Article

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

Department of Immunology and Infectious Diseases, Harvard University, Cambridge, Massachusetts, United States
Science (Impact Factor: 31.48). 11/2004; 306(5695):457-61. DOI: 10.1126/science.1103160
Source: PubMed

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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