Article

Molecular determinants of FGF-21 activity - Synergy and cross-talk with PPARγ signaling

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Journal of Cellular Physiology (Impact Factor: 3.87). 01/2007; 210(1):1-6. DOI: 10.1002/jcp.20847
Source: PubMed

ABSTRACT Fibroblast growth factor (FGF)-21 is a novel regulator of insulin-independent glucose transport in 3T3-L1 adipocytes and has glucose and triglyceride lowering effects in rodent models of diabetes. The precise mechanisms whereby FGF-21 regulates metabolism remain to be determined. Here we describe the early signaling events triggered by FGF-21 treatment of 3T3-L1 adipocytes and reveal a functional interplay between FGF-21 and peroxisome proliferator-activated receptor gamma (PPARgamma) pathways that leads to a marked stimulation of glucose transport. While the early actions of FGF-21 on 3T3-L1 adipocytes involve rapid accumulation of intracellular calcium and phosphorylation of Akt, GSK-3, p70(S6K), SHP-2, MEK1/2, and Stat3, continuous treatment for 72 h induces an increase in PPARgamma protein expression. Moreover, chronic activation of the PPARgamma pathway in 3T3-L1 adipocytes with the PPARgamma agonist and anti-diabetic agent, rosiglitazone (BRL 49653), enhances FGF-21 action to induce tyrosine phosphorylation of FGF receptor-2. Strikingly, treatment of cells with FGF-21 and rosiglitazone in combination leads to a pronounced increase in expression of the GLUT1 glucose transporter and a marked synergy in stimulation of glucose transport. Together these results reveal a novel synergy between two regulators of glucose homeostasis, FGF-21 and PPARgamma, and further define FGF-21 mechanism of action.

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Available from: Alexei Kharitonenkov, Aug 11, 2015
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    • "The present study demonstrated that AhR activation induced Fgf21 expression in both mouse liver and WAT (Figs. 4 and 5). In contrast, PPAR isoforms differentially regulated Fgf21 expression in the liver and WAT (Badman et al., 2007; Inagaki et al., 2007; Lundasen et al., 2007; Moyers et al., 2007; Suzuki et al., 2008; Wang et al., 2008). For example , PPARα activation by fasting, Wy-14643 administration, and feeding a ketogenic-diet can only induce Fgf21 expression in the liver; whereas PPARγ activation can only induce Fgf21 expression in WAT. "
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    ABSTRACT: The toxic effects of dioxins, such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (-105/+1 base pair). Fgf21-null mice administered 200μg/kg of TCDD died within 20days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver.
    Toxicology and Applied Pharmacology 04/2014; 278(1). DOI:10.1016/j.taap.2014.04.013
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    • "The present study demonstrated that AhR activation induced Fgf21 expression in both mouse liver and WAT (Figs. 4 and 5). In contrast, PPAR isoforms differentially regulated Fgf21 expression in the liver and WAT (Badman et al., 2007; Inagaki et al., 2007; Lundasen et al., 2007; Moyers et al., 2007; Suzuki et al., 2008; Wang et al., 2008). For example , PPARα activation by fasting, Wy-14643 administration, and feeding a ketogenic-diet can only induce Fgf21 expression in the liver; whereas PPARγ activation can only induce Fgf21 expression in WAT. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The toxic effects of dioxins, such as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), mainly through activation of the aryl hydrocarbon receptor (AhR) are well documented. Fibroblast growth factor (Fgf) 21 plays critical roles in metabolic adaptation to fasting by increasing lipid oxidation and ketogenesis in the liver. The present study was performed to determine whether activation of the AhR induces Fgf21 expression. In mouse liver, TCDD increased Fgf21 mRNA in both dose- and time-dependent manners. In addition, TCDD markedly increased Fgf21 mRNA expression in cultured mouse and human hepatocytes. Moreover, TCDD increased mRNA (in liver) and protein levels (in both liver and serum) of Fgf21 in wild-type mice, but not in AhR-null mice. Chromatin immunoprecipitation assays showed that TCDD increased AhR protein binding to the Fgf21 promoter (− 105/+ 1 base pair). Fgf21-null mice administered 200 μg/kg of TCDD died within 20 days, whereas wild-type mice receiving the same treatment were still alive at one month after administration. This indicates that TCDD-induced Fgf21 expression protects against TCDD toxicity. Diethylhexylphthalate (DEHP) pretreatment attenuated TCDD-induced Fgf21 expression in mouse liver and white adipose tissue, which may explain a previous report that DEHP pretreatment decreases TCDD-induced wasting. In conclusion, Fgf21 appears to be a target gene of AhR-signaling pathway in mouse and human liver.
    Toxicology and Applied Pharmacology 01/2014;
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    • "In this report we demonstrate an important role for FGF21 in regulating PPARg activity in WAT. FGF21 was previously shown to be induced by PPARg agonists in WAT and to cooperate with rosiglitazone in promoting differentiation and glucose uptake in 3T3-L1 adipocytes in vitro (Moyers et al., 2007; Muise et al., 2008; Wang et al., 2008; Zhang et al., 2008). We now show that lean mice lacking FGF21 have decreased PPARg activity in WAT and corresponding reductions in WAT mass and adipocyte size. "
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    ABSTRACT: Fibroblast growth factor-21 (FGF21) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism. Here, we report that FGF21 is also an inducible, fed-state autocrine factor in adipose tissue that functions in a feed-forward loop to regulate the activity of peroxisome proliferator-activated receptor γ (PPARγ), a master transcriptional regulator of adipogenesis. FGF21 knockout (KO) mice display defects in PPARγ signaling including decreased body fat and attenuation of PPARγ-dependent gene expression. Moreover, FGF21-KO mice are refractory to both the beneficial insulin-sensitizing effects and the detrimental weight gain and edema side effects of the PPARγ agonist rosiglitazone. This loss of function in FGF21-KO mice is coincident with a marked increase in the sumoylation of PPARγ, which reduces its transcriptional activity. Adding back FGF21 prevents sumoylation and restores PPARγ activity. Collectively, these results reveal FGF21 as a key mediator of the physiologic and pharmacologic actions of PPARγ.
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