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Science 293 (5535): 1673-1677

Copyright © 2001 by the American Association for the Advancement of Science

Reversal of Obesity- and Diet-Induced Insulin Resistance with Salicylates or Targeted Disruption of Ikkbeta

Minsheng Yuan,1* Nicky Konstantopoulos,1* Jongsoon Lee,1* Lone Hansen,1 Zhi-Wei Li,2 Michael Karin,2 Steven E. Shoelson1dagger

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the Ikappa B kinase beta  (IKKbeta ) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta , rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta +/-) protected against the development of insulin resistance during high-fat feeding and in obese Lepob/ob mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.

1 Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
2 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: Steven.Shoelson{at}

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K. L. Mullen, J. M. Tishinsky, L. E. Robinson, and D. J. Dyck (2010)
Am J Physiol Regulatory Integrative Comp Physiol 299, R500-R508
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Vitamin C inhibits leptin secretion and some glucose/lipid metabolic pathways in primary rat adipocytes.
D. F. Garcia-Diaz, J. Campion, F. I. Milagro, N. Boque, M. J. Moreno-Aliaga, and J. A. Martinez (2010)
J. Mol. Endocrinol. 45, 33-43
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2009 World Congress on the Insulin Resistance Syndrome: Cardiovascular Disease Concepts.
Z. T. Bloomgarden (2010)
Diabetes Care 33, e85-e89
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Potential Role of Salicylates in Type 2 Diabetes.
M. M. Rumore and K. S. Kim (2010)
Annals of Pharmacotherapy 44, 1207-1221
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Dietary fatty acids modulate antigen presentation to hepatic NKT cells in nonalcoholic fatty liver disease.
J. Hua, X. Ma, T. Webb, J. J. Potter, M. Oelke, and Z. Li (2010)
J. Lipid Res. 51, 1696-1703
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Macrophage {alpha}1 AMP-activated Protein Kinase ({alpha}1AMPK) Antagonizes Fatty Acid-induced Inflammation through SIRT1.
Z. Yang, B. B. Kahn, H. Shi, and B.-z. Xue (2010)
J. Biol. Chem. 285, 19051-19059
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Fat Cell-Specific Ablation of Rictor in Mice Impairs Insulin-Regulated Fat Cell and Whole-Body Glucose and Lipid Metabolism.
A. Kumar, J. C. Lawrence Jr., D. Y. Jung, H. J. Ko, S. R. Keller, J. K. Kim, M. A. Magnuson, and T. E. Harris (2010)
Diabetes 59, 1397-1406
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Lipid-induced insulin resistance is prevented in lean and obese myotubes by AICAR treatment.
B. T. Bikman, D. Zheng, M. A. Reed, R. C. Hickner, J. A. Houmard, and G. L. Dohm (2010)
Am J Physiol Regulatory Integrative Comp Physiol 298, R1692-R1699
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Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice.
Y. Ilan, R. Maron, A.-M. Tukpah, T. U. Maioli, G. Murugaiyan, K. Yang, H. Y. Wu, and H. L. Weiner (2010)
PNAS 107, 9765-9770
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"Control" laboratory rodents are metabolically morbid: Why it matters.
B. Martin, S. Ji, S. Maudsley, and M. P. Mattson (2010)
PNAS 107, 6127-6133
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Amelioration of Glucose Intolerance by the Synthetic Androstene HE3286: Link to Inflammatory Pathways.
T. Wang, S. Villegas, Y. Huang, S. K. White, C. Ahlem, M. Lu, J. M. Olefsky, C. Reading, J. M. Frincke, D. Alleva, et al. (2010)
J. Pharmacol. Exp. Ther. 333, 70-80
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Exercise maintains euglycemia in association with decreased activation of c-Jun NH2-terminal kinase and serine phosphorylation of IRS-1 in the liver of ZDF rats.
M. A. Kiraly, J. Campbell, E. Park, H. E. Bates, J. T. Y. Yue, V. Rao, S. G. Matthews, G. Bikopoulos, M. Rozakis-Adcock, A. Giacca, et al. (2010)
Am J Physiol Endocrinol Metab 298, E671-E682
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SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity.
T. Yoshizaki, S. Schenk, T. Imamura, J. L. Babendure, N. Sonoda, E. J. Bae, D. Y. Oh, M. Lu, J. C. Milne, C. Westphal, et al. (2010)
Am J Physiol Endocrinol Metab 298, E419-E428
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Uncoupling of Inflammation and Insulin Resistance by NF-{kappa}B in Transgenic Mice through Elevated Energy Expenditure.
T. Tang, J. Zhang, J. Yin, J. Staszkiewicz, B. Gawronska-Kozak, D. Y. Jung, H. J. Ko, H. Ong, J. K. Kim, R. Mynatt, et al. (2010)
J. Biol. Chem. 285, 4637-4644
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Pathogenesis of non-alcoholic fatty liver disease.
J. K. Dowman, J.W. Tomlinson, and P.N. Newsome (2010)
QJM 103, 71-83
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Impaired oxidative metabolism and inflammation are associated with insulin resistance in ER{alpha}-deficient mice.
V. Ribas, M. T. A. Nguyen, D. C. Henstridge, A.-K. Nguyen, S. W. Beaven, M. J. Watt, and A. L. Hevener (2010)
Am J Physiol Endocrinol Metab 298, E304-E319
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