The c-Jun N-terminal kinase mediates the induction of oxidative stress and insulin resistance by palmitate and toll-like receptor 2 and 4 ligands in 3T3-L1 adipocytes.
Saturated fatty acids (SFAs) are known to induce inflammation and insulin resistance in adipocytes through toll-like receptor-4 (Tlr4) signaling, but the mechanisms are not well delineated. Furthermore, the potential roles of Tlr2 and the c-Jun N-terminal kinase (JNK) in inflammation in adipocytes have not been investigated. We demonstrated that palmitate, lipopolysaccharide (LPS), and the toll-like receptor-2 (Tlr2) agonist, zymosan A (ZymA), induced insulin resistance in a time- and dose-dependent manner in 3T3-L1 adipocytes. Corresponding with the reduction of insulin sensitivity was an increased expression of IL-6, as well as activation of the proinflammatory transcription factors, nuclear factor kappa B, and activator protein-1. Reactive oxygen species (ROS) accumulation was also observed in palmitate and Tlr agonist treated adipocytes. The JNK inhibitor, SP600125, attenuated insulin resistance mediated by SFA and Tlr agonists, which corresponded with a diminished proinflammatory response and reduced ROS accumulation. Collectively, these results demonstrated Tlr2 involvement in adipocyte inflammation and therefore implicated the receptor as a potential target for SFA. Moreover, activation of JNK also appeared to be essential to Tlr2-, as well as Tlr4-induced insulin resistance and oxidative stress.
Davis
J E
JE
Iowa State University, Food Science Human Nutrition, Ames, IA, USA.
Gabler
N K
NK
Walker-Daniels
J
J
Spurlock
M E
ME
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D007333:Insulin Resistance; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D010168:Palmitates / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
D010168:Palmitates; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D048670:MAP Kinase Kinase 4