TY - JOUR
T1 - JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes
AU - Nguyen, M. T.Audrey
AU - Satoh, Hiroaki
AU - Favelyukis, Svetlana
AU - Babendure, Jennie L.
AU - Imamura, Takeshi
AU - Sbodio, Juan I.
AU - Zalevsky, Jonathan
AU - Dahiyat, Bassil I.
AU - Chi, Nai Wen
AU - Olefsky, Jerrold M.
PY - 2005/10/21
Y1 - 2005/10/21
N2 - Lipid infusion and high fat feeding are established causes of systemic and adipose tissue insulin resistance. In this study, we treated 3T3-L1 adipocytes with a mixture of free fatty acids (FFAs) to investigate the molecular mechanisms underlying fat-induced insulin resistance. FFA treatment impaired insulin receptor-mediated signal transduction and decreased insulin-stimulated GLUT4 translocation and glucose transport. FFAs activated the stress/inflammatory kinases c-Jun N-terminal kinase (JNK) and IKKβ, and the suppressor of cytokine signaling protein 3, increased secretion of the inflammatory cytokine tumor necrosis factor (TNF)-α, and decreased secretion of adiponectin into the medium. RNA interference-mediated down-regulation of JNK blocked JNK activation and prevented most of the FFA-induced defects in insulin action. Blockade of TNF-α signaling with neutralizing antibodies to TNF-α or its receptors or with a dominant negative TNF-α peptide had a partial effect to inhibit FFA-induced cellular insulin resistance. We found that JNK activation by FFAs was not inhibited by blocking TNF-α signaling, whereas the FFA-induced increase in TNF-α secretion was inhibited by RNA interference-mediated JNK knockdown. Together, these results indicate that 1) JNK can be activated by FFAs through TNF-α-independent mechanisms, 2) activated JNK is a major contributor to FFA-induced cellular insulin resistance, and 3) TNF-α is an autocrine/paracrine downstream effector of activated JNK that can also mediate insulin resistance.
AB - Lipid infusion and high fat feeding are established causes of systemic and adipose tissue insulin resistance. In this study, we treated 3T3-L1 adipocytes with a mixture of free fatty acids (FFAs) to investigate the molecular mechanisms underlying fat-induced insulin resistance. FFA treatment impaired insulin receptor-mediated signal transduction and decreased insulin-stimulated GLUT4 translocation and glucose transport. FFAs activated the stress/inflammatory kinases c-Jun N-terminal kinase (JNK) and IKKβ, and the suppressor of cytokine signaling protein 3, increased secretion of the inflammatory cytokine tumor necrosis factor (TNF)-α, and decreased secretion of adiponectin into the medium. RNA interference-mediated down-regulation of JNK blocked JNK activation and prevented most of the FFA-induced defects in insulin action. Blockade of TNF-α signaling with neutralizing antibodies to TNF-α or its receptors or with a dominant negative TNF-α peptide had a partial effect to inhibit FFA-induced cellular insulin resistance. We found that JNK activation by FFAs was not inhibited by blocking TNF-α signaling, whereas the FFA-induced increase in TNF-α secretion was inhibited by RNA interference-mediated JNK knockdown. Together, these results indicate that 1) JNK can be activated by FFAs through TNF-α-independent mechanisms, 2) activated JNK is a major contributor to FFA-induced cellular insulin resistance, and 3) TNF-α is an autocrine/paracrine downstream effector of activated JNK that can also mediate insulin resistance.
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U2 - 10.1074/jbc.M504611200
DO - 10.1074/jbc.M504611200
M3 - Article
C2 - 16085647
AN - SCOPUS:27444445460
SN - 0021-9258
VL - 280
SP - 35361
EP - 35371
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 42
ER -