Integrated Regulation of Hepatic Metabolism by Fibroblast Growth Factor 21 (FGF21) in Vivo

Fibroblast growth factor (FGF21) plays an important role in regulating hepatic oxidation of fatty acids and gluconeogenesis in response to fasting and during consumption of a ketogenic diet. However, the metabolic pathways through which FGF21 regulates hepatic function are not well defined. To identify the effects of FGF21 on the liver in vivo, we administered FGF21 to mice and analyzed acute effects on signaling and gene expression. We found that FGF21 acts directly on the liver to stimulate phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), suggesting that PGC-1α may play a role in regulating FGF21 action. However, studies using mice with liver-specific ablation of PGC-1α revealed the same regulation of gluconeogenic gene expression by FGF21 as seen in wild-type mice, indicating that PGC-1α is not necessary for the effect of FGF21 on glucose metabolism. These data demonstrate that FGF21 acts directly on the liver to modulate hepatic metabolism. The direct effects we examined are not dependent on PGC-1α. In addition, FGF21 treatment is associated with decreased serum insulin levels that my affect hepatic function.

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The Orphan Nuclear Receptor ERRγ Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression

PLoS ONE ◽

10.1371/journal.pone.0159425 ◽

2016 ◽

Vol 11 (7) ◽

pp. e0159425 ◽

Cited By ~ 8

Author(s):

Yoon Seok Jung ◽

Ji-Min Lee ◽

Don-Kyu Kim ◽

Yong-Soo Lee ◽

Ki-Sun Kim ◽

...

Keyword(s):

Gene Expression ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Nuclear Receptor ◽

Cb1 Receptor ◽

Fibroblast Growth Factor 21 ◽

Orphan Nuclear Receptor ◽

Fibroblast Growth

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Serum Fibroblast Growth Factor 21 Levels Are Correlated with the Severity of Diabetic Retinopathy

Journal of Diabetes Research ◽

10.1155/2014/929756 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 9

Author(s):

Yuan Lin ◽

Ye-cheng Xiao ◽

Hong Zhu ◽

Qing-yan Xu ◽

Lei Qi ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Serum Insulin ◽

Conditional Logistic Regression ◽

Fasting Blood Glucose ◽

Fibroblast Growth Factor 21 ◽

Diabetic Patients ◽

Model Assessment ◽

Fibroblast Growth

The aim of the study was to assess serum fibroblast growth factor 21 (FGF21) concentrations in Chinese type 2 diabetic patients with and without retinopathy and to assess the association between FGF21 and the severity of retinopathy. 117 diabetic patients were compared with 68 healthy controls. Fasting blood glucose, serum total cholesterol, serum triglycerides, serum insulin, and serum FGF21 levels were estimated. FGF21 concentrations in the patients were significantly higher than those in control. In the patient group there was a significant positive correlation between FGF21, insulin level, and homeostasis model assessment index. Serum FGF21 concentrations in patients with proliferative diabetic retinopathy or nonproliferative diabetic retinopathy were significantly higher than those in patients without diabetic retinopathy. When the presence of diabetes was defined as the final variable in the conditional logistic regression model with the FGF21 concentration as the continuous variable, FGF21 was significantly involved in the model. This study shows that the increase in serum concentration of FGF21 was associated with the severity of diabetic retinopathy and suggests that FGF21 may play a role in the pathogenesis of diabetic retinopathy and its degree.

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Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver

Journal of Endocrinology ◽

10.1530/joe-14-0440 ◽

2014 ◽

Vol 224 (3) ◽

pp. 289-301 ◽

Cited By ~ 11

Author(s):

Aijun Zhang ◽

Douglas H Sieglaff ◽

Jean Philippe York ◽

Ji Ho Suh ◽

Stephen D Ayers ◽

...

Keyword(s):

Growth Factor ◽

Thyroid Hormone ◽

Fibroblast Growth Factor ◽

Thyroid Hormone Receptor ◽

Expression Profiles ◽

Fibroblast Growth Factor 21 ◽

Small Subset ◽

Fibroblast Growth ◽

Serum Triglycerides

Thyroid hormone (TH) acts through specific receptors (TRs), which are conditional transcription factors, to induce fibroblast growth factor 21 (FGF21), a peptide hormone that is usually induced by fasting and that influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While TH and FGF21 display overlapping actions when administered, including reductions in serum lipids, according to the current models these hormones act independentlyin vivo. In this study, we examined mechanisms of regulation of FGF21 expression by TH and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (triiodothyronine (T3)) and the TRβ-selective thyromimetic GC1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRβ. T3also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRβ1, which binds a TRE within intron 2 of FGF21. Gene expression profiles of WT andFgf21-knockout mice are very similar, indicating that FGF21 is dispensable for the majority of hepatic T3gene responses. A small subset of genes displays diminished T3response in the absence of FGF21. However, most of these are not obviously directly involved in T3-dependent hepatic metabolic processes. Consistent with these results, T3-dependent effects on serum cholesterol are maintained in theFgf21−/−background and we observe no effect of theFgf21-knockout background on serum triglycerides and glucose. Our findings indicate that T3regulates the genes involved in classical hepatic metabolic responses independently of FGF21.

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Fasting decreases plasma FGF21 in obese subjects and the expression of FGF21 receptors in adipose tissue in both lean and obese subjects

Journal of Endocrinology ◽

10.1530/joe-18-0002 ◽

2018 ◽

Vol 239 (1) ◽

pp. 73-80 ◽

Cited By ~ 10

Author(s):

Eva B Nygaard ◽

Cathrine Ørskov ◽

Thomas Almdal ◽

Henrik Vestergaard ◽

Birgitte Andersen

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Lipid Metabolism ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Adipose Tissues ◽

Blood Samples ◽

Obese Subjects

Fibroblast growth factor 21 (FGF21) is a metabolic regulator of energy and lipid metabolism. FGF21 is highly expressed in liver while FGF21 receptors (beta-klotho (KLB) and FGFR1c) are highly expressed in white adipose tissues (WATs). Plasma FGF21 has been shown to be increased after 7–10 days of fasting but oppositely plasma FGF21 is also increased in obesity. The aim of this study was to measure the effect of 60 h of fasting on plasma FGF21 levels in obese and lean subjects and to determine the gene expression of KLB and FGFR1c in the subcutaneous WAT before, during and after 60 h of fasting. Eight obese (BMI >30 kg/m2) and seven lean subjects (BMI <25 kg/m2) were fasted for 60 h and blood samples were taken at time 0 and after 12, 36 and 60 h of fasting. A biopsy from the subcutaneous WAT was taken at time 0, 12 and 60 h of fasting. FGF21 was measured in plasma by an ELISA and mRNA expression of KLB and FGFR1c was measured in WAT by quantitative PCR (qPCR). The fast significantly decreased plasma FGF21 in obese subjects while no change in plasma FGF21 was observed in lean subjects. Interestingly, KLB was significantly decreased in WAT in response to fasting in both lean and obese subjects indicating a potential important adaptive regulation of KLB in response to fasting.

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Activation of the Farnesoid X Receptor Induces Hepatic Expression and Secretion of Fibroblast Growth Factor 21

Journal of Biological Chemistry ◽

10.1074/jbc.m112.375907 ◽

2012 ◽

Vol 287 (30) ◽

pp. 25123-25138 ◽

Cited By ~ 83

Author(s):

Holly A. Cyphert ◽

Xuemei Ge ◽

Alison B. Kohan ◽

Lisa M. Salati ◽

Yanqiao Zhang ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Farnesoid X Receptor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Hepatic Expression

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FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure

Circulation Heart Failure ◽

10.1161/circheartfailure.121.008910 ◽

2021 ◽

Author(s):

Salah Sommakia ◽

Naredos H. Almaw ◽

Sandra H. Lee ◽

Dinesh K.A. Ramadurai ◽

Iosif Taleb ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Growth Factor ◽

Ejection Fraction ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Reduced Ejection Fraction ◽

End Stage ◽

Signaling Circuit

Background: Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling. Methods: To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters. Results: Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4–1040.3] pg/mL, n=40; controls: 146.0 [86.3–205.7] pg/mL, n=20, P =1.9×10 −5 ). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion. Conclusions: Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.

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Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0227 ◽

2014 ◽

Vol 92 (11) ◽

pp. 927-935 ◽

Cited By ~ 21

Author(s):

Wenhe Zhu ◽

Changwen Wang ◽

Lei Liu ◽

Yan Li ◽

Xiaokun Li ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Cell Damage ◽

Density Lipoprotein ◽

Serum Levels ◽

Lipoprotein Cholesterol ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth

Fibroblast growth factor 21 (FGF-21), which is a modulator of glucose and lipid homeostasis, acts as a novel therapeutic reagent for many metabolic perturbations. However, its potential as a treatment for cardiovascular disease, especially atherosclerosis (AS) has not been fully explored. Here, we report that recombinant FGF-21 improves resistance to cell damage from oxidative stress in vitro, and from atherosclerosis in vivo. Human umbilical vein endothelial cells (HUVECs) were induced with H2O2, followed by treatment with high purity recombinant FGF-21. The results indicated that FGF-21 significantly enhanced cell viability and decreased the degree of DNA fragmentation in HUVECs, as caused by H2O2 stress induction. Further studies revealed that FGF-21 inhibited H2O2-induced cell apoptosis by preventing the activation of mitogen-activated protein kinase (MAPK) signaling pathways. In an established rat model, FGF-21 dramatically improved the condition of atherosclerotic rats by decreasing serum levels of total triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and total cholesterol (TC), and by increasing the serum levels of high density lipoprotein cholesterol (HDL-C). FGF-21 also has antioxidant effects in the atherosclerotic rat, such that increased levels of superoxide dismutase, reduced glutathione, and reduced malondialdehyde were observed. These data provide novel insight into the potential use of FGF-21 in the prevention and treatment of human cardiovascular diseases.

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