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JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes.
J Biol Chem. 2005 Oct 21; 280(42):35361-71.JB

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 IKKbeta, and the suppressor of cytokine signaling protein 3, increased secretion of the inflammatory cytokine tumor necrosis factor (TNF)-alpha, 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-alpha signaling with neutralizing antibodies to TNF-alpha or its receptors or with a dominant negative TNF-alpha 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-alpha signaling, whereas the FFA-induced increase in TNF-alpha secretion was inhibited by RNA interference-mediated JNK knockdown. Together, these results indicate that 1) JNK can be activated by FFAs through TNF-alpha-independent mechanisms, 2) activated JNK is a major contributor to FFA-induced cellular insulin resistance, and 3) TNF-alpha is an autocrine/paracrine downstream effector of activated JNK that can also mediate insulin resistance.

Authors+Show Affiliations

Division of Endocrinology-Metabolism, University of California, San Diego, La Jolla, California 92093-0673, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16085647

Citation

Nguyen, M T Audrey, et al. "JNK and Tumor Necrosis Factor-alpha Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes." The Journal of Biological Chemistry, vol. 280, no. 42, 2005, pp. 35361-71.
Nguyen MT, Satoh H, Favelyukis S, et al. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem. 2005;280(42):35361-71.
Nguyen, M. T., 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-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. The Journal of Biological Chemistry, 280(42), 35361-71.
Nguyen MT, et al. JNK and Tumor Necrosis Factor-alpha Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes. J Biol Chem. 2005 Oct 21;280(42):35361-71. PubMed PMID: 16085647.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - JNK and tumor necrosis factor-alpha 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, Y1 - 2005/08/05/ PY - 2005/8/9/pubmed PY - 2005/12/15/medline PY - 2005/8/9/entrez SP - 35361 EP - 71 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 280 IS - 42 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 IKKbeta, and the suppressor of cytokine signaling protein 3, increased secretion of the inflammatory cytokine tumor necrosis factor (TNF)-alpha, 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-alpha signaling with neutralizing antibodies to TNF-alpha or its receptors or with a dominant negative TNF-alpha 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-alpha signaling, whereas the FFA-induced increase in TNF-alpha secretion was inhibited by RNA interference-mediated JNK knockdown. Together, these results indicate that 1) JNK can be activated by FFAs through TNF-alpha-independent mechanisms, 2) activated JNK is a major contributor to FFA-induced cellular insulin resistance, and 3) TNF-alpha is an autocrine/paracrine downstream effector of activated JNK that can also mediate insulin resistance. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/16085647/JNK_and_tumor_necrosis_factor_alpha_mediate_free_fatty_acid_induced_insulin_resistance_in_3T3_L1_adipocytes_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16085647 DB - PRIME DP - Unbound Medicine ER -