title: Mitogen-activated protein kinase (MAPK) phosphatase-1 and -4 attenuate p38 MAPK during dexamethasone-induced insulin resistance in 3T3-L1 adipocytes.
abstract: 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-lambda 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 insulin-induced 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.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, 2333 AL Leiden, The Netherlands.
authors.forename: Merlijn
authors.initials: M
authors.lastname: Bazuine
authors.forename: Françoise
authors.initials: F
authors.lastname: Carlotti
authors.forename: Roos S Jahangir
authors.initials: RS
authors.lastname: Tafrechi
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.forename: J Antonie
authors.initials: JA
authors.lastname: Maassen
mesh_terms: D041721:3T3-L1 Cells / Q000187:drug effects / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000493:pharmacokinetics; D051275:Glucose Transporter Type 4; D017874:Immediate-Early Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D054639:Mitogen-Activated Protein Kinase Phosphatases; D009004:Monosaccharide Transport Proteins / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D054645:Protein Phosphatase 1; D021381:Protein Transport / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018053:Arsenites; D018797:Cell Cycle Proteins; D051275:Glucose Transporter Type 4; D017874:Immediate-Early Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; C104821:DUSP9 protein, human; D054638:Dual Specificity Phosphatase 1; D054637:Dual-Specificity Phosphatases; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; D005947:Glucose; C015001:arsenite