Epigenomic and transcriptional control of insulin resistance.
Epigenomic and transcriptional control of insulin resistance.
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DOI：
10.1111/joim.12547
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发表时间：
2016-11
影响因子：
11.1
通讯作者：
Rosen ED
中科院分区：
文献类型：
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作者：
Rosen ED
胰岛素抵抗是2型糖尿病和代谢综合征的定义特征之一，并且伴随许多其他临床病症，从肥胖到脂肪代谢障碍到糖皮质激素过量。在确定胰岛素抵抗的机制方面，已经做出了非凡的努力，大多数注意力集中在改变的信号以及线粒体和内质网应激上。在这里，将讨论胰岛素抵抗的核机制，包括转录和表观基因组效应。涉及转录因子、转录辅因子和染色质修饰酶的三个水平的控制将被考虑。第一个例子包括脂肪组织中的PPARγ和各种胰岛素敏感组织中的糖皮质激素受体和FoxO 1。这些蛋白质与辅因子如PGC-1α和CRTC 2以及染色质修饰酶（包括DNA甲基转移酶和组蛋白乙酰转移酶）协同作用，调节促进胰岛素刺激的葡萄糖摄取、胰岛素生成或影响全身胰岛素作用的其他途径的关键基因。此外，与2型糖尿病风险增加相关的遗传变异通常与改变的转录因子结合有关，或者通过影响转录因子本身，或者更常见地通过改变非编码调节区的结合亲和力。最后，将讨论在对抗代谢性疾病的斗争中用于治疗开发的几种途径，包括这些因子及其相关途径的小分子抑制剂和激活剂。
Insulin resistance is one of the defining features of Type 2 diabetes and the metabolic syndrome, and accompanies many other clinical conditions, ranging from obesity to lipodystrophy to glucocorticoid excess. Extraordinary efforts have gone into defining the mechanisms that underlie insulin resistance, with most attention focused on altered signaling as well as mitochondrial and endoplasmic reticulum stress. Here, nuclear mechanisms of insulin resistance, including transcriptional and epigenomic effects, will be discussed. Three levels of control involving transcription factors, transcriptional co-factors, and chromatin-modifying enzymes will be considered. Well-studied examples of the first include PPARγ in adipose tissue and the glucocorticoid receptor and FoxO1 in a variety of insulin-sensitive tissues. These proteins work in concert with co-factors such as PGC-1α and CRTC2, and chromatin-modifying enzymes including DNA methyltransferases and histone acetyltransferases, to regulate key genes that promote insulin-stimulated glucose uptake, gluconeogenesis, or other pathways that affect systemic insulin action. Furthermore, genetic variation associated with increased risk of Type 2 diabetes is often related to altered transcription factor binding, either by affecting the transcription factor itself, or more commonly by changing the binding affinity of a non-coding regulatory region. Finally, several avenues for therapeutic exploitation in the battle against metabolic disease will be discussed, including small-molecule inhibitors and activators of these factors and their related pathways.
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DOI：
10.1073/pnas.0808207105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Coste, Agnes;Louet, Jean-Francois;Auwerx, Johan
通讯作者：
Auwerx, Johan
影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
Banks, Alexander S.;McAllister, Fiona E.;Camporez, Joao Paulo G.;Zushin, Peter-James H.;Jurczak, Michael J.;Laznik-Bogoslavski, Dina;Shulman, Gerald I.;Gygi, Steven P.;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
29
作者：
Farese RV Jr;Zechner R;Newgard CB;Walther TC
通讯作者：
Walther TC
影响因子：
82.9
作者：
通讯作者：
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