Graduate School of Peking Union Medical College, No. 9, Dongdansantiao, Dongcheng District, Beijing 100730, China; Department of Biochemistry & Immunology, Capital Institute of Pediatrics, No. 2, Yabao Road, Chaoyang District, Beijing 100020, China.
Graduate School of Peking Union Medical College, No. 9, Dongdansantiao, Dongcheng District, Beijing 100730, China.
J Nutr Biochem. 2018 Sep;59:76-83. doi: 10.1016/j.jnutbio.2018.05.010. Epub 2018 Jun 2.
Folic acid (FA) supplementation may protect from obesity and insulin resistance, the effects and mechanism of FA on chronic high-fat-diet-induced obesity-related metabolic disorders are not well elucidated. We adopted a genome-wide approach to directly examine whether FA supplementation affects the DNA methylation profile of mouse adipose tissue and identify the functional consequences of these changes. Mice were fed a high-fat diet (HFD), normal diet (ND) or an HFD supplemented with folic acid (20 μg/ml in drinking water) for 10 weeks, epididymal fat was harvested, and genome-wide DNA methylation analyses were performed using methylated DNA immunoprecipitation sequencing (MeDIP-seq). Mice exposed to the HFD expanded their adipose mass, which was accompanied by a significant increase in circulating glucose and insulin levels. FA supplementation reduced the fat mass and serum glucose levels and improved insulin resistance in HFD-fed mice. MeDIP-seq revealed distribution of differentially methylated regions (DMRs) throughout the adipocyte genome, with more hypermethylated regions in HFD mice. Methylome profiling identified DMRs associated with 3787 annotated genes from HFD mice in response to FA supplementation. Pathway analyses showed novel DNA methylation changes in adipose genes associated with insulin secretion, pancreatic secretion and type 2 diabetes. The differential DNA methylation corresponded to changes in the adipose tissue gene expression of Adcy3 and Rapgef4 in mice exposed to a diet containing FA. FA supplementation improved insulin resistance, decreased the fat mass, and induced DNA methylation and gene expression changes in genes associated with obesity and insulin secretion in obese mice fed a HFD.
叶酸（FA）补充可能有助于预防肥胖和胰岛素抵抗，但 FA 对慢性高脂肪饮食诱导的肥胖相关代谢紊乱的作用和机制尚不清楚。我们采用全基因组方法直接研究 FA 补充是否会影响小鼠脂肪组织的 DNA 甲基化谱，并确定这些变化的功能后果。将小鼠喂食高脂肪饮食（HFD）、正常饮食（ND）或补充叶酸的 HFD（饮用水中 20μg/ml）10 周，采集附睾脂肪，并使用甲基化 DNA 免疫沉淀测序（MeDIP-seq）进行全基因组 DNA 甲基化分析。暴露于 HFD 的小鼠会增加脂肪量，同时循环葡萄糖和胰岛素水平显著升高。FA 补充可减少 HFD 喂养小鼠的脂肪量和血清葡萄糖水平，并改善胰岛素抵抗。MeDIP-seq 揭示了整个脂肪细胞基因组中差异甲基化区域（DMR）的分布，HFD 小鼠中更多的区域呈高甲基化状态。甲基组分析确定了与 HFD 小鼠对 FA 补充反应相关的 3787 个注释基因的 DMRs。通路分析显示，与胰岛素分泌、胰腺分泌和 2 型糖尿病相关的脂肪基因中的新的 DNA 甲基化变化。在暴露于含有 FA 的饮食中的小鼠中，差异 DNA 甲基化对应于与肥胖和胰岛素分泌相关的脂肪组织基因的 Adcy3 和 Rapgef4 的基因表达变化。FA 补充可改善胰岛素抵抗，减少脂肪量，并诱导肥胖 HFD 喂养小鼠中与肥胖和胰岛素分泌相关的基因的 DNA 甲基化和基因表达变化。
