JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes

M. T.Audrey Nguyen, Hiroaki Satoh, Svetlana Favelyukis, Jennie L. Babendure, Takeshi Imamura, Juan I. Sbodio, Jonathan Zalevsky, Bassil I. Dahiyat, Nai Wen Chi, Jerrold M. Olefsky

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308 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)35361-35371
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number42
DOIs
StatePublished - Oct 21 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Nguyen, M. T. A., Satoh, H., Favelyukis, S., Babendure, J. L., Imamura, T., Sbodio, J. I., Zalevsky, J., Dahiyat, B. I., Chi, N. W., & Olefsky, J. M. (2005). JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. Journal of Biological Chemistry, 280(42), 35361-35371. https://doi.org/10.1074/jbc.M504611200