the study and the study was completed with 48 patients. Patients were divided into two groups as diet only (DI, n = 24) and diet and physical activity intervention (DPA, n = 24). Patients in DI group received a diet program while DPA group received a diet combined with a physical activity intervention for 12 weeks. Additional 24 healthy subjects were recruited to compare the baseline levels of proteins. Serum protein levels, anthropometric measurements, and biochemical parameters were assessed. Irisin, FGF21, visfatin, and FSTL1 levels significantly decreased in both groups after 12-week intervention (p < 0.001). However, there were no differences in protein levels between DI and DPA groups (p > 0.05). Likewise, the total change in weight was similar in both DI (-4.35 kg) and DPA (-4.85 kg) groups (p > 0.05). A 5% reduction in initial body weight with DPA therapy resulted in a stronger correlation between the changes in irisin, visfatin, and FSTL1 levels and fasting glucose and HbA1c levels. These results demonstrate that serum irisin, FGF21, visfatin, and FSTL1 levels decreased in response to weight loss interventions. Weight loss induced by DI or DPA therapies had similar lowering effects on these proteins in subjects with IGM, and these myokines might be related to glucose metabolism biomarkers.

Epigenetic Regulation of Processes Related to High Level of Fibroblast Growth Factor 21 in Obese Subjects.

We hypothesised that epigenetics may play an important role in mediating fibroblast growth factor 21 (FGF21) resistance in obesity. We aimed to evaluate DNA methylation changes and miRNA pattern in obese subjects associated with high serum FGF21 levels. The study included 136 participants with BMI 27–45 kg/m2. Fasting FGF21, glucose, insulin, GIP, lipids, adipokines, miokines and cytokines were measured and compared in high serum FGF21 (n = 68) group to low FGF21 (n = 68) group. Human DNA Methylation Microarrays were analysed in leukocytes from each group (n = 16). Expression of miRNAs was evaluated using quantitative PCR-TLDA. The study identified differentially methylated genes in pathways related to glucose transport, insulin secretion and signalling, lipid transport and cellular metabolism, response to nutrient levels, thermogenesis, browning of adipose tissue and bone mineralisation. Additionally, it detected transcription factor genes regulating FGF21 and fibroblast growth factor receptor and vascular endothelial growth factor receptor pathways regulation. Increased expression of hsa-miR-875-5p and decreased expression of hsa-miR-133a-3p, hsa-miR-185-5p and hsa-miR-200c-3p were found in the group with high serum FGF21. These changes were associated with high FGF21, VEGF and low adiponectin serum levels. Our results point to a significant role of the epigenetic regulation of genes involved in metabolic pathways related to FGF21 action.

Acute cardiac overload does not induce cardiac or skeletal expression of fibroblast growth factor 23 in rats

ObjectiveElevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular events, particularly heart failure. Although FGF23 has been reported to induce cardiac hypertrophy, recent studies demonstrated that cardiac hypertrophy and myocardial infarction induce FGF23 production by cardiomyocytes. We aimed to explore whether acute cardiac overload increases cardiac and skeletal FGF23 expression and circulating FGF23 levels.MethodsWe administered 30 μL/g bodyweight of isotonic saline intraperitoneally in rats to induce acute cardiac overload. We measured serum FGF23 levels and other parameters of mineral metabolism at 2, 6, and 24 h after saline or sham injection. We also analyzed gene expression in the heart, calvarium, femur, and kidney at 2 and 24 h after injection.ResultsAcute saline injection induced cardiac overload as evidenced by a significant upregulation of brain natriuretic peptide along with a trend towards increased expression of atrial natriuretic peptide and mild hyponatremia. However, there were no changes in serum FGF23 levels or FGF23 expression in the heart, calvarium, or femur.ConclusionsAcute cardiac overload by saline injection in rats did neither induce FGF23 expression in the heart or bone nor did it increase serum FGF23 levels. These findings suggest that more severe or long-term cardiac damage is required for induction of FGF23 expression.

Serum Levels of FGF21, β-Klotho, and BDNF in Stable Coronary Artery Disease Patients With Depressive Symptoms: A Cross-Sectional Single-Center Study.

Background: The incidence of depressive symptoms (DS) in patients with stable coronary artery disease (SCAD) is significantly higher than those in healthy population, and that DS are independent risk factors for cardiovascular events. Previous studies have reported that fibroblast growth factor 21 (FGF21), β-klotho, mature brain-derived neurotrophic factor (mBDNF), and BDNF precursor (proBDNF) play important roles in the pathogenesis and treatment of coronary heart disease and depression. With this in mind, the present study aimed to clarify the relationship between FGF21, β-klotho, mBDNF, and proBDNF and SCAD with comorbid depression, in addition to also exploring the underlying mechanisms of these disease processes.Methods: A total of 116 patients with SCAD and 45 healthy controls were recruited. Patients with SCAD were further divided into two subgroups based on the Zung Self-Rating Depression Scale (SDS), which were characterized as those with no DS (NDS) and those with DS. Baseline data were collected, and serum levels of FGF21, β-klotho, mBDNF, and proBDNF were determined.Results: In SCAD patients, Gensini scores—denoting the degree of coronary arteriostenosis—were significantly greater in the DS group than in the NDS group. There was also a positive correlation between the Gensini scores and the SDS scores. Patients in the SCAD group demonstrated a lower serum FGF21. Serum β-klotho, mBDNF, and mBDNF/proBDNF were also significantly lower in the DS group than in the NDS group. Furthermore, β-klotho and mBDNF were negatively correlated with the SDS scores. Additionally, SCAD patients were divided into lower- and higher-level groups using hierarchical cluster analysis, with the results highlighting that patients in the lower mBDNF group had a higher incidence of DS.Conclusions: The depression score was positively correlated with the severity of coronary artery stenosis, and serum FGF21, β-klotho, mBDNF, and proBDNF were closely related to the development of DS in patients with SCAD. These observations suggest FGF21, β-klotho, mBDNF, and proBDNF as potential diagnostic and/or therapeutic targets for SCAD with co-morbid depression.

Influence of ursodeoxycholic acid therapy on levels of fibroblast growth factor 21, adiponectin and biochemical parameters in intrahepatic cholestasis of pregnancy

The aim was to assess whether fibroblast growth factor 21 (FGF-21) and adiponectin influence intrahepatic cholestasis of pregnancy (ICP) pathogenesis and whether ursodeoxycholic acid (UDCA) has an impact on their levels. 50 pregnant women with ICP (ICP PW), 50 with uncomplicated pregnancy (HPW) and 50 healthy nonpregnant women (HW) were included. In ICP PW the first blood sample was drawn at the time of diagnosis, while in HPW it was drawn in the 28th week of pregnancy. The next blood samples were drawn in the 32nd and 36th week of pregnancy and one day after delivery. UDCA was administered when ICP was diagnosed. In ICP PW serum FGF-21 concentration was the lowest at the time of diagnosis with an evident increase after UDCA administration. Serum FGF-21 levels were significantly higher in ICP PW than in HPW from the first to the last measurement. There was a negative association between adiponectin and bile acids (BAs) levels in the later stage of pregnancy in ICP PW. Up-regulated FGF-21 serum levels in ICP patients compared to HPW persisted after delivery, suggesting its role in disease pathophysiology. The negative association between serum adiponectin and BAs of the later stage of pregnancy may suggest its role in regulation of BAs concentration. UDCA exerts a beneficial effect on insulin sensitivity and up-regulates FGF-21 in ICP.

Assessment of retinol-binding protein-4, fibroblast growth factor-21, and dipeptidyl peptidase-4 in relation to obesity and insulin resistance of type 2 diabetes mellitus among Egyptian patients

Background/aim The relation between obesity, inflammation, and insulin resistance (IR) shows that adipose tissue plays a significant secretory role. Adipokines such as retinol-binding protein-4 (RBP-4), fibroblast growth factor-21 (FGF21), and dipeptidyl peptidase-4 (DPP4) exhibit pleiotropic biological activities and might be valuable biomarkers involved in the pathogenesis of type 2 diabetes mellitus (T2DM). The present study aims to assess serum levels of RBP-4, FGF21, and DPP4 and correlate their relation with obesity and IR in Egyptian patients with T2DM. Patients and methods This study included 130 patients with T2DM (70 obese and 60 nonobese) enrolled from the inpatient and outpatient clinics of the National Institute of Diabetes and Endocrinology (NIDE), Cairo, Egypt, in addition to 70 age-matched and sex-matched healthy individuals (35 obese and 35 nonobese). Serum level assessments of RBP-4, FGF21, and DPP4 were carried out on all participants using Enzyme Linked Immuno-Sorbent Assay technique. Results Serum levels of RBP-4, FGF21, and DPP4 showed statistically significant differences in all studied groups (P&lt;0.01). RBP-4, FGF21, and DPP4 were all correlated positively with BMI, fasting insulin, and HOMA-IR. RPB-4 was negatively correlated with high-density lipoprotein-cholesterol. Both RBP-4 and FGF21 were significantly associated with IR (odds ratio=1.264; P&lt;0.001, and odds ratio=1.059; P&lt;0.01, respectively), whereas receiver operating characteristic curves analysis revealed that serum levels of RBP-4 were most significant [area under curve (AUC)=0.826, P=&lt;0.001], followed by FGF21 (AUC=0.774, P&lt;0.001) and finally DPP4 (AUC=0.677, P&lt;0.001). Conclusions Obesity and IR were found to be significantly associated with RBP-4, FGF21, and DPP4. They were higher in all obese groups, with the diabetic obese group having the highest concentrations. Of the three adipokines studied, RBP-4 has the strongest link. This finding will bolster the adipose-derived factors use as biomarkers and targets for treating and managing obesity and T2DM.

Fibroblast Growth Factor 21 Predicts and Promotes Vascular Calcification in Haemodialysis Patients

Background: Cardiovascular disease (CVD) is the leading cause of death in haemodialysis (HD) patients. Vascular calcification (VC) is dramatically accelerated and is strongly associated with CVD events and mortality in HD patients. VC coexists with osteoporosis in many studies. Fibroblast growth factor 21 (FGF21) which is known as an adipocytokine is a new hypoglycemic strategy and is inversely related to bone mineral density. Methods: To evaluate the contribution of FGF21 to VC in HD patients, we detected circulating FGF21 levels and measured the whole thoracic aorta calcification scores (TACS) and calcification scores of the 3 segments of thoracic aorta, including ascending thoracic aorta (ATACS), aortic arch (AoACS), and descending thoracic aorta (DTACS) of our HD patients in this cross-sectional study. In addition, we pre-incubated human aortic endothelial cells (HAECs) with FGF21 in the presence or absence of parathyroid hormone (PTH) in vitro. Results: The median serum FGF21 level in HD patients was 11-fold higher than that in healthy controls. Ln(FGF21) was positively correlated with Ln(TACS+1), Ln(ATACS+1), Ln(AoACS+1), and Ln(DTACS+1), respectively, in HD patients. Serum FGF21 was independently associated with TACS and ATACS, AoACS, and DTACS. FGF21 which was combined with age, calcium, and intact PTH demonstrated a high area under the curve of 0.84 with optimal sensitivity (84%) and specificity (71%) for the prediction of VC in HD patients. Our vitro results showed that FGF21 enhanced the calcification effect of PTH on HAECs by increasing calcium deposition and endothelial-to-mesenchymal transition. Conclusions: Circulating FGF21 was notably higher and was a potential predictor and promoter of VC in HD patients.