title: Cyclin-dependent kinase-5 is a key molecule in tumor necrosis factor-α-induced insulin resistance.
abstract: The mechanism of TNF-α-induced insulin resistance has remained unresolved with evidence for down-regulation of insulin effector targets effects or blockade of proximal as well as distal insulin signaling events depending upon the dose, time, and cell type examined. To address this issue we examined the acute actions of TNF-α in differentiated 3T3L1 adipocytes. Acute (5-15 min) treatment with 20 ng/ml (~0.8 nm) TNF-α had no significant effect on IRS1-associated phosphatidylinositol 3-kinase. In contrast, TNF-α increased insulin-stimulated cyclin-dependent kinase-5 (CDK5) phosphorylation on tyrosine residue 15 through an Erk-dependent pathway and up-regulated the expression of the CDK5 regulator protein p35. In parallel, TNF-α stimulation also resulted in the phosphorylation and GTP loading of the Rho family GTP-binding protein, TC10α. TNF-α enhanced the depolymerization of cortical F-actin and inhibited insulin-stimulated glucose transporter-4 (GLUT4) translocation. Treatment with the MEK inhibitor, PD98059, blocked the TNF-α-induced increase in CDK5 phosphorylation and the depolymerization of cortical F-actin. Conversely, siRNA-mediated knockdown of CDK5 or treatment with the MEK inhibitor restored the impaired insulin-stimulated GLUT4 translocation induced by TNF-α. Furthermore, siRNA-mediated knockdown of p44/42 Erk also rescued the TNF-α inhibition of insulin-stimulated GLUT4 translocation. Together, these data demonstrate that TNF-α-mediated insulin resistance of glucose uptake can occur through a MEK/Erk-dependent activation of CDK5.
authors.affiliation: Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.forename: Shuichi
authors.initials: S
authors.lastname: Okada
authors.forename: Kihachi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
mesh_terms: D041721:3T3-L1 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D058105:Polymerization / Q000187:drug effects; D034622:RNA Interference / Q000187:drug effects; D011972:Receptor, Insulin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D005419:Flavonoids; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C495693:Slc2a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C503260:Rhoq protein, mouse; D020741:rho GTP-Binding Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one