This Article Full Text Full Text (PDF) All Versions of this Article: 18/8/2024    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gao, Z. Articles by Ye, J. Search for Related Content PubMed PubMed Citation Articles by Gao, Z. Articles by Ye, J.

Inhibition of Insulin Sensitivity by Free Fatty Acids Requires Activation of Multiple Serine Kinases in 3T3-L1 Adipocytes

Pennington Biomedical Research Center (Z.G., X.Z., A.Z., M.L., J.Y.), Louisiana State University, Baton Rouge, Louisiana 70808; Western Human Nutrition Research Center and Department of Nutrition (D.H.), University of California, Davis, California 95616; and Diabetes Unit (M.J.Q.), National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892-1755

Address all correspondence and requests for reprints to: Jianping Ye, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, Louisiana 70808. E-mail: yej{at}pbrc.edu.

Insulin receptor substrate (IRS) has been suggested as a molecular target of free fatty acids (FFAs) for insulin resistance. However, the signaling pathways by which FFAs lead to the inhibition of IRS function remain to be established. In this study, we explored the FFA-signaling pathway that contributes to serine phosphorylation and degradation of IRS-1 in adipocytes and in dietary obese mice. Linoleic acid, an FFA used in this study, resulted in a reduction in insulin-induced glucose uptake in 3T3-L1 adipocytes. This mimics insulin resistance induced by high-fat diet in C57BL/6J mice. The reduction in glucose uptake is associated with a decrease in IRS-1, but not IRS-2 or GLUT4 protein abundance. Decrease in IRS-1 protein was proceeded by IRS-1 (serine 307) phosphorylation that was catalyzed by serine kinases inhibitor B kinase (IKK) and c-JUN NH₂-terminal kinase (JNK). IKK and JNK were activated by linoleic acid and inhibition of the two kinases led to prevention of IRS-1 reduction. We demonstrate that protein kinase C (PKC) is expressed in adipocytes. In 3T3-L1 adipocytes and fat tissue, PKC was activated by fatty acids as indicated by its phosphorylation status, and by its protein level, respectively. Activation of PKC contributes to IKK and JNK activation as inhibition of PKC by calphostin C blocked activation of the latter kinases. Inhibition of either PKC or IKK plus JNK by chemical inhibitors resulted in protection of IRS-1 function and insulin sensitivity in 3T3-L1 adipocytes. These data suggest that: 1) activation of PKC contributes to IKK and JNK activation by FFAs; 2) IKK and JNK mediate PKC signals for IRS-1 serine phosphorylation and degradation; and 3) this molecular mechanism may be responsible for insulin resistance associated with hyperlipidemia.

This article has been cited by other articles:

				S. Lee, E. G. Lynn, J.-a Kim, and M. J. Quon Protein Kinase C-{zeta} Phosphorylates Insulin Receptor Substrate-1, -3, and -4 But Not -2: Isoform Specific Determinants of Specificity in Insulin Signaling Endocrinology, May 1, 2008; 149(5): 2451 - 2458. [Abstract] [Full Text] [PDF]

				W. Bakker, P. Sipkema, C. D.A. Stehouwer, E. H. Serne, Y. M. Smulders, V. W.M. van Hinsbergh, and E. C. Eringa Protein Kinase C {theta} Activation Induces Insulin-Mediated Constriction of Muscle Resistance Arteries Diabetes, March 1, 2008; 57(3): 706 - 713. [Abstract] [Full Text] [PDF]

				J.-a Kim, Y. Wei, and J. R. Sowers Role of Mitochondrial Dysfunction in Insulin Resistance Circ. Res., February 29, 2008; 102(4): 401 - 414. [Abstract] [Full Text] [PDF]

				G. Boden, W. Song, L. Pashko, and K. Kresge In Vivo Effects of Insulin and Free Fatty Acids on Matrix Metalloproteinases in Rat Aorta Diabetes, February 1, 2008; 57(2): 476 - 483. [Abstract] [Full Text] [PDF]

				J. Yin, Z. Gao, D. Liu, Z. Liu, and J. Ye Berberine improves glucose metabolism through induction of glycolysis Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E148 - E156. [Abstract] [Full Text] [PDF]

				E. Park, V. Wong, X. Guan, A. I Oprescu, and A. Giacca Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo J. Endocrinol., November 1, 2007; 195(2): 323 - 331. [Abstract] [Full Text] [PDF]

				J. A. A. Pires, J. B. Pescara, and R. R. Grummer Reduction of Plasma NEFA Concentration by Nicotinic Acid Enhances the Response to Insulin in Feed-Restricted Holstein Cows J Dairy Sci, October 1, 2007; 90(10): 4635 - 4642. [Abstract] [Full Text] [PDF]

				R. Yang, D. M. Wilcox, D. L. Haasch, P. M. Jung, P. T. Nguyen, M. J. Voorbach, S. Doktor, S. Brodjian, E. N. Bush, E. Lin, et al. Liver-specific Knockdown of JNK1 Up-regulates Proliferator-activated Receptor {gamma} Coactivator 1beta and Increases Plasma Triglyceride despite Reduced Glucose and Insulin Levels in Diet-induced Obese Mice J. Biol. Chem., August 3, 2007; 282(31): 22765 - 22774. [Abstract] [Full Text] [PDF]

				R. Muniyappa, M. Montagnani, K. K. Koh, and M. J. Quon Cardiovascular Actions of Insulin Endocr. Rev., August 1, 2007; 28(5): 463 - 491. [Abstract] [Full Text] [PDF]

				W. Guo, S. Wong, W. Xie, T. Lei, and Z. Luo Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E576 - E586. [Abstract] [Full Text] [PDF]

				A. R. Subauste and C. F. Burant Role of FoxO1 in FFA-induced oxidative stress in adipocytes Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E159 - E164. [Abstract] [Full Text] [PDF]

				A. Herschkovitz, Y.-F. Liu, E. Ilan, D. Ronen, S. Boura-Halfon, and Y. Zick Common Inhibitory Serine Sites Phosphorylated by IRS-1 Kinases, Triggered by Insulin and Inducers of Insulin Resistance J. Biol. Chem., June 22, 2007; 282(25): 18018 - 18027. [Abstract] [Full Text] [PDF]

				M. Qatanani and M. A. Lazar Mechanisms of obesity-associated insulin resistance: many choices on the menu Genes & Dev., June 15, 2007; 21(12): 1443 - 1455. [Abstract] [Full Text] [PDF]

				J. A. A. Pires, A. H. Souza, and R. R. Grummer Induction of Hyperlipidemia by Intravenous Infusion of Tallow Emulsion Causes Insulin Resistance in Holstein Cows J Dairy Sci, June 1, 2007; 90(6): 2735 - 2744. [Abstract] [Full Text] [PDF]

				N. Bashan, K. Dorfman, T. Tarnovscki, I. Harman-Boehm, I. F. Liberty, M. Bluher, S. Ovadia, T. Maymon-Zilberstein, R. Potashnik, M. Stumvoll, et al. Mitogen-Activated Protein Kinases, Inhibitory-{kappa}B Kinase, and Insulin Signaling in Human Omental Versus Subcutaneous Adipose Tissue in Obesity Endocrinology, June 1, 2007; 148(6): 2955 - 2962. [Abstract] [Full Text] [PDF]

				H.-Y. Liu, Q. F. Collins, Y. Xiong, F. Moukdar, E. G. Lupo Jr., Z. Liu, and W. Cao Prolonged Treatment of Primary Hepatocytes with Oleate Induces Insulin Resistance through p38 Mitogen-activated Protein Kinase J. Biol. Chem., May 11, 2007; 282(19): 14205 - 14212. [Abstract] [Full Text] [PDF]

				M. P Corcoran, S. Lamon-Fava, and R. A Fielding Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise Am. J. Clinical Nutrition, March 1, 2007; 85(3): 662 - 677. [Abstract] [Full Text] [PDF]

				M. Bajaj, R. Medina-Navarro, S. Suraamornkul, C. Meyer, R. A. DeFronzo, and L. J. Mandarino Paradoxical Changes in Muscle Gene Expression in Insulin-Resistant Subjects After Sustained Reduction in Plasma Free Fatty Acid Concentration Diabetes, March 1, 2007; 56(3): 743 - 752. [Abstract] [Full Text] [PDF]

				Z. Gao, Z. Wang, X. Zhang, A. A. Butler, A. Zuberi, B. Gawronska-Kozak, M. Lefevre, D. York, E. Ravussin, H.-R. Berthoud, et al. Inactivation of PKC{theta} leads to increased susceptibility to obesity and dietary insulin resistance in mice Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E84 - E91. [Abstract] [Full Text] [PDF]

				M. A. Bogoyevitch and B. Kobe Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases Microbiol. Mol. Biol. Rev., December 1, 2006; 70(4): 1061 - 1095. [Abstract] [Full Text] [PDF]

				K. Morino, K. F. Petersen, and G. I. Shulman Molecular Mechanisms of Insulin Resistance in Humans and Their Potential Links With Mitochondrial Dysfunction Diabetes, December 1, 2006; 55(Supplement_2): S9 - S15. [Abstract] [Full Text] [PDF]

				G. Svegliati-Baroni, C. Candelaresi, S. Saccomanno, G. Ferretti, T. Bachetti, M. Marzioni, S. De Minicis, L. Nobili, R. Salzano, A. Omenetti, et al. A Model of Insulin Resistance and Nonalcoholic Steatohepatitis in Rats: Role of Peroxisome Proliferator-Activated Receptor-{alpha} and n-3 Polyunsaturated Fatty Acid Treatment on Liver Injury Am. J. Pathol., September 1, 2006; 169(3): 846 - 860. [Abstract] [Full Text] [PDF]

				Q. F. Collins, Y. Xiong, E. G. Lupo Jr., H.-Y. Liu, and W. Cao p38 Mitogen-activated Protein Kinase Mediates Free Fatty Acid-induced Gluconeogenesis in Hepatocytes J. Biol. Chem., August 25, 2006; 281(34): 24336 - 24344. [Abstract] [Full Text] [PDF]

				B. Draznin Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85{alpha}: The Two Sides of a Coin. Diabetes, August 1, 2006; 55(8): 2392 - 2397. [Abstract] [Full Text] [PDF]

				H. Malhi, S. F. Bronk, N. W. Werneburg, and G. J. Gores Free Fatty Acids Induce JNK-dependent Hepatocyte Lipoapoptosis J. Biol. Chem., April 28, 2006; 281(17): 12093 - 12101. [Abstract] [Full Text] [PDF]

				J.-a Kim, M. Montagnani, K. K. Koh, and M. J. Quon Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms Circulation, April 18, 2006; 113(15): 1888 - 1904. [Abstract] [Full Text] [PDF]

				N. Warwar, S. Efendic, C.-G. Ostenson, E. P. Haber, E. Cerasi, and R. Nesher Dynamics of Glucose-Induced Localization of PKC Isoenzymes in Pancreatic {beta}-Cells: Diabetes-Related Changes in the GK Rat Diabetes, March 1, 2006; 55(3): 590 - 599. [Abstract] [Full Text] [PDF]

				Z. Gao, Q. He, B. Peng, P. J. Chiao, and J. Ye Regulation of Nuclear Translocation of HDAC3 by I{kappa}B{alpha} Is Required for Tumor Necrosis Factor Inhibition of Peroxisome Proliferator-activated Receptor {gamma} Function J. Biol. Chem., February 17, 2006; 281(7): 4540 - 4547. [Abstract] [Full Text] [PDF]

				G. S. Hotamisligil Role of Endoplasmic Reticulum Stress and c-Jun NH2-Terminal Kinase Pathways in Inflammation and Origin of Obesity and Diabetes Diabetes, December 1, 2005; 54(suppl_2): S73 - S78. [Abstract] [Full Text] [PDF]

				M. T. A. Nguyen, H. Satoh, S. Favelyukis, J. L. Babendure, T. Imamura, J. I. Sbodio, J. Zalevsky, B. I. Dahiyat, N.-W. Chi, and J. M. Olefsky JNK and Tumor Necrosis Factor-{alpha} Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes J. Biol. Chem., October 21, 2005; 280(42): 35361 - 35371. [Abstract] [Full Text] [PDF]

				K. M. Ajuwon and M. E. Spurlock Palmitate Activates the NF-{kappa}B Transcription Factor and Induces IL-6 and TNF{alpha} Expression in 3T3-L1 Adipocytes J. Nutr., August 1, 2005; 135(8): 1841 - 1846. [Abstract] [Full Text] [PDF]

				J.-a Kim, K. K. Koh, and M. J. Quon The Union of Vascular and Metabolic Actions of Insulin in Sickness and in Health Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 889 - 891. [Full Text] [PDF]

				H. Sugita, M. Fujimoto, T. Yasukawa, N. Shimizu, M. Sugita, S. Yasuhara, J. A. J. Martyn, and M. Kaneki Inducible Nitric-oxide Synthase and NO Donor Induce Insulin Receptor Substrate-1 Degradation in Skeletal Muscle Cells J. Biol. Chem., April 8, 2005; 280(14): 14203 - 14211. [Abstract] [Full Text] [PDF]

				P. A. Tataranni and E. Ortega A Burning Question: Does an Adipokine-Induced Activation of the Immune System Mediate the Effect of Overnutrition on Type 2 Diabetes? Diabetes, April 1, 2005; 54(4): 917 - 927. [Abstract] [Full Text] [PDF]

				C. Rask-Madsen and G. L. King Proatherosclerotic Mechanisms Involving Protein Kinase C in Diabetes and Insulin Resistance Arterioscler. Thromb. Vasc. Biol., March 1, 2005; 25(3): 487 - 496. [Abstract] [Full Text] [PDF]

				N. Sato, K. Kobayashi, T. Inoguchi, N. Sonoda, M. Imamura, N. Sekiguchi, N. Nakashima, and H. Nawata Adenovirus-Mediated High Expression of Resistin Causes Dyslipidemia in Mice Endocrinology, January 1, 2005; 146(1): 273 - 279. [Abstract] [Full Text] [PDF]