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Mitogen-Activated Protein Kinase (MAPK) Phosphatase-1 and -4 Attenuate p38 MAPK during Dexamethasone-Induced Insulin Resistance in 3T3-L1 Adipocytes

Department of Molecular Cell Biology (M.B., F.C., R.S.J.T., R.C.H., J.A.M.), Leiden University Medical Center, 2333 AL Leiden, The Netherlands; and Unité Mixte de Recherche 6548 (F.C.), Université de Nice, 06108 Nice, France

Address all correspondence and requests for reprints to: Dr. J. A. Maassen, Signal Transduction Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Wassenaarseweg 72, PO Box 9503, 2333 AL Leiden, The Netherlands. E-mail: J.A.Maassen{at}LUMC.NL.

Prolonged use of glucocorticoids induces pronounced insulin resistance in vivo. In vitro, treatment of 3T3-L1 adipocytes with dexamethasone for 48 h reduces the maximal level of insulin- and stress (arsenite)-induced glucose uptake by approximately 50%. Although phosphatidylinositol 3-kinase signaling was slightly attenuated, phosphorylation of its downstream effectors such as protein kinase B and protein kinase C- remained intact. Nor was any effect of dexamethasone treatment observed on insulin- or arsenite-induced translocation of glucose transporter 4 (GLUT4) toward the plasma membrane. However, for a maximal response to either arsenite- or insulin-induced glucose uptake in these cells, functional p38 MAPK signaling is required. Dexamethasone treatment markedly attenuated p38 MAPK phosphorylation coincident with an up-regulation of the MAPK phosphatases MKP-1 and MKP-4. Employing lentivirus-mediated ectopic expression in fully differentiated 3T3-L1 adipocytes demonstrated a differential effect of these phosphatases: whereas MKP-1 was a more potent inhibitor of insulininduced glucose uptake, MKP-4 more efficiently inhibited arsenite-induced glucose uptake. This coincided with the effects of these phosphatases on p38 MAPK phosphorylation, i.e. MKP-1 and MKP-4 attenuated p38 MAPK phosphorylation by insulin and arsenite, respectively. Taken together, these data provide evidence that in 3T3-L1 adipocytes dexamethasone inhibits the activation of the GLUT4 in the plasma membrane by a p38 MAPK-dependent process, rather than in a defect in GLUT4 translocation per se.

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Ligands:   Dexamethasone  |  RU486

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