Kang Sona, Tsai Linus T, Zhou Yiming, Evertts Adam, Xu Su, Griffin Michael J, Issner Robbyn, Whitton Holly J, Garcia Benjamin A, Epstein Charles B, Mikkelsen Tarjei S, Rosen Evan D
Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
Nat Cell Biol. 2015 Jan;17(1):44-56. doi: 10.1038/ncb3080. Epub 2014 Dec 15.
Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-α or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.
胰岛素抵抗是2型糖尿病（T2D）的主要特征，也是多种临床病症的常见并发症，包括肥胖、衰老和使用类固醇等。目前尚不完全清楚如此众多的损伤如何导致共同的表型。此外，尽管有证据表明这些途径可能起重要作用，但对于这种疾病的转录和表观遗传基础知之甚少。在这里，我们比较了由细胞因子肿瘤坏死因子-α或类固醇地塞米松诱导的胰岛素抵抗的细胞自主模型，以构建与细胞胰岛素抵抗相关的详细转录和表观基因组图谱。这些数据预测糖皮质激素受体和维生素D受体是胰岛素抵抗的共同介质，我们通过功能获得和功能丧失研究对其进行了验证。这些研究定义了细胞胰岛素抵抗中常见的转录和表观基因组特征，从而能够识别致病机制。
