Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Obesity (Silver Spring). 2010 Feb;18(2):314-21. doi: 10.1038/oby.2009.246. Epub 2009 Aug 13.
Epigenetic mechanisms are likely to be involved in the development of obesity. This study was designed to examine the role of a DNA methyltransferase (Dnmt3a), in obese adipose tissue. The gene expression of Dnmts was examined by quantitative real-time PCR analysis. Transgenic mice overexpressing Dnmt3a in the adipose tissue driven by the aP2 promoter were created (Dnmt3a mice). DNA methylation of downregulated genes was examined using bisulfite DNA methylation analysis. Dnmt3a mice were fed a methyl-supplemented or high-fat diet, and subjected to body weight measurement and gene expression analysis of the adipose tissue. Expression of Dnmt3a was markedly upregulated in the adipose tissue of obese mice. The complementary DNA (cDNA) microarray analysis of Dnmt3a mice revealed a slight decrease in the gene expression of secreted frizzled-related protein 1 (SFRP1) and marked increase in that of interferon responsive factor 9 (IRF9). In the SFRP1 promoter, DNA methylation was not markedly increased in Dnmt3a mice relative to wild-type mice. In experiments with a high-fat diet or methyl-supplemented diet, body weight did not differ significantly with the genotypes. Gene expression levels of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) were higher in Dnmt3a mice than in wild-type mice on a high-fat diet. This study suggests that increased expression of Dnmt3a in the adipose tissue may contribute to obesity-related inflammation. The data highlight the potential role of Dnmt3a in the adult tissue as well as in the developing embryo and cancer.
表观遗传机制可能参与肥胖的发生。本研究旨在探讨 DNA 甲基转移酶（Dnmt3a）在肥胖脂肪组织中的作用。通过定量实时 PCR 分析检测 Dnmts 的基因表达。创建了脂肪组织中过表达 Dnmt3a 的转基因小鼠（Dnmt3a 小鼠），其驱动基因由 aP2 启动子表达。使用亚硫酸氢盐 DNA 甲基化分析检测下调基因的 DNA 甲基化。Dnmt3a 小鼠给予甲基补充或高脂肪饮食，并进行体重测量和脂肪组织基因表达分析。肥胖小鼠脂肪组织中 Dnmt3a 的表达明显上调。Dnmt3a 小鼠的 cDNA 微阵列分析显示分泌卷曲相关蛋白 1（SFRP1）的基因表达略有下降，干扰素反应因子 9（IRF9）的基因表达显著增加。在 SFRP1 启动子中，Dnmt3a 小鼠的 DNA 甲基化与野生型小鼠相比没有明显增加。在高脂肪饮食或甲基补充饮食实验中，基因型之间的体重差异无统计学意义。高脂肪饮食的 Dnmt3a 小鼠中炎症细胞因子如肿瘤坏死因子-α（TNF-α）和单核细胞趋化蛋白-1（MCP-1）的基因表达水平高于野生型小鼠。本研究表明，脂肪组织中 Dnmt3a 的表达增加可能导致肥胖相关的炎症。这些数据突出了 Dnmt3a 在成年组织以及胚胎和癌症中的潜在作用。
