Plasma FGF21 Levels Research Articles

The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity.

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.

Dietary isoleucine content defines the metabolic and molecular response to a Western diet.

The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain- independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD.

Abstract 17336: A Hepato-Cardiac FGF21 Signaling Axis Promotes Cardiac Hypertrophy

FGF21 is expressed mainly in the liver and other organs, including the heart. The role of FGF21 is controversial, with potential benefits for obesity and certain heart conditions, but also associations with heart failure and increased mortality. We found higher serum FGF21 levels (2.5-fold) in left ventricular hypertrophy patients (N=31) compared to those without hypertrophy (N=45). Similarly, mice subjected to Transverse Aortic Constriction (TAC) had elevated plasma FGF21 levels and hepatic expression. Surprisingly, a time course experiment showed that liver FGF21 production peaked 3 days post-TAC (prior to the onset of hypertrophy), while an unexpected increase of cardiac FGF21 expression was observed 2 weeks post-TAC, coinciding with hypertrophy and dysfunction. FGF21 expression in skeletal muscle did not change. As in mice, hypertensive individuals (N=6) showed a 14-fold increase in cardiac FGF21 mRNA levels compared to normotensive (N=6). To delineate the role of hepatic and cardiac FGF21 in hypertrophy, TAC was performed on mice with hepatocyte- (HEP-FGF21-KO) or cardiomyocyte-specific (CM-FGF21-KO) FGF21 ablation. Both HEP-FGF21-KO and CM-FGF21-KO mice were protected from hypertrophy, pro-hypertrophic signaling, fibrosis, and cardiac dysfunction. Notably, hepatocyte FGF21 deletion prevented cardiac FGF21 upregulation with TAC, suggesting control of CM FGF21 expression by liver-derived FGF21 and highlighting the role of CM FGF21 in driving cardiac hypertrophy. This was confirmed by treatment of AC16 human cardiomyocytes with recombinant FGF21 that increased endogenous FGF21 expression and cell size. RNAseq analysis revealed attenuation of cardiac fibrosis- and hypertrophy-related transcriptome in both HEP-FGF21-KO and CM-FGF21-KO mice. To explore if FGF21 increase is a cause and not a consequence of cardiac hypertrophy, we developed anti-sense oligonucleotides against FGF21 and administered them in C57BL/6 mice with TAC. ASO-FGF21 treatment attenuated cardiac hypertrophy and fibrosis and improved cardiac function. Thus, FGF21 emerges as a therapeutic target for pathological cardiac hypertrophy.

Epigenetic regulation of GABA catabolism in iPSC-derived neurons: The molecular links between FGF21 and histone methylation

ObjectiveFibroblast growth factor 21 (FGF21) analogs have been tested as potential therapeutics for substance use disorders. Prior research suggests that FGF21 administration might affect alcohol consumption and reward behaviors. Our recent report showed that plasma FGF21 levels were positively correlated with alcohol use in patients with alcohol use disorder (AUD). FGF21 has a short half-life (0.5–2 h) and crosses the blood–brain barrier. Therefore, we set out to identify molecular mechanisms for both the naïve form of FGF21 and a long-acting FGF21 molecule (PF-05231023) in induced pluripotent stem cell (iPSC)-derived forebrain neurons. MethodsWe performed RNA-seq in iPSC-derived forebrain neurons treated with naïve FGF21 or PF-05231023 at physiologically relevant concentrations. We obtained plasma levels of FGF21 and GABA from our previous AUD clinical trial (n = 442). We performed ELISA for FGF21 in both iPSC-derived forebrain neurons and forebrain organoids. We determined protein interactions using co-immunoprecipitation. Finally, we applied ChIP assays to confirm the occupancy of REST, EZH2 and H3K27me3 by FGF21 using iPSC-derived forebrain neurons with and without drug exposure. ResultsWe identified 4701 and 1956 differentially expressed genes in response to naïve FGF21 or PF-05231023, respectively (FDR < 0.05). Notably, 974 differentially expressed genes overlapped between treatment with naïve FGF21 and PF-05231023. REST was the most important upstream regulator of differentially expressed genes. The GABAergic synapse pathway was the most significant pathway identified using the overlapping genes. We also observed a significant positive correlation between plasma FGF21 and GABA concentrations in AUD patients. In parallel, FGF21 and PF-05231023 significantly induced GABA levels in iPSC-derived neurons. Finally, functional genomics studies showed a drug-dependent occupancy of REST, EZH2, and H3K27me3 in the promoter regions of genes involved in GABA catabolism which resulted in transcriptional repression. ConclusionsOur results highlight a significant role in the epigenetic regulation of genes involved in GABA catabolism related to FGF21 action.(The ClinicalTrials.gov Identifier: NCT00662571)

FGF21 and GDF15 are elevated in Barth Syndrome and are correlated to important clinical measures

Barth Syndrome (BTHS) is a rare X-linked disorder that is caused by defects TAFAZZIN, which leads to an abnormal cardiolipin (CL) profile of the inner mitochondrial membrane and clinical features including cardiomyopathy, neutropenia and skeletal myopathy. The ratio of monolysocardiolipin (MLCL, the remodeling intermediate of cardiolipin) to remodeled CL is always abnormal in Barth Syndrome and 3-methylglutaconic acid is often elevated affected patients, however neither of these biomarkers has been shown to temporally correlate to clinical status. In this study, we measured plasma FGF21 and GDF15 levels in 16 individuals with Barth Syndrome and evaluated whether these biomarkers were correlated to the MLCL/CL ratio in patient bloodspots and clinical laboratory parameters indicative of organ involvement in Barth Syndrome including: neutrophil and monocyte counts, liver function, and cardiac function (NT-proBNP). We found that FGF21 and GDF15 were elevated in all 16 patients and that FGF21 was significantly correlated to AST, ALT GGT, percentage of neutrophils comprising total white blood cells, percent monocytes comprising total white blood cells, and NT-proBNP levels. GDF-15 was significantly positively associated with NT-proBNP. We conclude that clinical measurements of FGF21 and GDF-15 may be relevant in the monitoring multi-organ system involvement in Barth Syndrome.

1696-P: Changes in Clinical and Metabolic Parameters Related to NAFLD in Obese Subjects Who Underwent Laparoscopic Sleeve Gastrectomy

More research is needed on the effect of laparoscopic sleeve gastrectomy (LSG) on NAFLD and related parameters. A total of 51 morbidly obese subjects with NAFLD who would undergo LSG were included, with liver biopsy performed during LSG in 46 patients. Various clinical parameters and blood biomarkers related to NAFLD were measured before and 6 months after LSG, which included fat content in the liver (LFC) and pancreas (PFC) by MRI-PDFF, liver stiffness measurement by MR elastography (MRE-LSM), and others. After LSG, there was a significant decrease in body weight and LFC: 102.0 ± 15.3 vs. 76.3 ± 14.3 kg and 19.4 ± 9.1% vs. 5.7 ± 2.9%, respectively, p &amp;lt;0.001 each. And, body fat on DXA, PFC, and visceral fat area measured by MRI, and, fasting plasma levels of total GIP and glucagon decreased significantly after bariatric surgery, with no change in total GLP-1 and peptide YY levels. Notably, there was a marked increase in plasma levels of FGF21 (547.1 ± 890.5 pg/ml vs. 1085 pg/ml ± 1883.75, p&amp;lt;0.05) and oxyntomodulin (436.0 ± 351.4 pg/ml vs. 1533.6 ± 624.4 pg/ml, p&amp;lt;0.001). These changes were accompanied by a significant reduction of NASH blood biomarkers such AKR1B10, cytokeratin 18, and complement C3. And, MRE-LSM, a marker of liver fibrosis, decreased significantly after LSG (3.1 ± 0.8 kPa vs. 2.7 ± 0.1 kPa, p &amp;lt;0.01), but enhanced liver fibrosis score did not. Only 15.2% of patients with biopsy-proven NAFLD showed more than 25% decrease in MRE-LSM, and baseline fibrosis degree was only the predictor of this decrease in MRE-LSM after LSG. Our results show that in patients with morbid obesity, marked reduction of body weight and LFC and a significant increase in plasma FGF21 and oxyntomodulin levels were observed 6 months after LSG, with the reduction of several markers of NASH. However, a meaningful MRE-LSM improvement was observed only in a small proportion of patients, which warrants long-term follow-up of patients with NASH/fibrosis who underwent LSG. Disclosure D.Lee: None. I.Park: None. Funding National Research Foundation of Korea (2021R1A5A2030333, 2019R1I1A2A02062305)

Decreased FGF19 and FGF21: possible underlying common pathogenic mechanism of metabolic and cognitive dysregulation in depression.

Accumulating studies suggested that major depressive disorder (MDD) was closely related to metabolic syndrome (MetS). Important endogenous regulators fibroblast growth factors (FGFs) 19 and 21 were also reported to participate in psychiatric disorders. This study aimed to investigate the role of FGF19 and FGF21 in MDD and to explore the possible pathogenic mechanism of metabolic and cognitive dysregulation in depression. A total of 59 MDD patients and 55 healthy control participants were recruited. The serum levels of FGF19 and FGF21 and lipid profiles were measured by means of enzymatic methods. Cognitive function was measured by repeatable battery for the assessment of neuropsychological status (RBANS) scores. The gene expression of PGC-1α and FNDC5 was determined by quantitative polymerase chain reaction (PCR). We found that plasma FGF19 and FGF21 levels were significantly decreased in patients with MDD. Meanwhile, triglyceride (TG) was significantly elevated and PGC-1α was significantly downregulated in MDD patients. Correlation analyses showed negative associations between TG and FGF19 levels. As for cognitive performance, both FGF19 and FGF21 levels were positively correlated with immediate memory. However, FGF19 levels were negatively correlated with language, and FGF21 levels were also negatively correlated with attention and delayed memory. Additionally, negative associations were found between FGF19 levels and PGC-1α. FGF21 levels were positively associated with PGC-1α and negatively associated with FNDC5. This study elucidated the role of FGF19 and FGF21 in MDD. MDD patients were confirmed to have metabolic and cognitive dysregulation, and this abnormality was linked to the decreased concentrations of FGF19 and FGF21 through the PGC-1α/FNDC5 pathway. Our results showed that the alterations of FGF19 and FGF21 levels may be a common pathogenic mechanism of metabolic and cognitive disturbances in patients with MDD.

The association of circulating fibroblast growth factor 21 levels with incident heart failure: The Multi-Ethnic Study of Atherosclerosis

BackgroundFibroblast growth factor 21 (FGF21) levels are often elevated in heart failure (HF), although this has not been assessed using a longitudinal study design. Therefore, we investigated the association between baseline plasma FGF21 levels and incident HF in the Multi-Ethnic Study of Atherosclerosis (MESA). MethodsA total of 5408 participants, free of clinically apparent cardiovascular disease, were included in the analysis, of which 342 developed HF over a median follow-up period of 16.7 years. Multivariable Cox regression analysis was performed and the additive value of FGF21 in the performance of risk prediction over other well-established cardiovascular biomarkers was assessed. ResultsThe mean age of the participants was 62.6 years with 47.6 % male. Regression spline analysis demonstrated a significant association of FGF21 levels with incident HF among participants with FGF21 levels ≥239.0 pg/mL (hazard ratio = 1.84 [95 % confidence interval 1.21, 2.80] per SD increase in ln-transformed levels) after adjustment for traditional cardiovascular risk factors and biomarkers, but not in participants with FGF21 levels <239.0 pg/mL (p for heterogeneity = 0.004). Among participants with FGF21 levels ≥239.0 pg/mL, FGF21 levels were associated with HF with preserved ejection fraction (HR [95 % CI] = 2.57 [1.51, 4.37]), but not HF with reduced ejection fraction. ConclusionsThe present study suggests baseline FGF21 levels could predict the development of incident HF with preserved ejection fraction, among participants with elevated FGF21 levels at baseline. This study may suggest a pathophysiological role of FGF21 resistance in HF with preserved ejection fraction.

Abstract 11626: A Hepato-Cardiac FGF21 Axis Activates a Cardiac FGF21 Autocrine Mechanism That Causes Hypertrophy With Pressure Overload

FGF21 is expressed mainly in the liver and other organs, including skeletal muscle and heart. It exerts its actions by binding to its receptors (FGFR) and the co-receptor β-klotho. Despite evidence about protective action of FGF21 in different animal disease models, elevated plasma FGF21 levels have been reported in patients with heart failure. Thus, it remains unknown whether elevation in human heart failure is part of the disease’s pathophysiology or a protective response. Staining of heart sections from end-stage heart failure patients showed increased FGF21 that correlated with higher plasma FGF21 levels. To assess the relative contribution of cardiac and extracardiac FGF21 in heart failure, we generated 3 animal models with cardiomyocyte- (CM-FGF21-KO), hepatocyte- (Alb-FGF21-KO) or skeletal muscle-specific FGF21 (MLC-FGF21-KO) deletion and subjected them to transverse aortic constriction (TAC) for 3 days, 2, 4, and 8 weeks. Hepatic expression and plasma levels of FGF21 were increased 3 days post-TAC. Cardiac FGF21 expression was also increased after 2 weeks of TAC. Surprisingly, the pro-hypertrophic effect of TAC was abolished in both Alb-FGF21-KO and CM-FGF21-KO mice. Interestingly, cardiac FGF21 expression was not increased in CM-FGF21-KO mice despite the high plasma FGF21 levels. The MLC-FGF21-KO mice were not protected. Thus, cardiomyocyte FGF21 upregulation mediates cardiac hypertrophy in response to pressure overload. To investigate if cardiomyocyte FGF21 expression is controlled by FGF21 that is released from the liver, we treated human AC16 cells with recombinant FGF21, which increased endogenous FGF21 mRNA and protein, pointing to an autoregulatory FGF21-based induction of cardiac FGF21 expression. This auto-regulatory loop was potentiated by increased expression of cardiac FGFR1 in wild-type mice subjected to TAC that was attenuated in CM-FGF21-KO mice. Accordingly, we observed increased pro-hypertrophic cardiac signaling (pAMPK, pERK,Bnp, Tnfα) in wild-type mice with TAC, but not in CM-FGF21 KO mice. Conclusively, a hepato-cardiac FGF21-based signaling axis governs cardiomyocyte FGF21 expression, which accounts for cardiac hypertrophy. Inhibition of either hepatic or cardiomyocyte FGF21 is cardioprotective.

1355-P: Carbohydrate Overfeeding Unmasks Severe Dysmetabolic Traits in Low-Birth-Weight Men

Background: Low birth weight (LBW) individuals are at increased risk of developing Type 2 diabetes (T2D) , especially when exposed to an affluent dietary pattern. Impaired subcutaneous adipose tissue expandability and ectopic fat storage may represent key features explaining the link between LBW and risk of T2D. We hypothesized that a 4-week simple carbohydrate overfeeding challenge (+25% energy) (COF) would adversely influence dysmetabolic traits including hepatic fat content in LBW compared to normal birth weight (NBW) men. Methods: Twenty-two non-obese LBW and 21 age- and BMI-matched NBW men with a mean age of 37.6 years were included. Body composition, hepatic fat (MR spectroscopy) , glucose and insulin metabolism, hepatic glucose production (HGP; deuterium glucose) , energy metabolism (indirect calorimetry) and selected plasma biomarkers (multiplex ELISA) were measured before and after 4 weeks COF. Results: Fasting plasma glucose and C-peptide levels, as well as energy expenditure (EE) and fat oxidation (FOX) rates increased significantly more in response to COF among the LBW compared to NBW subjects (all P&amp;lt;0.05) . However, despite significantly increased baseline hepatic fat content, COF resulted in similar body weight and hepatic fat content increments in LBW compared to NBW subjects. HGP and hepatic insulin resistance were unaffected by COF in both groups. Fasting plasma adiponectin levels were significantly reduced in LBW versus NBW subjects before and after COF, whereas plasma leptin and FGF21 levels were increased (both P&amp;lt;0.005) after COF in LBW men only. Conclusion: LBW compared to NBW subjects respond to COF with differential increments in plasma glucose, C-peptide, leptin and FGF21 levels, as well as increased EE and FOX rates. The results underscore the importance of LBW individuals avoiding simple carbohydrate overfeeding. Further studies are needed to understand the role of increased hepatic fat and insulin resistance as key mechanisms linking LBW with increased risk of T2D. Disclosure C.Brøns: Stock/Shareholder; Novo Nordisk. A.B.Thuesen: None. L.Justesen: None. L.Elingaard-larsen: None. J.Størling: None. E.R.Danielsen: None. T.Hansen: None. A.A.Vaag: Stock/Shareholder; AstraZeneca. Funding Novo Nordisk Foundation (NNF15OC0016692) , Aase and Ejnar Danielsens Fond, Augustinus Foundation, Simon Spies Fonden, TrygFonden.

Cardio-protective effect of dapagliflozin against doxorubicin induced cardiomyopathy in rats.

Cancer is the second most common non-communicable disease group in the world and its frequency is increasing. In parallel, side effects of drugs used in cancer treatment are frequently encountered. Doxorubicin (DOX) is one of the most effective multi-purpose anticancer drugs. However, its use is significantly limited due to the risk of cardiotoxicity. Sodium-glucose cotransporter-2 inhibitors are a group of antidiabetic drugs that have been shown to reduce cardiovascular events. Our aim is to examine the preventive effect of dapagliflozin on DOX-induced cardiac damage. We used 30 albino rats. 20 of 30 rats were administered doxorubicin for cardiomyopathy model. The rats in the DOX arm were divided into two groups: those given penicillin and placebo. After the rats were terminated, tissues were prepared for histopathological and immunohistochemical examination. TNF-α, pro-BNP, troponin T and plasma FGF-21 levels were also measured in plasma. The mean concentrations of cTnT and pro-BNP in the plasma of the DOX treated rats demonstrated a significantly higher value compared to the control group. Treatment with dapagliflozin caused a significant reduction in plasma cTnT, pro-BNP and TNF-α levels concentrations compared to the DOX control group (p < 0.001). The group of rats treated with dapagliflozin was effective in significantly decreasing the FGF-21 concentration and the percentage of fibronectin immunoexpression compared to the DOX control group (p < 0.0001). This study revealed, for the first time, that dapagliflozin can improve DOX-induced cardiac dysfunction and pathological changes in non-diabetic rats. This result has shown that dapaglifozin, may be promising in terms of preventing cardiac damage that may develop in cancer treatment.

MO697: FGF-21 Correlates with Overhydration: Is There a Role for Peritoneal GLUT-1?

Abstract BACKGROUND AND AIMS FGF-21 is a hepatokine that stimulates glucose uptake through GLUT-1. The presence of this glucose transporter in peritoneal fibroblasts is driven by peritoneal glucose exposure and is related to impaired ultrafiltration, predisposing to overhydration. The study was designed to determine FGF-21 levels in peritoneal effluent and serum, and its possible association with overhydration. METHOD Prevalent and incident peritoneal dialysis (PD) patients without diabetes were included. FGF-21 (dialysate and serum) was obtained during a 3.86% glucose peritoneal equilibration test. Peritoneal glucose load was calculated. The presence or absence of local peritoneal production was assessed by comparing the dialysate to plasma (D/P) ratio of FGF-21 (MW 32 kD) with that of albumin (MW 67 kD). Hydration status was assessed by bioimpedance. Spearman's correlations were performed. RESULTS A total of 58 patients (38 incident, 20 prevalent) were included, mean age 54 years, 67% males, PD duration from 1 to 75 months, mean 10.4. Residual GFR was 6.4 ± 3.5 mL/min/1.73 m2 and D/P creatinine 0.65 ± 0.12. Peritoneal glucose load was 110.5 g/day (range 40.8–226.9). Dialysate FGF-21 was 42.5 ± 47.0 pg/mL and serum FGF-21 943.9 ± 1164.8 pg/mL, giving a D/P ratio of 0.07. D/P albumin was 0.009, indicating that dialysate FGF-21 concentrations can be explained by transport from the circulation, without local peritoneal production. Serum FGF-21 was positively correlated with dialysate FGF-21, extracellular water excess and total peritoneal glucose load (all P &amp;lt; 0.01). Some association was present with PD duration (P &amp;lt; 0.05). No relationship was found between plasma FGF-21 and plasma insulin, D/P creatinine, or residual kidney function. CONCLUSION FGF-21 in peritoneal effluent is likely not locally produced, but caused by transport from the circulation. The associations between plasma FGF-21 levels with PD duration, peritoneal glucose load and overhydration, all indicate an effect of peritoneal glucose absorption from the peritoneal cavity into the interstitium with an insulin-independent storage into interstitial adipocytes, where it may stimulate the expression of GLUT-1.

High Protein Diet Feeding Aggravates Hyperaminoacidemia in Mice Deficient in Proglucagon-Derived Peptides.

(1) Background: Protein stimulates the secretion of glucagon (GCG), which can affect glucose metabolism. This study aimed to analyze the metabolic effect of a high-protein diet (HPD) in the presence or absence of proglucagon-derived peptides, including GCG and GLP-1. (2) Methods: The response to HPD feeding for 7 days was analyzed in mice deficient in proglucagon-derived peptides (GCGKO). (3) Results: In both control and GCGKO mice, food intake and body weight decreased with HPD and intestinal expression of Pepck increased. HPD also decreased plasma FGF21 levels, regardless of the presence of proglucagon-derived peptides. In control mice, HPD increased the hepatic expression of enzymes involved in amino acid metabolism without the elevation of plasma amino acid levels, except branched-chain amino acids. On the other hand, HPD-induced changes in the hepatic gene expression were attenuated in GCGKO mice, resulting in marked hyperaminoacidemia with lower blood glucose levels; the plasma concentration of glutamine exceeded that of glucose in HPD-fed GCGKO mice. (4) Conclusions: Increased plasma amino acid levels are a common feature in animal models with blocked GCG activity, and our results underscore that GCG plays essential roles in the homeostasis of amino acid metabolism in response to altered protein intake.

From the Editor’s Desk...

From the Editor’s Desk...

Plasma FGF-21 and Sclerostin Levels, Glycemia, Adiposity, and Insulin Sensitivity in Normoglycemic Black and White Adults.

Increased circulating fibroblast growth factor (FGF)-21 and sclerostin levels have been reported in patients with type 2 diabetes (T2D). We assessed the association of FGF-21 and sclerostin with adiposity, glycemia, and glucoregulatory measures in healthy subjects. We studied 20 normoglycemic Black and White offspring of parents with T2D. Assessments included oral glucose tolerance test, insulin sensitivity (Si-clamp), insulin secretion (homeostasis model assessment index of b-cell function [HOMA-B]), and body fat (dual-energy X-ray absorptiometry). Fasting plasma FGF-21 and sclerostin levels were measured with enzyme-linked immunosorbent assays. The participants’ mean (+SD) age was 50.4 ± 5.97 years; body mass index (BMI) 32.5 ± 5.86 kg/m2; fasting plasma glucose (FPG) 96.1 ± 5.21 mg/dL, and 2-hour postload glucose 116 ± 5.45 mg/dL. FGF-21 levels were similar in Black people vs White people (0.36 ± 0.15 ng/mL vs 0.39 ± 0.25 ng/mL), men vs women (0.45 ± 0.14 vs 0.44 ± 0.07 ng/mL), correlated positively with BMI (r = 0.23, P = .05) and waist circumference (r = 0.27, P = .04), and inversely with FPG (r = –0.26, P = .05). Sclerostin levels also were similar in Black people (33.5 ± 17.1 pmol/L) vs White people (34.2 ± 6.41 pmol/L), men vs women (35.3 ± 9.01 pmol/L vs 32.3 ± 15.8 pmol/L), and correlated inversely with FPG (r = –0.11 to –0.44) but not adiposity measures. The correlation coefficient between Si-clamp values and FGF-21 levels was –0.31 (P = .09) compared with 0.04 (P = .89) for sclerostin levels. FGF-21 and sclerostin levels were not correlated with each other or HOMA-B. Among healthy Black and White subjects, plasma FGF-21 and sclerostin showed differential associations with adiposity but concordant association with FPG levels.

Association of Elevated Plasma FGF21 and Activated FGF21 Signaling in Visceral White Adipose Tissue and Improved Insulin Sensitivity in Gestational Diabetes Mellitus Subtype: A Case-Control Study.

ObjectiveTo study the discrepancy of the insulin sensitivity alteration pattern, circulating fibroblast growth factor (FGF21) levels and FGF21 signaling in visceral white adipose tissue (vWAT) of gestational diabetes mellitus (GDM) subtypes.Methods26 GDM women with either a predominant of insulin-secretion defect (GDM-dysfunction, n = 9) or insulin-sensitivity defect (GDM-resistance, n = 17) and 13 normal glucose tolerance (NGT) women scheduled for caesarean-section at term were studied. Blood and vWAT samples were collected at delivery.ResultsThe insulin sensitivity was improved from the 2nd trimester to delivery in the GDM-resistance group. Elevated circulating FGF21 concentration at delivery, increased FGF receptor 1c and decreased klotho beta gene expression, enhanced ERK1/2 phosphorylation, and increased GLUT1, IR-B, PPAR-γ gene expression in vWAT were found in the GDM-resistance group as compared with the NGT group. The circulating FGF21 concentration was negatively correlated with fasting blood glucose (r = -0.574, P < 0.001), and associated with the GDM-resistance group (r = 0.574, P < 0.001) in pregnant women at delivery. However, we observed no insulin sensitivity alteration in GDM-dysfunction and NGT groups during pregnancy. No differences of plasma FGF21 level and FGF21 signaling in vWAT at delivery were found between women in the GDM-dysfunction and the NGT group.ConclusionsWomen with GDM heterogeneity exhibited different insulin sensitivity alteration patterns. The improvement of insulin sensitivity may relate to the elevated circulating FGF21 concentration and activated FGF21 signaling in vWAT at delivery in the GDM-resistance group.

Association of plasma FGF21 levels with muscle mass and muscle strength in a national multicentre cohort study: Korean Frailty and Aging Cohort Study

despite of the beneficial effects of fibroblast growth factor (FGF) 21 in several metabolic diseases, the association of plasma FGF21 with muscle mass and muscle strength is still unclear. a total of 386 community-dwelling older adults aged 70-84years were analysed. Appendicular skeletal muscle mass was measured using dual-energy X-ray absorptiometry and normalised to the square of height (ASM/ht2). Muscle strength was assessed using the hand grip strength (HGS) test. The definitions of low muscle mass (LMM) and low muscle strength (LMS) were based on the Asian Working Group for Sarcopenia. plasma FGF21 was significantly lower in participants with LMM than in those with normal muscle mass (289.7 [192.4-448.3] vs. 345.6 [238.6-503.2] pg/ml, P = 0.008). In contrast, the LMS group had a significantly higher plasma FGF21 level than the normal muscle strength group (369.7 [244.4-591.1] vs. 309.7 [205.3-444.8] pg/ml, P = 0.006). In the partial correlation analysis, following adjustment for age, sex and body mass index, FGF21 levels had no significant association with ASM/ht2, but were negatively associated with HGS (r = -0.112, P = 0.029). Furthermore, after multivariate adjustment for confounding variables, the odds ratio for the risk of LMS was 2.32 (95% confidence interval 1.20-4.46) when comparing the highest with the lowest FGF21 quartile. circulating FGF21 levels are negatively associated with muscle strength but are not independently correlated with muscle mass.

FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance

SUMMARYFgf21 (fibroblast growth factor 21) is a regulatory hepatokine that, in pharmacologic form, powerfully promotes weight loss and glucose homeostasis. Although “Fgf21 resistance” is inferred from higher plasma Fgf21 levels in insulin-resistant mice and humans, diminished Fgf21 function is understood primarily via Fgf21 knockout mice. By contrast, we show that modestly reduced Fgf21—owing to cell-autonomous suppression by hepatic FoxO1—contributes to dysregulated metabolism in LDKO mice (Irs1L/L·Irs2L/L·CreAlb), a model of severe hepatic insulin resistance caused by deletion of hepatic Irs1 (insulin receptor substrate 1) and Irs2. Knockout of hepatic Foxo1 in LDKO mice or direct restoration of Fgf21 by adenoviral infection restored glucose utilization by BAT (brown adipose tissue) and skeletal muscle, normalized thermogenic gene expression in LDKO BAT, and corrected acute cold intolerance of LDKO mice. These studies highlight the Fgf21-dependent plasticity and importance of BAT function to metabolic health during hepatic insulin resistance.

Impact of Acutely Increased Endogenous- and Exogenous Ketone Bodies on FGF21 Levels in Humans

ABSTRACT Purpose Fibroblast growth factor (FGF) 21 is a circulating hormone with metabolic regulatory importance. In mice, FGF21 increases in response to a ketogenic diet and fasting. In humans, a similar increase is only observed after prolonged starvation. We aim to study the acute effects of ketone bodies on circulating FGF21 levels in humans. Methods Participants from three randomized, placebo-controlled crossover studies, with increased endogenous or exogenous ketone bodies, were included. Study 1: patients with type 1 diabetes (T1D) (n = 9) were investigated after a) insulin deprivation and lipopolysaccharide (LPS) injection and b) insulin-controlled euglycemia. Study 2: patients with T1D (n = 9) were investigated after a) total insulin deprivation for 9 hours and b) insulin-controlled euglycemia. Study 3: Healthy adults (n = 9) were examined during a) 3-hydroxybutyrate (OHB) infusion and b) saline infusion. Plasma FGF21 was measured with immunoassay in serial samples. Results Circulating OHB levels were significantly increased to 1.3, 1.5, and 5.5 mmol/l in the three studies, but no correlations with FGF21 levels were found. Also, no correlations between FGF21, insulin, or glucagon were found. Insulin deprivation and LPS injection resulted in increased plasma FGF21 levels at t = 120 min (p = .005) which normalized at t = 240 min. Conclusion We found no correlation between circulating FGF21 levels and levels of ketone bodies. This suggests that it is not ketosis per se which controls FGF21 production, but instead a rather more complex regulatory mechanism. Trial registration clinicaltrials.gov ID number: Study 1: NCT02157155 (5/6-2014), study 2: NCT02077348 (4/3-2014), and study 3: NCT02357550 (6/2-2015)

P1499FGF21 CORRELATES POSITIVELY WITH ARTERIOVENOUS FISTULA OCCLUSION IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Arteriovenous fistula occlusion lead to insufficient dialysis, increases the probability of hemodialysis complications, even life-threatening. Fibroblast growth factor 21 (FGF21) is increased progressively with a decline of renal function and higher plasma FGF-21 level can be used as a meaningful index to evaluate microinflammation, lipid metabolism and predict dialysis-related complications such as cardiovascular diseases in end stage renal disease patients. This study aimed to investigate the relationship and role of FGF21 in arteriovenous fistula occlusion in our hemodialysis patients cohort. Method We screened 802 HD patients in Nanjing Zhongda Hospital (n=450) and The First People’s Hospital of Changzhou (n=352) according to a strict inclusion criteria and exclusion criteria. We recorded demographic information, blood data before dialysis and serum FGF21 levels and counted the frequency of arteriovenous fistula occlusion in our hemodialysis cohort. We used bivariate correlation analyses to assess the correlation of the frequency of arteriovenous fistula occlusion with serum FGF21 and other clinical parameters. Stepwise multivariate linear regression analyses were employed to evaluate variables independently associated with the frequency of arteriovenous fistula occlusion. P &amp;lt; 0.05 was considered to be statistically significant. SPSS Software, version 22.0 was used for all statistical analyses. Results In this cross-sectional study, of 802 hemodialysis patients screened, 76 were eligible. The median dialysis vintage was 6.4 years (range 0.5 to 23). Serum FGF21 levels were significantly positive associated with the frequency of arteriovenous fistula occlusion (r = 0.321, P = 0.005). In addition, the frequency of arteriovenous fistula occlusion was correlated with the level of hemoglobin (r = -0.277, P = 0.015), the level of albumin (r = -0.269, P = 0.019) and left ventricular mass (r = 0.272, P = 0.018). The result showed that serum FGF21 (β = 0.259, P= 0.022) and left ventricular mass (β = 0.223, P =0.048) were factors independently associated with the frequency of arteriovenous fistula occlusion in hemodialysis patients. Conclusion We reported for the first time that serum FGF21 and Left ventricular mass were independently associated with arteriovenous fistula occlusion. These findings provide a novel insight about FGF21 on arteriovenous fistula occlusion in hemodialysis patients and may indicate a new therapeutic target for arteriovenous fistula occlusion. Figure 1. Correlation of serum FGF21 and LVMI with the frequency of arteriovenous fistula occlusion in HD patients.