Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes
Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes
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DOI：
10.1126/science.1103160
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发表时间：
2004-10-15
期刊：
影响因子：
56.9
通讯作者：
Hotamisligil, GS
中科院分区：
文献类型：
--
作者：
Özcan, U;Cao, Q;Hotamisligil, GS
肥胖有助于2型糖尿病的发展，但潜在的机制知之甚少。使用细胞培养和小鼠模型，我们表明肥胖会导致内质网（ER）应力。反过来，这种应力通过过度激活C-JUN N末端激酶（JNK）和随后的胰岛素受体底物-1（IRS-1）的丝氨酸磷酸化（IRS-1）抑制胰岛素受体信号传导。缺乏X-box结合蛋白-1（XBP-1）的小鼠是调节ER应力反应的转录因子，会产生胰岛素抵抗。这些发现表明，ER应激是分子，细胞和生物水平上周围胰岛素抵抗和2型糖尿病的核心特征。对该途径的药理学操纵可能为治疗这些常见疾病提供新的机会。
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.