Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes

Umut Özcan, Qiong Cao, Erkan Yilmaz, Ann Hwee Lee, Neal N. Iwakoshi, Esra Özdelen, Gürol Tuncman, Cem Görgün, Laurie H. Glimcher, Gökhan S. Hotamisligil

Research output: Contribution to journalArticlepeer-review

2966 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)457-461
Number of pages5
JournalScience
Volume306
Issue number5695
DOIs
StatePublished - Oct 15 2004
Externally publishedYes

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