Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
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.
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References and Notes
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We thank the Hotamisligil laboratory for their contributions and J. Gound and L. Beppu for technical assistance. Supported in part by NIH grants AI32412 (L.H.G.), DK52539 (G.S.H.), American Diabetes Association (G.S.H.), PO5-CA100707 (L.H.G., A.H.L.), an Irvington Institute Postdoctoral Fellowship Award (N.I.), an NIH training grant T32-DK07703 (Q.C.), and a postdoctoral fellowship from the Iaccoca Foundation (G.T.). L.H.G. holds equity in MannKind Corporation, which has licensed the XBP-1 technology.
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Published In
Science
Volume 306 | Issue 5695
15 October 2004
15 October 2004
Copyright
American Association for the Advancement of Science.
Submission history
Received: 23 July 2004
Accepted: 9 September 2004
Published in print: 15 October 2004
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www.sciencemag.org/cgi/content/full/306/5695/457/DC1
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