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Science 2 February 1996:
Vol. 271. no. 5249, pp. 665 - 670
DOI: 10.1126/science.271.5249.665
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Reports

IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-- and Obesity-Induced Insulin Resistance

Gökhan S. Hotamisligil (1),  Pascal Peraldi,  Adriane Budavari,  Ramsey Ellis,  Morris F. White,  Bruce M. Spiegelman (2)

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-alpha was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.


G. S. Hotamisligil, P. Peraldi, A. Budavari, R. Ellis, B. M. Spiegelman, Department of Cellular and Molecular Biology, Dana-Farber Cancer Institute, and Department of Cell Biology, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
M. F. White, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
(1) Present address: Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA.
(2) To whom correspondence should be addressed. E-mail: bruce_spiegelman{at}dfci.harvard.edu


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J. Clin. Endocrinol. Metab. 91, 3553-3558
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Insulin Resistance Accelerates Muscle Protein Degradation: Activation of the Ubiquitin-Proteasome Pathway by Defects in Muscle Cell Signaling.
X. Wang, Z. Hu, J. Hu, J. Du, and W. E. Mitch (2006)
Endocrinology 147, 4160-4168
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Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85{alpha}: The Two Sides of a Coin..
B. Draznin (2006)
Diabetes 55, 2392-2397
   Abstract »    Full Text »    PDF »
Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance.
G. Tuncman, J. Hirosumi, G. Solinas, L. Chang, M. Karin, and G. S. Hotamisligil (2006)
PNAS 103, 10741-10746
   Abstract »    Full Text »    PDF »
TNF{alpha} up-regulates apelin expression in human and mouse adipose tissue.
D. Daviaud, J. Boucher, S. Gesta, C. Dray, C. Guigne, D. Quilliot, A. Ayav, O. Ziegler, C. Carpene, J.-S. Saulnier-Blache, et al. (2006)
FASEB J 20, 1528-1530
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The Reduced Energy Intake of Rats Fed a High-Protein Low-Carbohydrate Diet Explains the Lower Fat Deposition, but Macronutrient Substitution Accounts for the Improved Glycemic Control.
C. Blouet, F. Mariotti, D. Azzout-Marniche, C. Bos, V. Mathe, D. Tome, and J.-F. Huneau (2006)
J. Nutr. 136, 1849-1854
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Protein Degradation by the Ubiquitin-Proteasome Pathway in Normal and Disease States.
S. H. Lecker, A. L. Goldberg, and W. E. Mitch (2006)
J. Am. Soc. Nephrol. 17, 1807-1819
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n-3 Fatty acids and the metabolic syndrome.
Y. A Carpentier, L. Portois, and W. J Malaisse (2006)
Am. J. Clinical Nutrition 83, S1499-1504S
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Mitochondrial Thioredoxin-2 Has a Key Role in Determining Tumor Necrosis Factor-{alpha}-Induced Reactive Oxygen Species Generation, NF-{kappa}B Activation, and Apoptosis.
J. M. Hansen, H. Zhang, and D. P. Jones (2006)
Toxicol. Sci. 91, 643-650
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TNF and TNF receptor expression and insulin sensitivity in human omental and subcutaneous adipose tissue -- influence of BMI and adipose distribution.
M. Good, F. M Newell, L. M Haupt, J. P Whitehead, L. J Hutley, and J. B Prins (2006)
Diabetes and Vascular Disease Research 3, 26-33
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An alternative spliced variant of circulating soluble tumor necrosis factor-{alpha} receptor-2 is paradoxically associated with insulin action..
J. M. Fernandez-Real, M. Straczkowski, B. Lainez, M. R Chacon, I. Kowalska, A. Lopez-Bermejo, A. Garcia-Espana, A. Nikolajuk, I. Kinalska, and W. Ricart (2006)
Eur. J. Endocrinol. 154, 723-730
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Glucose Abnormalities in Patients with Hepatitis C Virus Infection: Epidemiology and pathogenesis.
A. Lecube, C. Hernandez, J. Genesca, and R. Simo (2006)
Diabetes Care 29, 1140-1149
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Intronic Polymorphisms within TFAP2B Regulate Transcriptional Activity and Affect Adipocytokine Gene Expression in Differentiated Adipocytes.
S. Tsukada, Y. Tanaka, H. Maegawa, A. Kashiwagi, R. Kawamori, and S. Maeda (2006)
Mol. Endocrinol. 20, 1104-1111
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Exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat.
V. B. O'Leary, C. M. Marchetti, R. K. Krishnan, B. P. Stetzer, F. Gonzalez, and J. P. Kirwan (2006)
J Appl Physiol 100, 1584-1589
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Impact of mitochondrial reactive oxygen species and apoptosis signal-regulating kinase 1 on insulin signaling..
K. Imoto, D. Kukidome, T. Nishikawa, T. Matsuhisa, K. Sonoda, K. Fujisawa, M. Yano, H. Motoshima, T. Taguchi, K. Tsuruzoe, et al. (2006)
Diabetes 55, 1197-1204
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