Serum Fibroblast Growth Factor 23 Concentrations Research Articles

Understanding the Mechanism of Fibroblast Growth Factor 21 Action in the Paraventricular Nucleus of the Hypothalamus: A Promising Candidate in the Treatment of Obesity and Metabolic Diseases

Fibroblast Growth Factor 21 (FGF21), when administered pharmacologically reduces body weight, increases insulin sensitivity and energy expenditure, and induces browning of white adipose tissue (WAT). Research has shown that FGF21 signaling in the brain is required for the induction of these metabolic benefits, with the paraventricular nucleus of the hypothalamus (PVN) as a potential primary site of action. However, the neuronal circuits and precise mechanisms mediating FGF21’s metabolic effects remain incompletely understood. Further, the role of the sympathetic nervous system (SNS) in this process remains unclear. Here, we aimed to address these questions using dietary methionine restriction (MR) as a tool to stimulate endogenous FGF21 production in WT and FGF21 KO mice fed a control or a high‐fat diet. Dietary MR rapidly and persistently increases serum FGF21 concentration by up to 8‐fold (p<0.0001). We found that in WT mice, MR increased energy expenditure and thermogenic markers in iWAT and BAT, an indication of increased SNS output to these tissues in WT, but not FGF21 KO mice. Additionally, we observed increased ERK phosphorylation in the PVN of the WT but not FGF21 KO mice, supporting PVN neurons as a likely target mediating FGF21 actions. To further investigate the role of FGF21 in the PVN, we used whole‐cell patch clamp recordings in retrogradely‐labelled presympathetic PVN neurons projecting to the rostral ventrolateral medulla (RVLM), and measured the effects of the FGF21 analog LY2405319 (500nM) on the firing activity of PVN‐RVLM neurons. Recordings in current‐clamp mode showed that FGF21 either increased (33% of recorded neurons) or decreased (67% of recorded neurons) the firing activity of these neurons suggesting that FGF21 effects may depend on their projecting targets. Recordings in voltage‐clamp mode also showed that FGF21 significantly decreased the degree of activity of GABAergic inhibitory inputs into these neurons. Thus, LY2405319 inhibited the frequency of GABA inhibitory postsynaptic current (IPSC) (42.02% decrease, p< 0.05), suggesting that FGF21 effects on presympathetic neurons in the PVN could be mediated by direct and/or indirect actions, including modulation of local network activity, such as local GABAergic interneurons. Taken together, our data support the hypothesis that FGF21 signals through PVN neurons to increase SNS output to adipose tissue, resulting in increased energy expenditure, reduced body weight, and improved insulin sensitivity.

Lower Serum Fibroblast Growth Factor 21 Levels are Associated with Normal Lumbar Spine Bone Mineral Density in Hemodialysis Patients.

Recent evidence has indicated that fibroblast growth factor 21 (FGF21) regulates longitudinal bone growth, with increased FGF21 levels leading to bone loss. The present study evaluated the relationship between bone mineral density (BMD) and serum FGF21 levels in patients undergoing hemodialysis (HD). We analyzed blood samples from 95 patients undergoing HD and measured BMD using dual-energy X-ray absorptiometry of the lumbar vertebrae (L2–L4). Serum FGF21 concentrations were determined using a commercially available enzyme-linked immunosorbent assay kit. Thirteen (11.6%) patients were found to have osteoporosis, 27 (28.4%) osteopenia, and 57 patients had normal BMD. Advanced age and decreased body mass index, height, body weight, waist circumference, and triglyceride level were associated with lower lumbar T-scores, as were increased alkaline phosphatase, urea reduction rate, fractional clearance index for urea, and FGF21 levels. Low log-FGF21, increased body mass index, increased pre-HD body weight, and increased logarithmically transformed triglycerides (log-TG) were found to be significantly and independently associated with lumbar BMD by multivariate forward stepwise linear regression analysis with adjustment for significant confounders. We conclude that high serum FGF21 level is negatively associated with BMD in patients undergoing HD.

Phosphorus Restriction Changes the Expression of Fibroblast Growth Factor 23 and Its Receptors in Laying Hens

Dietary phosphorus oversupply wastes non-renewable natural resources and raises environmental concerns in animal agriculture. We hypothesized that laying hens do not need large safety margins for dietary phosphorus because of the existence of fibroblast growth factor 23 (FGF23). In experiment 1, a total of 504 Hy-Line Brown laying hens (40-week-old) were randomly assigned to seven diets (for each diet, six replicates of 12 hens), containing 0.12, 0.17, 0.22, 0.27, 0.32, 0.37, and 0.42% non-phytate phosphorus, respectively, for 15 weeks. In experiment 2, a total of 14 Hy-Line Brown laying hens (40-week-old) were randomly assigned to two diets: (1) phosphorus restricted (n = 7) diet containing 0.14% non-phytate phosphorus, and (2) regular phosphorus (n = 7) diet containing 0.32% non-phytate phosphorus, for 21 days. Laying performance and egg quality were investigated in experiments 1 and 2. Phosphorus excretion and physiological changes were determined in experiment 2. It was found that dietary non-phytate phosphorus levels had no effects (P > 0.05) on laying performance and egg quality in either experiment. In experiment 2, laying hens fed 0.14% non-phytate phosphorus had decreased phosphorus excretion (by 52.6%, P < 0.001) when compared to those fed 0.32% non-phytate phosphorus. In response to the 0.14% non-phytate phosphorus diet, laying hens in experiment 2 exhibited: (1) suppressed calvaria mRNA expressions of FGF23 (by 57.8%, P < 0.001) and fibroblast growth factor receptor 1 (FGFR1, by 52.8%, P = 0.012), (2) decreased serum levels of FGF23 (by 41.7%, P = 0.011) and phosphorus (by 40.3%, P < 0.001), (3) decreased kidney mRNA expressions of FGFR1 (by 66.0%, P = 0.040) and FGFR4 (by 63.3%, P = 0.012) and decreased kidney protein expression of type 2a sodium-phosphorus co-transporter (NPt2a, by 51%, P = 0.025), (4) increased duodenum protein expression of NPt2b (by 45%, P = 0.032), and (5) increased excretion of calcium (by 22.9%, P ≤ 0.024). Collectively, decreasing dietary non-phytate phosphorus by up to 0.12% had no negative effects on egg-production performance but significantly decreased phosphorus excretion in laying hens. The laying hens adjusted to low-phosphorus diets by increasing intestinal NPt2b protein production, which was associated with decreased serum FGF23 concentration. Decreasing dietary non-phytate phosphorus is suggested to laying-hen nutritionists.

Inhibitors of canonical Wnt signaling pathway and inorganic phosphate imbalance in experimental chronic kidney disease

BACKGROUND. The molecular mechanisms of the initial stages of inorganic phosphate (Pi) metabolic disorders in chronic kidney disease (CKD) remain poorly understood.THE AIM. To test the hypothesis about changes in canonical Wnt signaling pathway inhibitors biosynthesis and a concomitant decrease in bone turnover as one of early mechanisms of Pi imbalance in CKD.MATERIAL AND METHODS. Creatinine (Cr), inorganic phosphate (Pi), serum parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), sclerostin (SOST) and Dickkopf-1 (DKK), renal SOST and DKK mRNA expression, albuminuria (Alb), proteinuria (uTP) levels, fractional (FEPi) and daily (uPi24) Pi excretion were analyzed in SHR rats (N = 52) with 3/4 nephrectomy (NE) or sham operation (SO) and observation periods of 2, 4, and 6 months.RESULTS. Experimental model was comparable with 1-2 stages of CKD. In groups NE4 and NE6, the concentration of sPi and renal Pi excretion (FEPi and uPi24) were significantly higher vs corresponding controls SO4 (p = 0.006, p &lt;0.010) and SO6 (p = 0.002, p = 0.028). Serum concentrations of FGF23 and PTH in NE and SO animals did not change significantly. In NE4 and NE6 groups, serum SOST and DKK concentrations were significantly higher vs controls (p &lt;0.049, p &lt;0.043), while the kidney expression SOST and DKK mRNA in NE rats did not change significantly or decreased (p = 0.002, p &lt;0.011). The serum concentration of OPG was higher in the NE6 vs SO6 control (p = 0.028).CONCLUSION. The initial stages of experimental CKD are characterized by an increase in serum concentrations of Dikkopf-1, sclerostin and osteoprotegerin. The obtained data suggest the possible role of canonical Wnt signaling inhibition and reduction of bone turnover in the pathogenesis of Pi metabolic disorders in early stages of CKD.

Assessment of fibroblast growth factor 23 in relation to peripheral arterial disease in type 2 diabetes mellitus

BackgroundPeripheral arterial disease (PAD) is a major vascular complication and the leading cause of amputation in people with diabetes. Fibroblast growth factor 23 (FGF-23) is a recently discovered 30-kD secreted hormone glycoprotein that plays a role in the complex and tightly regulated mechanisms of mineral metabolism. Increase in serum FGF-23 concentration was an independent predictor of coronary artery diseases in patients with mild chronic kidney disease and of mortality in patients undergoing hemodialysis. Recently, FGF-23 has been found to be associated with total body atherosclerosis and vascular dysfunction.ObjectiveTo evaluate the relation between FGF-23 and PAD in patients having type 2 diabetes with normal kidney function.Patients and methodsA case-control study was conducted on 120 diabetic patients, where 60 patients having type 2 diabetes with PAD were compared with 60 patients having type 2 diabetes without PAD. All patients were subjected to full history taking, thorough clinical examination, ankle-brachial index assessment, and laboratory measurement of glycated hemoglobin%, estimated glomerular filtration rate, microalbuminuria, lipid profile, serum ionized calcium and phosphorous, and serum FGF-23.ResultsSignificantly higher serum FGF-23 was found in diabetic patients with PAD compared with diabetic patients without PAD. Logistic regression analysis showed that duration of diabetes, triglycerides level, phosphorous level, glycated hemoglobin, and FGF-23 were independent predictors for PAD.ConclusionFGF-23 level was higher in type 2 diabetic patients with PAD, which highlights a possible implication of FGF-23 in the pathogenesis of PAD in type 2 diabetes.

High Plasma Erythropoietin Predicts Incident Fractures in Elderly Men with Normal Renal Function: The MrOS Sweden Cohort.

Preclinical studies on the role of erythropoietin (EPO) in bone metabolism are contradictory. Regeneration models indicate an anabolic effect on bone healing, whereas models on physiologic bone remodeling indicate a catabolic effect on bone mass. No human studies on EPO and fracture risk are available. It is known that fibroblast growth factor 23 (FGF23) affects bone mineralization and that serum concentration of FGF23 is higher in men with decreased estimated glomerular filtration rate (eGFR). Recently, a direct association between EPO and FGF23 has been shown. We have explored the potential association between EPO and bone mineral density (BMD), fracture risk, and FGF23 in humans. Plasma levels of EPO were analyzed in 999 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) study, MrOS Sweden. The mean ± SD EPO was 11.5 ± 9.0 IU/L. Results were stratified by eGFR 60 mL/min. For men with eGFR ≥60 mL/min (n = 728), EPO was associated with age (r = 0.13, p < 0.001), total hip BMD (r = 0.14, p < 0.001), intact (i)FGF23 (r = 0.11, p = 0.004), and osteocalcin (r = -0.09, p = 0.022). The association between total hip BMD and EPO was independent of age, body mass index (BMI), iFGF23, and hemoglobin (beta = 0.019, p < 0.001). During the 10-year follow-up, 164 men had an X-ray-verified fracture, including 117 major osteoporotic fractures (MOF), 39 hip fractures, and 64 vertebral fractures. High EPO was associated with higher risk for incident fractures (hazard ratio [HR] = 1.43 per tertile EPO, 95% confidence interval [CI] 1.35-1.63), MOF (HR = 1.40 per tertile EPO, 95% CI 1.08-1.82), and vertebral fractures (HR = 1.42 per tertile EPO, 95% CI 1.00-2.01) in a fully adjusted Cox regression model. In men with eGFR<60 mL/min, no association was found between EPO and BMD or fracture risk. We here demonstrate that high levels of EPO are associated with increased fracture risk and increased BMD in elderly men with normal renal function. © 2019 American Society for Bone and Mineral Research.

Serum Fibroblast Growth Factor 21 Levels Are Positively Associated with Metabolic Syndrome in Patients with Type 2 Diabetes.

Background Fibroblast growth factor 21 (FGF21) acts as a potent metabolic regulator. Serum FGF21 levels were significantly higher in obesity and type 2 diabetes mellitus (T2DM) populations. The aim of this study was to evaluate the relationship between serum FGF21 levels and metabolic syndrome (MetS) in T2DM patients. Methods Fasting blood samples were obtained from 126 T2DM patients. MetS and its components were defined according to the diagnostic criteria from the International Diabetes Federation. Serum FGF21 concentrations were measured using a commercially available enzyme-linked immunosorbent assay. Results Among these patients, 84 (66.7%) had MetS. Female gender, hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference (WC), body weight (BW), body mass index (BMI), body fat mass, fasting glucose, glycated hemoglobin level (HbA1c), triglyceride level (TG), urine albumin-to-creatinine ratio (UACR), insulin level, homeostasis model assessment of insulin resistance (HOMA-IR), and FGF21 levels were higher, whereas high-density lipoprotein cholesterol level (HDL-C) and estimated glomerular filtration rate (eGFR) were lower in DM patients with MetS. Univariate linear analysis revealed that hypertension, BMI, WC, body fat mass, SBP, DBP, logarithmically transformed TG (log-TG), low-density lipoprotein cholesterol (LDL-C) level, log-glucose, log-creatinine, log-UACR, log-insulin, and log-HOMA-IR positively correlated, whereas HDL-C and eGFR negatively correlated with serum FGF21 levels in T2DM patients. Multivariate forward stepwise linear regression analysis revealed that body fat mass (adjusted R2 change = 0.218; P=0.008) and log-TG (adjusted R2 change = 0.036; P < 0.001) positively correlated, whereas eGFR (adjusted R2 change = 0.033; P=0.013) negatively correlated with serum FGF21 levels in T2DM patients. Conclusions This study showed that higher serum FGF21 levels were positively associated with MetS in T2DM patients and significantly positively related to body fat mass and TG but negatively related to eGFR in these subjects.

Metabolic response to fasting predicts weight gain during low-protein overfeeding in lean men: further evidence for spendthrift and thrifty metabolic phenotypes

Greater increase in 24-h energy expenditure (24EE) during overfeeding and smaller decrease in 24EE during fasting ("spendthrift" metabolic phenotype) are associated with more weight loss during sustained caloric restriction in overweight subjects. The aim of this study was to investigate whether these acute metabolic responses can also predict weight gain during sustained overfeeding in lean individuals. Seven lean men participated in this study. Prior to overfeeding, 24EE responses to fasting and 200% normal-protein overfeeding were measured in a whole-room indirect calorimeter. Volunteers underwent 6 wk of 150% low-protein (2%) overfeeding followed by another wk of weight-maintaining diet, during which 24EE was revaluated. Body composition, 24EE, and various hormone concentrations, including fibroblast growth factor 21 (FGF21), were assessed at baseline, at wk 1, 3, and 6 of the overfeeding period, and 1 wk following overfeeding through the use of dual-energy X-ray absorptiometry, indirect calorimetry, and ELISA. Cumulative energy surplus was calculated from 24EE, daily physical activity, and direct measurements of calories of nutrient intake, feces, and urine by bomb calorimetry. The average weight gain during 6 wk of low-protein overfeeding was 3.8 kg (6.1%, min: +2.5%, max: +8.0%). During 24-h fasting at baseline, 24EE decreased on average (mean ± SD) by 158±81 kcal/d (P=0.007). Subjects with less 24EE decrease during fasting (more metabolically spendthrift individuals) gained less weight (r=-0.84, P=0.03), less fat mass (r=-0.81, P=0.049), and stored less calories (r=-0.91, P=0.03) during overfeeding. Following overfeeding, increased 24EE above requirements for achieved body size was associated with less weight and fat mass gain (r=-0.78, P=0.04) and with the increase in 24EE during 200% normal-protein overfeeding measured at baseline (r=0.91, P=0.005). Serum FGF21 concentrations increased up to 44-fold during overfeeding (P< 0.0001). Low-protein overfeeding may be an important tool to identify metabolic phenotypes (spendthrift compared with thrifty) that characterize susceptibility to weight gain. This trial was registered at clinicaltrials.gov as NCT00687115.

Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease

Iron deficiency, anemia, hyperphosphatemia, and increased fibroblast growth factor 23 (FGF23) are common and interrelated complications of chronic kidney disease (CKD) that are linked to CKD progression, cardiovascular disease and death. Ferric citrate is an oral phosphate binder that decreases dietary phosphate absorption and serum FGF23 concentrations while increasing iron stores and hemoglobin in patients with CKD. Here we compared the effects of ferric citrate administration versus a mineral sufficient control diet using the Col4a3 knockout mouse model of progressive CKD and age-matched wild-type mice. Ferric citrate was given to knockout mice for four weeks beginning at six weeks of age when they had overt CKD, or for six weeks beginning at four weeks of age when they had early CKD. Ten-week-old knockout mice on the control diet showed overt iron deficiency, anemia, hyperphosphatemia, increased serum FGF23, hypertension, decreased kidney function, and left ventricular systolic dysfunction. Ferric citrate rescued iron deficiency and anemia in knockout mice regardless of the timing of treatment initiation. Circulating levels and bone expression of FGF23 were reduced in knockout mice given ferric citrate with more pronounced reductions observed when ferric citrate was initiated in early CKD. Ferric citrate decreased serum phosphate only when it was initiated in early CKD. While ferric citrate mitigated systolic dysfunction in knockout mice regardless of timing of treatment initiation, early initiation of ferric citrate also reduced renal fibrosis and proteinuria, improved kidney function, and prolonged life span. Thus, initiation of ferric citrate treatment early in the course of murine CKD lowered FGF23, slowed CKD progression, improved cardiac function and significantly improved survival.

The role of vitamin D replacement therapy in serum FGF23 concentration in children with myelomeningocele compared with healthy children - a preliminary study.

Background Fibroblast growth factor 23 (FGF23) is a recently discovered bone-derived regulator of vitamin D metabolism and phosphate homeostasis. It inhibits phosphate reabsorption and calcitriol production by the kidney. Myelomeningocele (MMC) remains the most severe form of neural tube defects involving serious locomotor disability, osteoporosis and pathologic fractures. We aimed to investigate the influence of vitamin D replacement therapy on serum FGF23 concentration in children with MMC and compare the results with healthy participants. Methods This prospective analysis was conducted on 16 children with MMC and 20 healthy children. Serum FGF23 levels were measured; for the studied group, before and after vitamin D replacement therapy with cholecalciferol (vitamin D3). The children's medical charts were analyzed to determine age, sex, anthropometric measurements, calcium and phosphate, cholecalciferol and renal function parameters. Results There were significant differences in vitamin D and FGF23 serum concentrations between the studied groups. The median vitamin D levels in the MMC group increased during replacement therapy (7 vs. 18.5 ng/mL, p = 0.29) in comparison to the median of 25.5 ng/mL in the control group. In MMC children we found a significant decrease in median serum FGF23 after vitamin D replacement therapy (from 42.1 to 0 RU/mL, p < 0.001). FGF23 correlated positively with albumin, serum and urine phosphate levels and negatively with alkaline phosphatase. Conclusions 1. Serum concentration of FGF-23 is increased in MMC children in comparison to a healthy control group. 2. Vitamin D replacement therapy decreases FGF23 concentrations in MMC children, although further studies are still warranted to gain detailed insight on the FGF23 in the MMC population. 3. Children with MMC present vitamin D deficiency. Nutrition supplemented with low doses of cholecalciferol (vitamin D3) (intakes reaching recommended daily allowances) was insufficient to correct 25(OH)-D level in that population of patients.

Oral vitamin D3 supplementation increases serum fibroblast growth factor 23 concentration in vitamin D-deficient patients: a systematic review and meta-analysis.

Studies have suggested that vitamin D supplementation may increase serum fibroblast growth factor 23 (FGF23) among vitamin D-deficient patients although the results were inconsistent across the studies. This systematic review and meta-analysis was conducted to summarize all available data. A systematic review was conducted using MEDLINE and EMBASE database from inception to February 2019 to identify studies that provided oral vitamin D3 supplement to vitamin D-deficient participants (25-hydroxyvitamin D < 20ng/mL). Mean serum FGF23 concentration and standard deviation of participants at baseline and after vitamin D3 supplementation were extracted to calculate standard mean difference (SMD). Pooled SMD was calculated by combining SMDs of each study using random effects model. Nine studies were eligible for the meta-analyses. Seven studies measured serum intact FGF23, and two studies measured serum C-terminal FGF23. The meta-analyses found that serum intact FGF23 increased significantly after oral vitamin D3 supplementation in vitamin D-deficient participants with the pooled SMD of 0.36 (95%CI, 0.14, 0.57; p = 0.001; I2 of 36%). Serum C-terminal FGF23 also increased after vitamin D3 supplementation in vitamin D-deficient participants with the pooled SMD of 0.28 although without reaching statistical significance (95%CI, - 0.08, 0.65; p = 0.13; I2 of 0%). Funnel plot of the meta-analysis of serum intact FGF23 did not provide a suggestive evidence for publication bias. Vitamin D supplementation leads to a significant increase in serum intact FGF23 among vitamin D-deficient patients. An increase in serum C-terminal FGF23 was also observed although the number of included studies was too small to demonstrate statistical significance. The present systematic review and meta-analysis revealed that serum intact FGF23 concentration increased significantly after oral vitamin D3 supplementation in vitamin D-deficient participants. An increase in serum C-terminal FGF23 concentration was also observed although the number of included studies was too small to demonstrate statistical significance.

Association of Intracranial Artery Calcification with Cognitive Impairment in Hemodialysis Patients

BackgroundChronic kidney disease (CKD) is one of risk factors for dementia and cognitive decline. Cardiovascular and dialysis-related factors might also be involved in the mechanism of cognitive impairment in hemodialysis patients. The objective of this study was to investigate whether cardiovascular risk factors including intracranial artery calcification and dialysis-related factors such as fibroblast growth factor 23 (FGF23) might be associated with cognitive impairment in hemodialysis patients.Material/MethodsA cross-sectional observational study included patients receiving in-center hemodialysis over 6 months at our hospital. All patients underwent non-contrast computed tomography (CT) examinations. Internal carotid artery (ICA) calcium scores were measured using the Agatston method. The Korean version of the Montreal Cognitive Assessment was used for measurement of cognitive function at each study visit. Serum concentrations of FGF23, osteoprotegerin, and klotho were analyzed using commercial enzyme-linked immunosorbent assay kits.ResultsThis study included 69 patients. Cognitive impairment was observed in 22 patients (31.9%), including 3 patients with dementia. ICA calcium score in patients with cognitive impairment was higher than that in those without cognitive impairment (177.3 versus 87.6, P=0.022). Intracranial artery calcification was significantly associated with cognitive impairment after adjusting for FGF23 and 25-OH vitamin D, but not significant after adjusting for age, FGF23, and 25-OH vitamin D. Low level of FGF23 was associated with cognitive impairment.ConclusionsIntracranial artery calcification and low FGF23 could be associated with cognitive impairment in hemodialysis patients. Longitudinal studies are needed to investigate whether intracranial artery calcification and FGF23 could affect cognitive function of hemodialysis patients.

The relationship between serum FGF-23 concentration and insulin resistance, prediabetes and dyslipidemia in obese children and adolescents.

Background Obesity is known to cause metabolic disturbances including insulin resistance, dyslipidemia and alters bone mineralization. The effects of obesity on fibroblast growth factor 23 (FGF-23), which is important in bone mineralization, have not yet been clarified. Our aim was to investigate the association between FGF-23 concentration and obesity-associated dysmetabolism. Methods Subjects comprised 46 obese children and adolescents. The same number of age-matched, healthy controls were recruited. Markers of bone mineralization and glucose metabolism were measured. Thyroid function and insulin resistance were investigated in both groups. In obese subjects; an oral glucose tolerance test (OGTT) was performed and hemoglobin A1c and lipid fractions were measured. Bone mineral density and hepatic steatosis were investigated. Results Serum FGF-23, α-klotho and 1,25(OH)2D3 concentrations were significantly lower while fasting insulin, fasting glucose, C-peptide and alkaline phosphatase (ALP) concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly higher in the obese group compared to controls. A significant negative correlation was observed between free tri-iodothyronine (fT3) and both FGF-23 and α-klotho in the obese group. Significant negative correlation was found between FGF-23 and C-peptide and a positive correlation was found between FGF-23 and high density lipoprotein-cholesterol (HDL-c) in the obese subjects with impaired glucose tolerance (IGT). Significant negative correlations were found between FGF-23 and both fasting insulin levels and C-peptide levels in the obese subjects with hepatic steatosis. Conclusions In our study, insulin resistance-associated hyperinsulinism and/or lower 1,25(OH)2D3 levels, both present in obese children and adolescents, may lead to decreased serum FGF-23 concentrations in obese subjects.

Everolimus assay* with automated pretreatment for the dimension chemistry systems

We examined the correlation between thyroid hormone (TH) concentrations and the serum fibroblast growth factor 21 (FGF21) concentration in septic patients and to assess the collaborative value of these factors in predicting 28-day mortality in septic patients.A total of 120 consecutive patients with sepsis were divided into two groups according to their survival or death within 28 days after initial diagnosis of sepsis.Patients in the non-survivor group had significantly higher serum FGF21 concentrations but lower total and free triiodothyronine (T3) and tetraiodothyronine (T4) concentrations than those in the survivor group. Thyroid hormone concentrations, including T3, free T3, T4 and free T4, were significantly negatively correlated with the ∆SOFA and APACHE II scores as well as the serum FGF21, IL-6, tumor necrosis factor-α, IL-10, procalcitonin, and C-reactive protein concentrations. Logistic regression analysis showed that the ∆SOFA score, serum FGF21 concentration, and free T3 concentration were significant predictors of 28-day mortality. The model with variables of ∆SOFA score and serum FGF21 and free T3 concentrations had the greatest area under the curve of 0.969.The addition of free T3 and serum FGF21 to ∆SOFA score provided a significantly improved ability to predict 28-day mortality in septic patients.

Association of fibroblast growth factor 23 with age-related cardiac diastolic function subclinical state in a healthy Chinese population

Objective: To determine the association of serum fibroblast growth factor-23 concentrations with age-related cardiac diastolic function subclinical state and whether this association differs by sex. Methods: Seven hundred sixteen healthy subjects (aged 35-89 years, 68.4% female) were selected from National Basic Research Program of China (973 Program-China Medical University subsection) between January 2014 and February 2015 and assigned into 4 groups according to sex and age:< 60 years old male and female group, ≥ 60 years old male and female group. Blood biochemical indicators and general clinical data of the subjects were measured. The glomerular filtration rate (eGFR) were estimated using the Modified Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI-ASIA) equation. The fibroblast factor 23 (FGF-23), C-reactive protein (CRP) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Cardiac structure and function parameters including left atrial diameter (LAD), inter-ventricular septum thickness (IVST), left ventricle posterior wall thickness (LVPWT), left ventricle mass index (LVMI),left atrial mass index (LAVI) and the ratio of peak velocity of early filling to the septal early peak diastolic mitral annulus velocity(E/e') were measured by echocardiography. Association between serum FGF-23 and aging-related diastolic function subclinical status was analyzed by binary Logistic regression analysis. Results: (1) Serum log-transformed FGF-23 levels were significantly higher in males than in females [(2.0±0.3) ng/L vs (1.9±0.4) ng/L, P<0.05]. (2) Cardiac diastolic function gradually decreased with age, and age related cardiac diastolic function decline of female was significantly higher than males[E/e':<60 years old male group (7.6±2.6), ≥ 60 years old male group (8.6±2.7), P<0.01;<60 years old female group (8.3±2.3), ≥ 60 years old female group (9.5±3.1), P<0.01; LAVI:<60 years old female group (14±5) ml/m(2), ≥ 60 years old female group (16±5) ml/m(2), P<0.01]. (3) Serum FGF-23 was significantly positively correlated with age (r=0.089, P<0.05) and LAVI (r=0.084, P<0.05) in total study population while with E/e' (r=0.149, P<0.05) only in males. There was no significant correlation between serum FGF-23 and cardiac diastolic function parameters in females. (4) Binary Logistic regression analysis showed that median and high FGF-23 were independently associated with age-related cardiac diastolic function decline (OR=2.831, 95% CI: 1.144-7.009, P=0.024; OR=2.548, 95% CI: 1.053-6.163, P=0.038) in males. Conclusions: Serum FGF-23 concentrations are associated with age-related cardiac diastolic function subclinical state in a healthy Chinese population. High levels of FGF-23 are independently associated with age-related cardiac diastolic function decline in males.

Evaluation of serum fibroblast growth factor-23 in patients with axial spondyloarthritis and its association with sclerostin, inflammation, and spinal damage.

The mechanisms underlying new bone formation in individuals with axial spondyloarthritis (axSpA) remain unclear; however, low levels of sclerostin (SOST) may be associated with development of syndesmophytes in those with ankylosing spondylitis (AS). Expression of fibroblast growth factor-23 (FGF-23), another osteocyte factor, is high in those with osteoporosis and chronic renal failure, but levels in those with axSpA are unknown. To evaluate serum FGF-23 and SOST levels in axSpA patients, and to assess their relationship with inflammation and structural damage. In total, 109 axSpA patients (55 with AS and 54 with non-radiographic axSpA) and 57 healthy control (HC) subjects were included in the analysis. Serum concentrations of FGF-23 and SOST were measured and correlation analysis was performed. The presence of syndesmophytes and the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) were used to assess structural damage. Levels of serum FGF-23 in axSpA patients were significantly higher than those in HCs [median (interquartile range-IQR) FGF-23 level, pg/ml; AxSpA = 144 (82.3-253.2), HC = 107 (63.3-192.8), p = 0.010]; however, there was no difference in SOST levels. FGF-23 levels correlated with the erythrocyte sedimentation rate (ESR) (r = 0.265, p = 0.006) and serum C-reactive protein (CRP) level (r = 0.229, p = 0.010). In the axSpA, SOST levels correlated negatively with mSASSS (r = - 0.283, p = 0.007), whereas those in the AS group correlated negatively with CRP (r = - 0.426, p = 0.001). Serum FGF-23 levels were high in axSpA patients. Increased FGF-23 was associated with inflammation, but not with SOST levels or disease activity. SOST correlated negatively with both inflammation and structural damage.

Predictive value of combined serum FGF21 and free T3 for survival in septic patients

BackgroundWe examined the correlation between thyroid hormone (TH) concentrations and the serum fibroblast growth factor 21 (FGF21) concentration in septic patients and to assess the collaborative value of these factors in predicting 28-day mortality in septic patients. MethodsA total of 120 consecutive patients with sepsis were divided into two groups according to their survival or death within 28 days after initial diagnosis of sepsis. ResultsPatients in the non-survivor group had significantly higher serum FGF21 concentrations but lower total and free triiodothyronine (T3) and tetraiodothyronine (T4) concentrations than those in the survivor group. Thyroid hormone concentrations, including T3, free T3, T4 and free T4, were significantly negatively correlated with the ∆SOFA and APACHE II scores as well as the serum FGF21, IL-6, tumor necrosis factor-α, IL-10, procalcitonin, and C-reactive protein concentrations. Logistic regression analysis showed that the ∆SOFA score, serum FGF21 concentration, and free T3 concentration were significant predictors of 28-day mortality. The model with variables of ∆SOFA score and serum FGF21 and free T3 concentrations had the greatest area under the curve of 0.969. ConclusionThe addition of free T3 and serum FGF21 to ∆SOFA score provided a significantly improved ability to predict 28-day mortality in septic patients.

Activation of hepatic estrogen receptor-α increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice

ObjectiveThe endogenous estrogen 17β-estradiol (E2) promotes metabolic homeostasis in premenopausal women. In a mouse model of post-menopausal metabolic syndrome, we reported that estrogens increased energy expenditure, thus preventing estrogen deficiency-induced adiposity. Estrogens' prevention of fat accumulation was associated with increased serum concentrations of fibroblast growth factor 21 (FGF21), suggesting that FGF21 participates in estrogens' promotion of energy expenditure. MethodsWe studied the effect of E2 on FGF21 production and the role of FGF21 in E2 stimulation of energy expenditure and prevention of adiposity, using female estrogen receptor (ER)- and FGF21-deficient mice fed a normal chow and a cohort of ovariectomized women from the French E3N prospective cohort study. ResultsE2 acting on the hepatocyte ERα increases hepatic expression and production of FGF21 in female mice. In vivo activation of ERα increases the transcription of Fgf21 via an estrogen response element outside the promoter of Fgf21. Treatment with E2 increases oxygen consumption and energy expenditure and prevents whole body fat accumulation in ovariectomized female WT mice. The effect of E2 on energy expenditure is not observed in FGF21-deficient mice. While E2 treatment still prevents fat accumulation in FGF21-deficient mice, this effect is decreased compared to WT mice. In an observational cohort of ovariectomized women, E2 treatment was associated with lower serum FGF21 concentrations, which may reflect a healthier metabolic profile. ConclusionsIn female mice, E2 action on the hepatocyte ERα increases Fgf21 transcription and FGF21 production, thus promoting energy expenditure and partially decreasing fat accumulation.

Parathyroid hormone and premature thymus ageing in patients with chronic kidney disease

Premature immune ageing, including thymic atrophy, is observed in patients with chronic kidney disease (CKD). Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), which are mineral and bone disorder (MBD)-related factors, affect immune cells and possibly cause thymic atrophy. We examined the cross-sectional association between thymic atrophy, evaluated as the number of CD3+CD4+CD45RA+CD31+ cells [recent thymic emigrants (RTE)/μL], and MBD-related factors [(serum PTH, FGF23, and alkaline phosphatase (ALP) level] in 125 patients with non-dialysis dependent CKD. Median estimated glomerular filtration rate (eGFR) was 17 mL/min/1.73 m2. Older age (r = −0.46), male sex (r = −0.34), lower eGFR (r = 0.27), lower serum-corrected calcium (r = 0.27), higher PTH (r = −0.36), and higher ALP level (r = −0.20) were identified as determinants of lower number of RTE. In contrast, serum concentrations of FGF23 and phosphorus were not correlated with RTE. Multivariate non-linear regression analysis indicated a negative association between serum PTH and log-transformed RTE (P = 0.030, P for non-linearity = 0.124). However, the serum levels of FGF23 and ALP were not associated with RTE. In patients with CKD, serum PTH concentrations were related to thymic atrophy which contributes to immune abnormality.

Risk of cardiovascular involvement in pediatric patients with X-linked hypophosphatemia.

To find out if cardiovascular alterations are present in pediatric patients with X-linked hypophosphatemia (XLH). Multicentre prospective clinical study on pediatric patients included in the RenalTube database ( www.renaltube.com ) with genetically confirmed diagnosis of XLH by mutations in the PHEX gene. The study's protocol consisted of biochemical work-up, 24-h ambulatory blood pressure monitoring (ABPM), carotid ultrasonography, and echocardiogram. All patients were on chronic treatment with phosphate supplements and 1-hydroxy vitamin D metabolites. Twenty-four patients (17 females, from 1 to 17years of age) were studied. Serum concentrations (X ± SD) of phosphate and intact parathyroid hormone were 2.66 ± 0.60mg/dl and 58.3 ± 26.8pg/ml, respectively. Serum fibroblast growth factor 23 (FGF23) concentration was 278.18 ± 294.45pg/ml (normal < 60pg/ml). Abnormally high carotid intima media thickness was found in one patient, who was obese and hypertensive as revealed by ABPM, which disclosed arterial hypertension in two other patients. Z scores for echocardiographic interventricular septum end diastole and left ventricular posterior wall end diastole were + 0.77 ± 0.77 and + 0.94 ± 0.86, respectively. Left ventricular mass index (LVMI) was 44.93 ± 19.18g/m2.7, and four patients, in addition to the obese one, had values greater than 51g/m2.7, indicative of left ventricular hypertrophy. There was no correlation between these echocardiographic parameters and serum FGF23 concentrations. XLH pediatric patients receiving conventional treatment have echocardiographic measurements of ventricular mass within normal reference values, but above the mean, and 18% have LVMI suggestive of left ventricular hypertrophy without correlation with serum FGF23 concentrations. This might indicate an increased risk of cardiovascular involvement in XLH.