scholarly journals Th2 Cytokines Increase the Expression of Fibroblast Growth Factor 21 in the Liver

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1298
Author(s):  
Seul-Gi Kang ◽  
Seong-Eun Lee ◽  
Min-Jeong Choi ◽  
Joon-Young Chang ◽  
Jung-Tae Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Intraperitoneal Administration ◽  
Janus Kinase ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Th2 Cytokines ◽  
Fibroblast Growth

Interleukin-4 (IL-4) and IL-13 are the major T helper 2 (Th2) cytokines, and they are involved in the regulation of metabolism in the adipose tissue. The liver contains diverse innate and adaptive immune cells, but it remains to be determined whether Th2 cytokines modulate energy metabolism in the liver. Here, using gene expression data from the Gene Expression Omnibus (GEO) and the BXD mouse reference population, we determined that the Th2 cytokines IL-4 and IL-13 increase the secretion of fibroblast growth factor 21 (FGF21) in the liver. In vitro experiments confirmed that FGF21 was highly expressed in response to IL-4 and IL-13, and this response was abolished by the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) blockade. Moreover, FGF21 expression in response to Th2 cytokines was augmented by selective peroxisome proliferator-activated receptor α (PPARα) inhibition. In vivo administration of IL-4 increased FGF21 protein levels in the liver in a STAT6-dependent manner, but FGF21 secretion in response to IL-4 was not observed in the epididymal white adipose tissue (eWAT) despite the activation of STAT6. Intraperitoneal administration of IL-33, an activator of type 2 immune responses, significantly increased the level of FGF21 in the serum and liver after 24 h, but repeated administration of IL-33 attenuated this effect. Taken together, these data demonstrate that the IL-4/IL-13–STAT6 axis regulates metabolic homeostasis through the induction of FGF21 in the liver.

scholarly journals Growth Hormone Stimulates Transcription of the Fibroblast Growth Factor 21 Gene in the Liver through the Signal Transducer and Activator of Transcription 5

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 750-758 ◽  
Author(s):  
Jie Yu ◽  
Lidan Zhao ◽  
Aihua Wang ◽  
Satyanarayana Eleswarapu ◽  
Xiaomei Ge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Mrna Expression ◽  
Fibroblast Growth Factor ◽  
Janus Kinase ◽  
Fibroblast Growth Factor 21 ◽  
Dependent Manner ◽  
Fibroblast Growth ◽  
Signal Transducer ◽  
Gh Receptor

Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Interestingly, FGF21 is also known to inhibit Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling from the GH receptor in the liver, where FGF21 mRNA is predominantly expressed. In this study, we tested the hypothesis that FGF21 gene expression in the liver is controlled by GH through STAT5. We found that GH injection to cattle increased FGF21 mRNA expression in the liver. Mapped by a 5′-rapid amplification of cDNA ends assay, transcription of the FGF21 gene in the bovine liver was mainly initiated from a nucleotide 24 bp downstream of a TATA box. The bovine FGF21 promoter contains three putative STAT5-binding sites. EMSA confirmed the ability of them to bind to liver STAT5 protein from GH-injected cattle. Chromatin immunoprecipitation assays demonstrated that GH administration increased the binding of STAT5 to the FGF21 promoter in the liver. Cotransfection analyses showed that GH induced reporter gene expression from the FGF21 promoter in a STAT5-dependent manner. GH also stimulated FGF21 mRNA expression in cultured mouse hepatocytes. These data together indicate that GH directly stimulates FGF21 gene transcription in the liver, at least in part, through STAT5. This finding, together with the fact that FGF21 inhibits GH-induced JAK2-STAT5 signaling in the liver, suggests a novel negative feedback loop that prevents excessive JAK2-STAT5 signaling from the GH receptor in the liver.

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

2018 ◽  
Vol 239 (1) ◽  
pp. 73-80 ◽  
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.

scholarly journals Fibroblast Growth Factor 21 and Thyroid Hormone Show Mutual Regulatory Dependency but Have Independent Actions In Vivo

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 2031-2040 ◽  
Author(s):  
Eleni M. Domouzoglou ◽  
ffolliott Martin Fisher ◽  
Inna Astapova ◽  
Elliott C. Fox ◽  
Alexei Kharitonenkov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Growth Factor ◽  
Thyroid Hormone ◽  
Fibroblast Growth Factor ◽  
Knockout Mice ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Brown Adipose ◽  
Circulating Levels

Thyroid hormone (TH) regulates fibroblast growth factor 21 (FGF21) levels in the liver and in the adipose tissue. In contrast, peripheral FGF21 administration leads to decreased circulating levels of TH. These data suggest that FGF21 and TH could interact to regulate metabolism. In the present study, we confirmed that TH regulates adipose and hepatic FGF21 expression and serum levels in mice. We next investigated the influence of TH administration on key serum metabolites, gene expression in the liver and brown adipose tissue, and energy expenditure in FGF21 knockout mice. Surprisingly, we did not observe any significant differences in the effects of TH on FGF21 knockout mice compared with those in wild-type animals, indicating that TH acts independently of FGF21 for the specific outcomes studied. Furthermore, exogenous FGF21 administration to hypothyroid mice led to similar changes in serum and liver lipid metabolites and gene expression in both hypothyroid and euthyroid mice. Thus, it appears that FGF21 and TH have similar actions to decrease serum and liver lipids despite having some divergent regulatory effects. Whereas TH leads to up-regulation in the liver and down-regulation in brown adipose tissue of genes involved in the lipid synthesis pathway (eg, fatty acid synthase (FASN) and SPOT14), FGF21 leads to the opposite changes in expression of these genes. In conclusion, TH and FGF21 act independently on the outcomes studied, despite their ability to regulate each other's circulating levels. Thus, TH and FGF21 may modulate the availability of each other in critical metabolic states.

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

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0159425 ◽  
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

scholarly journals Identification of Sp1 as a Transcription Activator to Regulate Fibroblast Growth Factor 21 Gene Expression

2017 ◽  
Vol 2017 ◽  
pp. 1-10
Author(s):  
Shuqin Chen ◽  
Huating Li ◽  
Jing Zhang ◽  
Shan Jiang ◽  
Mingliang Zhang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Target Genes ◽  
Proximal Promoter ◽  
Fibroblast Growth Factor 21 ◽  
Obese Mouse ◽  
Primary Role ◽  
Fibroblast Growth ◽  
Transcription Activator

Fibroblast growth factor 21 (FGF21) is a metabolic hormone with multiple beneficial effects on lipid and glucose homeostasis. Previous study demonstrated that FGF21 might be one of the Sp1 target genes. However, the transcriptional role of Sp1 on FGF21 in adipose tissue and liver has not been reported. In this study, we found that the proximal promoter of mouse FGF21 is located between −63 and −20 containing two putative Sp1-binding sites. Sp1 is a mammalian transcription factor involved in the regulation of many genes during physiological and pathological processes. Our study showed that overexpression of Sp1 or suppressing Sp1 expression resulted in increased or reduced FGF21 promoter activity, respectively. Mutation analysis demonstrated that the Sp1-binding site located between −46 and −38 plays a primary role in transcription of FGF21. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Sp1 specifically bound to this region. Furthermore, the binding activity of Sp1 was significantly increased in adipose tissues of HFD-induced obese mouse and liver of DEN-treated mouse. Thus, our results demonstrate that Sp1 positively regulates the basal transcription of FGF21 in the liver and adipose tissue and contributes to the obesity-induced FGF21 upregulation in mouse adipose tissue and hepatic FGF21 upregulation in hepatocarcinogenesis.

scholarly journals Central Fibroblast Growth Factor 21 Browns White Fat via Sympathetic Action in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2470-2481 ◽  
Author(s):  
Nicholas Douris ◽  
Darko M. Stevanovic ◽  
ffolliott M. Fisher ◽  
Theodore I. Cisu ◽  
Melissa J. Chee ◽  
...  
Keyword(s):  
Nervous System ◽  
Adipose Tissue ◽  
Growth Factor ◽  
Sympathetic Nervous System ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Male Mice ◽  
Sympathetic Nervous ◽  
The Brain

Fibroblast growth factor 21 (FGF21) has multiple metabolic actions, including the induction of browning in white adipose tissue. Although FGF21 stimulated browning results from a direct interaction between FGF21 and the adipocyte, browning is typically associated with activation of the sympathetic nervous system through cold exposure. We tested the hypothesis that FGF21 can act via the brain, to increase sympathetic activity and induce browning, independent of cell-autonomous actions. We administered FGF21 into the central nervous system via lateral ventricle infusion into male mice and found that the central treatment increased norepinephrine turnover in target tissues that include the inguinal white adipose tissue and brown adipose tissue. Central FGF21 stimulated browning as assessed by histology, expression of uncoupling protein 1, and the induction of gene expression associated with browning. These effects were markedly attenuated when mice were treated with a β-blocker. Additionally, neither centrally nor peripherally administered FGF21 initiated browning in mice lacking β-adrenoceptors, demonstrating that an intact adrenergic system is necessary for FGF21 action. These data indicate that FGF21 can signal in the brain to activate the sympathetic nervous system and induce adipose tissue thermogenesis.

scholarly journals Increased Circulating and Epicardial Adipose Tissue mRNA Expression of Fibroblast Growth Factor-21 After Cardiac Surgery: Possible Role in Postoperative Inflammatory Response and Insulin Resistance

2011 ◽  
pp. 757-767 ◽  
Author(s):  
T. KOTULÁK ◽  
J. DRÁPALOVÁ ◽  
P. KOPECKÝ ◽  
Z. LACINOVÁ ◽  
P. KRAMÁŘ ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Cardiac Surgery ◽  
Growth Factor ◽  
Mrna Expression ◽  
Fibroblast Growth Factor ◽  
Serum Glucose ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Baseline Serum

We studied the changes in serum fibroblast growth factor-21 (FGF-21) concentrations, its mRNA, and protein expression in skeletal muscle and adipose tissue of 15 patients undergoing cardiac surgery. Blood samples were obtained: prior to initiation of anesthesia, prior to the start of extracorporeal circulation, upon completion of the surgery, and 6, 24, 48, and 96 hours after the end of the surgery. Tissue sampling was performed at the start and end of surgery. The mean baseline serum FGF-21 concentration was 63.1 (43.03-113.95) pg/ml and it increased during surgery with peak 6 hours after its end [385.5 (274.55-761.65) pg/ml, p<0.001], and returned to baseline value [41.4 (29.15-142.83) pg/ml] 96 hours after the end of the surgery. Serum glucose, insulin, CRP, IL-6, IL-8, MCP-1, and TNF-alpha concentrations significantly increased during the surgery. Baseline FGF-21 mRNA expression in skeletal muscle was higher than in both adipose tissue depots and it was not affected by the surgery. Epicardial fat FGF-21 mRNA increased after surgery. Muscle FGF-21 mRNA positively correlated with blood glucose levels at the end of the surgery. Our data suggest a possible role of FGF-21 in the regulation of glucose metabolism and insulin sensitivity in surgery-related stress.

scholarly journals Inducible Loss of the Aryl Hydrocarbon Receptor Activates Perigonadal White Fat Respiration and Brown Fat Thermogenesis via Fibroblast Growth Factor 21

2019 ◽  
Vol 20 (4) ◽  
pp. 950 ◽  
Author(s):  
Nathaniel Girer ◽  
Dwayne Carter ◽  
Nisha Bhattarai ◽  
Mehnaz Mustafa ◽  
Larry Denner ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Growth Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Fibroblast Growth Factor ◽  
Knockout Mouse ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Knockout Mouse Model ◽  
Aryl Hydrocarbon ◽  
Brown Adipose

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor highly expressed in hepatocytes. Researchers have employed global and liver-specific conditional Ahr knockout mouse models to characterize the physiological roles of the AHR; however, the gestational timing of AHR loss in these models can complicate efforts to distinguish the direct and indirect effects of post-gestational AHR deficiency. Utilizing a novel tamoxifen-inducible AHR knockout mouse model, we analyzed the effects of hepatocyte-targeted AHR loss in adult mice. The data demonstrate that AHR deficiency significantly reduces weight gain and adiposity, and increases multilocular lipid droplet formation within perigonadal white adipose tissue (gWAT). Protein and mRNA expression of fibroblast growth factor 21 (FGF21), an important hepatokine that activates thermogenesis in brown adipose tissue (BAT) and gWAT, significantly increases upon AHR loss and correlates with a significant increase of BAT and gWAT respiratory capacity. Confirming the role of FGF21 in mediating these effects, this phenotype is reversed in mice concomitantly lacking AHR and FGF21 expression. Chromatin immunoprecipitation analyses suggest that the AHR may constitutively suppress Fgf21 transcription through binding to a newly identified xenobiotic response element within the Fgf21 promoter. The data demonstrate an important AHR-FGF21 regulatory axis that influences adipose biology and may represent a “druggable” therapeutic target for obesity and its related metabolic disorders.

scholarly journals Fibroblast Growth Factor-21, Leptin, and Adiponectin Responses to Acute Cold-Induced Brown Adipose Tissue Activation

2020 ◽  
Vol 105 (3) ◽  
pp. e520-e531 ◽  
Author(s):  
Lijuan Sun ◽  
Jianhua Yan ◽  
Hui Jen Goh ◽  
Priya Govindharajulu ◽  
Sanjay Verma ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Growth Factor ◽  
Brown Adipose Tissue ◽  
Fibroblast Growth Factor ◽  
Cold Exposure ◽  
Maximum Temperature ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Adiponectin Concentration ◽  
Brown Adipose

Abstract Background Adipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored. Objective Our study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults. Design Nineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity. Main Outcome Measures Plasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNFα) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA). Results Plasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P  = 0.03), and inversely correlated with MR sFF (coefficient, −404; P  = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Conclusion Higher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults. Highlights A higher adiponectin concentration at baseline was associated with higher cold-induced supraclavicular BAT PET SUV mean and IRT Tscv max, and lower MR supraclavicular FF. Adiponectin levels maybe a novel predictor for cold-induced sBAT activity.

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