Article

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

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
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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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    • "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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    • "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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