Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. Export

@article{citeulike:272225, abstract = {Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an approximately 6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3-4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-theta activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser(307) phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-theta leading to increased IRS-1 Ser(307) phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity.}, address = {Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.}, author = {Yu, C. and Chen, Y. and Cline, G. W. and Zhang, D. and Zong, H. and Wang, Y. and Bergeron, R. and Kim, J. K. and Cushman, S. W. and Cooney, G. J. and Atcheson, B. and White, M. F. and Kraegen, E. W. and Shulman, G. I.}, citeulike-article-id = {272225}, citeulike-linkout-0 = {http://dx.doi.org/10.1074/jbc.M200958200}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/12006582}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=12006582}, day = {27}, doi = {10.1074/jbc.M200958200}, issn = {0021-9258}, journal = {J Biol Chem}, keywords = {fattyacids, ffa, insulin, insulinresistance, irs}, month = {December}, number = {52}, pages = {50230--50236}, posted-at = {2005-08-03 15:53:28}, priority = {2}, title = {Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle.}, url = {http://dx.doi.org/10.1074/jbc.M200958200}, volume = {277}, year = {2002} }

TY - JOUR ID - citeulike:272225 L3 - citeulike-article-id:272225 N2 - Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an approximately 6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3-4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-theta activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser(307) phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-theta leading to increased IRS-1 Ser(307) phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity. IS - 52 JF - J Biol Chem SN - 0021-9258 AD - Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA. EP - 50236 TI - Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. VL - 277 SP - 50230 KW - fattyacids KW - ffa KW - insulin KW - insulinresistance KW - irs AU - Yu, C AU - Chen, Y AU - Cline, GW AU - Zhang, D AU - Zong, H AU - Wang, Y AU - Bergeron, R AU - Kim, JK AU - Cushman, SW AU - Cooney, GJ AU - Atcheson, B AU - White, MF AU - Kraegen, EW AU - Shulman, GI PY - 2002/12/27/ UR - http://dx.doi.org/10.1074/jbc.M200958200 ER -