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Science 306 (5695): 457-461

Copyright © 2004 by the American Association for the Advancement of Science

Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

Umut Özcan,1* Qiong Cao,1* Erkan Yilmaz,1 Ann-Hwee Lee,2 Neal N. Iwakoshi,2 Esra Özdelen,1 Gürol Tuncman,1 Cem Görgün,1 Laurie H. Glimcher,2,3 Gökhan S. Hotamisligil1{dagger}

Abstract: Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate–1 (IRS-1). Mice deficient in X-box–binding protein–1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases.

1 Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
2 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard Medical School, Boston, MA 02115, USA.
3 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

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* These authors contributed equally to this work.

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

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T. Kondo, K. Sasaki, R. Matsuyama, S. Morino-Koga, H. Adachi, M. A. Suico, J. Kawashima, H. Motoshima, N. Furukawa, H. Kai, et al. (2012)
Diabetes 61, 838-847
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Bariatric surgery to unload the stressed heart: a metabolic hypothesis.
M. F. Algahim, S. Sen, and H. Taegtmeyer (2012)
Am J Physiol Heart Circ Physiol 302, H1539-H1545
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Lipid Peroxidation Product 4-Hydroxy-trans-2-nonenal Causes Endothelial Activation by Inducing Endoplasmic Reticulum Stress.
E. Vladykovskaya, S. D. Sithu, P. Haberzettl, N. S. Wickramasinghe, M. L. Merchant, B. G. Hill, J. McCracken, A. Agarwal, S. Dougherty, S. A. Gordon, et al. (2012)
J. Biol. Chem. 287, 11398-11409
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Chronic Activation of mTOR Complex 1 Is Sufficient to Cause Hepatocellular Carcinoma in Mice.
S. Menon, J. L. Yecies, H. H. Zhang, J. J. Howell, J. Nicholatos, E. Harputlugil, R. T. Bronson, D. J. Kwiatkowski, and B. D. Manning (2012)
Science Signaling 5, ra24
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12/15-Lipoxygenase signaling in the endoplasmic reticulum stress response.
B. K. Cole, N. S. Kuhn, S. M. Green-Mitchell, K. A. Leone, R. M. Raab, J. L. Nadler, and S. K. Chakrabarti (2012)
Am J Physiol Endocrinol Metab 302, E654-E665
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Hepatic TRAF2 Regulates Glucose Metabolism Through Enhancing Glucagon Responses.
Z. Chen, L. Sheng, H. Shen, Y. Zhao, S. Wang, R. Brink, and L. Rui (2012)
Diabetes 61, 566-573
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Lipolysis Response to Endoplasmic Reticulum Stress in Adipose Cells.
J. Deng, S. Liu, L. Zou, C. Xu, B. Geng, and G. Xu (2012)
J. Biol. Chem. 287, 6240-6249
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Functional RNA Interference (RNAi) Screen Identifies System A Neutral Amino Acid Transporter 2 (SNAT2) as a Mediator of Arsenic-induced Endoplasmic Reticulum Stress.
R. S. Oh, W.-C. Pan, A. Yalcin, H. Zhang, T. R. Guilarte, G. S. Hotamisligil, D. C. Christiani, and Q. Lu (2012)
J. Biol. Chem. 287, 6025-6034
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Role of TRIB3 in Diabetic and Overnutrition-Induced Atherosclerosis.
J. R. Sowers (2012)
Diabetes 61, 265-266
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Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding.
A. Purushotham, Q. Xu, and X. Li (2012)
FASEB J 26, 656-667
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Dissociation of Inositol-requiring Enzyme (IRE1{alpha})-mediated c-Jun N-terminal Kinase Activation from Hepatic Insulin Resistance in Conditional X-box-binding Protein-1 (XBP1) Knock-out Mice.
M. J. Jurczak, A.-H. Lee, F. R. Jornayvaz, H.-Y. Lee, A. L. Birkenfeld, B. A. Guigni, M. Kahn, V. T. Samuel, L. H. Glimcher, and G. I. Shulman (2012)
J. Biol. Chem. 287, 2558-2567
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O2 Regulates Skeletal Muscle Progenitor Differentiation through Phosphatidylinositol 3-Kinase/AKT Signaling.
A. J. Majmundar, N. Skuli, R. C. Mesquita, M. N. Kim, A. G. Yodh, M. Nguyen-McCarty, and M. C. Simon (2012)
Mol. Cell. Biol. 32, 36-49
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Drivers of Oxidative Stress in Acute Pancreatitis: The Role of Nutrition Therapy.
S. A. McClave (2012)
JPEN J Parenter Enteral Nutr 36, 24-35
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Confronting The Urgent Challenge Of Diabetes: An Overview.
J. E. Fradkin (2012)
Health Aff. 31, 12-19
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Endoplasmic Reticulum Stress and Glycogen Synthase Kinase-3{beta} Activation in Apolipoprotein E-Deficient Mouse Models of Accelerated Atherosclerosis.
C. S. McAlpine, A. J. Bowes, M. I. Khan, Y. Shi, and G. H. Werstuck (2012)
Arterioscler Thromb Vasc Biol 32, 82-91
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Endoplasmic Reticulum Stress Inhibits STAT3-Dependent Suppression of Hepatic Gluconeogenesis via Dephosphorylation and Deacetylation.
K. Kimura, T. Yamada, M. Matsumoto, Y. Kido, T. Hosooka, S.-i. Asahara, T. Matsuda, T. Ota, H. Watanabe, Y. Sai, et al. (2012)
Diabetes 61, 61-73
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New IBD genetics: common pathways with other diseases.
C. W. Lees, J. C. Barrett, M. Parkes, and J. Satsangi (2011)
Gut 60, 1739-1753
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