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

Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana, United States
Journal of Cellular Physiology (Impact Factor: 3.84). 01/2007; 210(1):1-6. DOI: 10.1002/jcp.20847
Source: PubMed


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
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    • "Concerning PPAR agonists, FGF21 is a downstream target of both PPAR-a and PPAR-g636465. In vitro studies have shown that combined FGF21 and the PPARg agonist rosiglitazone markedly increase the expression of the glucose transporter GLUT-1, resulting in a pronounced stimulation of glucose uptake[66]. Data from studies in animal models had suggested that FGF21 was indispensable for the anti-diabetic effects of PPAR-g agonists[67]. "
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    ABSTRACT: Diabetes mellitus, especially type 2 diabetes, remains the dominant metabolic disease worldwide, with an expected increase in prevalence of over 50% in the next 20 years. Our knowledge about the pathophysiology of type 2 diabetes continues to be incomplete, with unmet medical need for new therapies. The characterization of the fibroblast growth factor (FGF) family and the discovery of endocrine FGFs provided new information on the mechanisms of regulation and homeostasis of carbohydrate metabolism. More specifically, FGF19 and FGF21 signaling pathways have been linked to different glucose metabolic processes, including hepatic glucose synthesis, glycogen synthesis, glucose uptake, and insulin sensitivity, among others, and these molecules have been further related to the pathophysiology of diabetes mellitus. In-depth comprehension of these growth factors may bring to light new potential therapeutic targets for the treatment of diabetes mellitus.
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    • "Cotreatment with FGF21 and a PPARγ agonist results in synergistic adipocyte differentiation and glucose uptake in adipose tissue [19]. Moreover, thiazolidinedione increases FGF21-induced tyrosine phosphorylation of the FGF receptor and induces β-Klotho expression [56,57]. ALA, a naturally occurring thiol antioxidant, is an essential cofactor for mitochondrial respiration [58] and is often used to manage diabetic complications [59,60]. "
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) is an attractive target for treating metabolic disease due to its wide-ranging beneficial effects on glucose and lipid metabolism. Circulating FGF21 levels are increased in insulin-resistant states; however, endogenous FGF21 fails to improve glucose and lipid metabolism in obesity, suggesting that metabolic syndrome is an FGF21-resistant state. Therefore, transcription factors for FGF21 are potential drug targets that could increase FGF21 expression in obesity and reduce FGF21 resistance. Despite many studies on the metabolic effects of FGF21, the transcriptional regulation of FGF21 gene expression remains controversial and is not fully understood. As the FGF21 transcription factor pathway is one of the most promising targets for the treatment of metabolic syndrome, further investigation of FGF21 transcriptional regulation is required.
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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.
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