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Moyers, J.S. et al.

Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling.

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. J. Cell. Physiol. 210: 1-6, 2007. (c) 2006 Wiley-Liss, Inc.[1]

References

Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling. Moyers, J.S., Shiyanova, T.L., Mehrbod, F., Dunbar, J.D., Noblitt, T.W., Otto, K.A., Reifel-Miller, A., Kharitonenkov, A. J. Cell. Physiol. (2007) [Pubmed]

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