Holness Mark J, Sugden Mary C
Centre for Diabetes and Metabolic Medicine, Institute of Cell and Molecular Science, Bart's and the London, Queen Mary's School of Medicine and Dentistry, London, UK.
Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):482-8. doi: 10.1097/01.mco.0000232912.69236.e0.
Epigenetic alterations are responsible for modulation of tissue-specific gene expression and genomic imprinting. Mechanisms include posttranslational modifications of core histones and DNA methylation. The review focuses on emerging data highlighting the potential for epigenetic modulation of gene expression in mediating early-life programming of increased risk of adult-onset disease. To illustrate these concepts, we focus on epigenetic programming of insulin resistance, obesity and type 2 diabetes, with emphasis on the potential role of the adipocyte and three of its products, fatty acids, leptin and tumour necrosis factor alpha.
Recent studies have highlighted potential mechanisms underlying epigenetic modification of tissue function that may predispose to later development of insulin resistance. These include altered regulation of adipocyte clonal expansion and terminal differentiation via epigenetic modification of peroxisome proliferator-activated receptor gamma, Foxo1 or cyclin D1 expression and signalling that, via altered adipocyte lipid sequestration, alters lipid delivery to nonadipose tissue and, therefore, insulin action or modification of adipokine or cytokine expression and signalling. Direct epigenetic modification of insulin action in muscle may be achieved through altered stearoyl-CoA desaturase 1 expression, which correlates with low fatty acid oxidation.
While poor early growth and an increased risk of type 2 diabetes in adulthood are undisputedly linked, the relative impact of environment or genotype remains unclear. Altered DNA methylation patterns could, potentially, serve as biomarkers for assessment of prognosis and could help in the development of prophylactic strategies.
表观遗传改变负责调节组织特异性基因表达和基因组印记。其机制包括核心组蛋白的翻译后修饰和DNA甲基化。本综述聚焦于新出现的数据，这些数据凸显了基因表达的表观遗传调节在介导成年发病疾病风险增加的早期生命编程中的潜力。为阐明这些概念，我们聚焦于胰岛素抵抗、肥胖和2型糖尿病的表观遗传编程，重点关注脂肪细胞及其三种产物脂肪酸、瘦素和肿瘤坏死因子α的潜在作用。
近期研究突出了组织功能表观遗传修饰的潜在机制，这些机制可能易导致后期胰岛素抵抗的发生。这些机制包括通过过氧化物酶体增殖物激活受体γ、Foxo1或细胞周期蛋白D1表达及信号传导的表观遗传修饰，改变脂肪细胞克隆扩增和终末分化的调节，这通过改变脂肪细胞脂质隔离，改变脂质向非脂肪组织的输送，进而改变胰岛素作用，或改变脂肪因子或细胞因子的表达及信号传导。肌肉中胰岛素作用的直接表观遗传修饰可通过改变硬脂酰辅酶A去饱和酶1的表达来实现，该表达与低脂肪酸氧化相关。
虽然早期生长不良与成年期2型糖尿病风险增加之间的关联无可争议，但环境或基因型的相对影响仍不清楚。DNA甲基化模式的改变可能作为评估预后的生物标志物，并有助于制定预防策略。
