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J Biol Chem, Vol. 274, Issue 34, 24202-24210, August 20, 1999
From The Garvan Institute of Medical Research, 384 Victoria Street,
Darlinghurst, New South Wales, Australia 2010
We have employed C2C12 myotubes to investigate
lipid inhibition of insulin-stimulated signal transduction and glucose
metabolism. Cells were preincubated for 18 h in the absence or
presence of free fatty acids (FFAs) and stimulated with insulin, and
the effects on glycogen synthesis and signaling intermediates were
determined. While the unsaturated FFAs oleate and linoleate inhibited
both basal and insulin-stimulated glycogen synthesis, the saturated FFA
palmitate reduced only insulin-stimulated glycogen synthesis, and was
found to inhibit insulin-stimulated phosphorylation of glycogen
synthase kinase-3 and protein kinase B (PKB). However, no effect of
palmitate was observed on tyrosine phosphorylation, p85 association, or
phosphatidylinositol 3-kinase activity in IRS-1 immunoprecipitates. In
contrast, palmitate promoted phosphorylation of mitogen-activated
protein MAP) kinases. Ceramide, a derivative of palmitate, has recently
been associated with similar inhibition of PKB, and here, ceramide
levels were found to be elevated 2-fold in palmitate-treated C2C12
cells. Incubation of C2C12 cells with ceramide closely reproduced the
effects of palmitate, leading to inhibition of glycogen synthesis and
PKB and to stimulation of MAP kinase. We conclude that
palmitate-induced insulin resistance occurs by a mechanism distinct
from that of unsaturated FFAs, and involves elevation of ceramide by
de novo synthesis, leading to PKB inhibition without
affecting IRS-1 function.
Ceramide Generation Is Sufficient to Account for the Inhibition
of the Insulin-stimulated PKB Pathway in C2C12 Skeletal Muscle Cells
Pretreated with Palmitate
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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S. Stratford, K. L. Hoehn, F. Liu, and S. A. Summers Regulation of Insulin Action by Ceramide: DUAL MECHANISMS LINKING CERAMIDE ACCUMULATION TO THE INHIBITION OF Akt/PROTEIN KINASE B J. Biol. Chem., August 27, 2004; 279(35): 36608 - 36615. [Abstract] [Full Text] [PDF]
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J. N. Clore, J. S. Stillman, J. Li, S. J. D. O'Keefe, and J. R. Levy Differential effect of saturated and polyunsaturated fatty acids on hepatic glucose metabolism in humans Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E358 - E365. [Abstract] [Full Text] [PDF]
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T. L. Wadsworth, J. M. Carroll, R. A. Mallinson, C. T. Roberts Jr., and C. E. Roselli Saw Palmetto Extract Suppresses Insulin-Like Growth Factor-I Signaling and Induces Stress-Activated Protein Kinase/c-Jun N-Terminal Kinase Phosphorylation in Human Prostate Epithelial Cells Endocrinology, July 1, 2004; 145(7): 3205 - 3214. [Abstract] [Full Text] [PDF]
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B. D. Hegarty, S. M. Furler, N. D. Oakes, E. W. Kraegen, and G. J. Cooney Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo--A Study Using the Novel PPAR{alpha}/{gamma} Agonist Tesaglitazar Endocrinology, July 1, 2004; 145(7): 3158 - 3164. [Abstract] [Full Text] [PDF]
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G. Perdomo, S. R. Commerford, A.-M. T. Richard, S. H. Adams, B. E. Corkey, R. M. O'Doherty, and N. F. Brown Increased {beta}-Oxidation in Muscle Cells Enhances Insulin-stimulated Glucose Metabolism and Protects against Fatty Acid-induced Insulin Resistance Despite Intramyocellular Lipid Accumulation J. Biol. Chem., June 25, 2004; 279(26): 27177 - 27186. [Abstract] [Full Text] [PDF]
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H. Nishizawa, M. Matsuda, Y. Yamada, K. Kawai, E. Suzuki, M. Makishima, T. Kitamura, and I. Shimomura Musclin, a Novel Skeletal Muscle-derived Secretory Factor J. Biol. Chem., May 7, 2004; 279(19): 19391 - 19395. [Abstract] [Full Text] [PDF]
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P. Weyrich, K. Kapp, G. Niederfellner, M. Melzer, R. Lehmann, H.-U. Haring, and R. Lammers Partitioning-Defective Protein 6 Regulates Insulin-Dependent Glycogen Synthesis via Atypical Protein Kinase C Mol. Endocrinol., May 1, 2004; 18(5): 1287 - 1300. [Abstract] [Full Text] [PDF]
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M. Straczkowski, I. Kowalska, A. Nikolajuk, S. Dzienis-Straczkowska, I. Kinalska, M. Baranowski, M. Zendzian-Piotrowska, Z. Brzezinska, and J. Gorski Relationship Between Insulin Sensitivity and Sphingomyelin Signaling Pathway in Human Skeletal Muscle Diabetes, May 1, 2004; 53(5): 1215 - 1221. [Abstract] [Full Text] [PDF]
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J. G. Burchfield, A. J. Lennard, S. Narasimhan, W. E. Hughes, V. C. Wasinger, G. L. Corthals, T. Okuda, H. Kondoh, T. J. Biden, and C. Schmitz-Peiffer Akt Mediates Insulin-stimulated Phosphorylation of Ndrg2: EVIDENCE FOR CROSS-TALK WITH PROTEIN KINASE C {theta} J. Biol. Chem., April 30, 2004; 279(18): 18623 - 18632. [Abstract] [Full Text] [PDF]
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C. de Alvaro, T. Teruel, R. Hernandez, and M. Lorenzo Tumor Necrosis Factor {alpha} Produces Insulin Resistance in Skeletal Muscle by Activation of Inhibitor {kappa}B Kinase in a p38 MAPK-dependent Manner J. Biol. Chem., April 23, 2004; 279(17): 17070 - 17078. [Abstract] [Full Text] [PDF]
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 Y. Li, J. Webster-Cyriaque, C. C. Tomlinson, M. Yohe, and S. Kenney Fatty Acid Synthase Expression Is Induced by the Epstein-Barr Virus Immediate-Early Protein BRLF1 and Is Required for Lytic Viral Gene Expression J. Virol., April 15, 2004; 78(8): 4197 - 4206. [Abstract] [Full Text] [PDF]
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H. Bays, L. Mandarino, and R. A. DeFronzo Role of the Adipocyte, Free Fatty Acids, and Ectopic Fat in Pathogenesis of Type 2 Diabetes Mellitus: Peroxisomal Proliferator-Activated Receptor Agonists Provide a Rational Therapeutic Approach J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 463 - 478. [Full Text] [PDF]
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 S. R. Stannard and N. A. Johnson Insulin resistance and elevated triglyceride in muscle: more important for survival than 'thrifty' genes? J. Physiol., February 1, 2004; 554(3): 595 - 607. [Abstract] [Full Text] [PDF]
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J. M. Adams II, T. Pratipanawatr, R. Berria, E. Wang, R. A. DeFronzo, M. C. Sullards, and L. J. Mandarino Ceramide Content Is Increased in Skeletal Muscle From Obese Insulin-Resistant Humans Diabetes, January 1, 2004; 53(1): 25 - 31. [Abstract] [Full Text] [PDF]
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J. W. Helge, A. Dobrzyn, B. Saltin, and J. Gorski Exercise and training effects on ceramide metabolism in human skeletal muscle Exp Physiol, January 1, 2004; 89(1): 119 - 127. [Abstract] [Full Text] [PDF]
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 D. J. Powell, E. Hajduch, G. Kular, and H. S. Hundal Ceramide Disables 3-Phosphoinositide Binding to the Pleckstrin Homology Domain of Protein Kinase B (PKB)/Akt by a PKC{zeta}-Dependent Mechanism Mol. Cell. Biol., November 1, 2003; 23(21): 7794 - 7808. [Abstract] [Full Text] [PDF]
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C. R. Bruce, M. J. Anderson, A. L. Carey, D. G. Newman, A. Bonen, A. D. Kriketos, G. J. Cooney, and J. A. Hawley Muscle Oxidative Capacity Is a Better Predictor of Insulin Sensitivity than Lipid Status J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5444 - 5451. [Abstract] [Full Text] [PDF]
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C. L. Kelpe, P. C. Moore, S. D. Parazzoli, B. Wicksteed, C. J. Rhodes, and V. Poitout Palmitate Inhibition of Insulin Gene Expression Is Mediated at the Transcriptional Level via Ceramide Synthesis J. Biol. Chem., August 8, 2003; 278(32): 30015 - 30021. [Abstract] [Full Text] [PDF]
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Y. Miyazaki, H. He, L. J. Mandarino, and R. A. DeFronzo Rosiglitazone Improves Downstream Insulin Receptor Signaling in Type 2 Diabetic Patients Diabetes, August 1, 2003; 52(8): 1943 - 1950. [Abstract] [Full Text] [PDF]
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T. K. T. Lam, A. Carpentier, G. F. Lewis, G. van de Werve, I. G. Fantus, and A. Giacca Mechanisms of the free fatty acid-induced increase in hepatic glucose production Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E863 - E873. [Abstract] [Full Text] [PDF]
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J. A. Chavez, T. A. Knotts, L.-P. Wang, G. Li, R. T. Dobrowsky, G. L. Florant, and S. A. Summers A Role for Ceramide, but Not Diacylglycerol, in the Antagonism of Insulin Signal Transduction by Saturated Fatty Acids J. Biol. Chem., March 14, 2003; 278(12): 10297 - 10303. [Abstract] [Full Text] [PDF]
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 R. A Defronzo Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance? The British Journal of Diabetes & Vascular Disease, January 1, 2003; 3(1_suppl): S24 - S40. [Abstract] [PDF]
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C. E. Wrede, L. M. Dickson, M. K. Lingohr, I. Briaud, and C. J. Rhodes Protein Kinase B/Akt Prevents Fatty Acid-induced Apoptosis in Pancreatic beta -Cells (INS-1) J. Biol. Chem., December 13, 2002; 277(51): 49676 - 49684. [Abstract] [Full Text] [PDF]
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D. E. Kelley, J. He, E. V. Menshikova, and V. B. Ritov Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes Diabetes, October 1, 2002; 51(10): 2944 - 2950. [Abstract] [Full Text] [PDF]
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 C.-L. M. Soltys, L. Buchholz, M. Gandhi, A. S. Clanachan, K. Walsh, and J. R. B. Dyck Phosphorylation of cardiac protein kinase B is regulated by palmitate Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1056 - H1064. [Abstract] [Full Text] [PDF]
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S. I. Itani, N. B. Ruderman, F. Schmieder, and G. Boden Lipid-Induced Insulin Resistance in Human Muscle Is Associated With Changes in Diacylglycerol, Protein Kinase C, and I{kappa}B-{alpha} Diabetes, July 1, 2002; 51(7): 2005 - 2011. [Abstract] [Full Text] [PDF]
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R. Cazzolli, D. L. Craig, T. J. Biden, and C. Schmitz-Peiffer Inhibition of glycogen synthesis by fatty acid in C2C12 muscle cells is independent of PKC-alpha , -epsilon , and -theta Am J Physiol Endocrinol Metab, June 1, 2002; 282(6): E1204 - E1213. [Abstract] [Full Text] [PDF]
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 H. Taegtmeyer, P. McNulty, and M. E. Young Adaptation and Maladaptation of the Heart in Diabetes: Part I: General Concepts Circulation, April 9, 2002; 105(14): 1727 - 1733. [Full Text] [PDF]
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G. F. Lewis, A. Carpentier, K. Adeli, and A. Giacca Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes Endocr. Rev., April 1, 2002; 23(2): 201 - 229. [Abstract] [Full Text] [PDF]
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L. H. Clerk, S. Rattigan, and M. G. Clark Lipid Infusion Impairs Physiologic Insulin-Mediated Capillary Recruitment and Muscle Glucose Uptake In Vivo Diabetes, April 1, 2002; 51(4): 1138 - 1145. [Abstract] [Full Text] [PDF]
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A. Cabrero, M. Alegret, R. M. Sanchez, T. Adzet, J. C. Laguna, and M. V. Carrera Increased Reactive Oxygen Species Production Down-regulates Peroxisome Proliferator-activated alpha Pathway in C2C12 Skeletal Muscle Cells J. Biol. Chem., March 15, 2002; 277(12): 10100 - 10107. [Abstract] [Full Text] [PDF]
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J. Mei, L. S. Holst, T. R. Landstrom, C. Holm, D. Brindley, V. Manganiello, and E. Degerman C2-Ceramide Influences the Expression and Insulin-Mediated Regulation of Cyclic Nucleotide Phosphodiesterase 3B and Lipolysis in 3T3-L1 Adipocytes Diabetes, March 1, 2002; 51(3): 631 - 637. [Abstract] [Full Text] [PDF]
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A. Dobrzyn and J. Gorski Ceramides and sphingomyelins in skeletal muscles of the rat: content and composition. Effect of prolonged exercise Am J Physiol Endocrinol Metab, February 1, 2002; 282(2): E277 - E285. [Abstract] [Full Text] [PDF]
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Y. T. Kruszynska, D. S. Worrall, J. Ofrecio, J. P. Frias, G. Macaraeg, and J. M. Olefsky Fatty Acid-Induced Insulin Resistance: Decreased Muscle PI3K Activation But Unchanged Akt Phosphorylation J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 226 - 234. [Abstract] [Full Text] [PDF]
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