Cheng Jia, Song Jia, He Xiaoyu, Zhang Meng, Hu Shuang, Zhang Shu, Yu Qilin, Yang Ping, Xiong Fei, Wang Dao Wen, Zhou Jianfeng, Ning Qin, Chen Zhishui, Eizirik Decio L, Zhou Zhiguang, Zhao Chunxia, Wang Cong-Yi
The Center for Biomedical Research, Key Laboratory of Organ Transplantation, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Diabetes. 2016 Nov;65(11):3384-3395. doi: 10.2337/db16-0151. Epub 2016 Aug 23.
Previous studies including ours demonstrated that methyl-CpG-binding domain 2 (MBD2) acts as a reader to decipher DNA methylome-encoded information. We thus in the current study used Mbd2 mice as a model to dissect the impact of high-fat diet (HFD) on DNA methylome relevant to the pathoetiology of obesity. It was interestingly noted that mice deficient in Mbd2 were protected from HFD-induced obesity and insulin resistance. Mechanistic study revealed that HFD rendered epididymal adipose tissues to undergo a DNA methylation turnover as evidenced by the changes of methylation levels and patterns. Specifically, HFD was noted with higher potency to induce DNA hypomethylation in genes relevant to energy storage than that in genes associated with energy expenditure. As a result, arrays of genes were subjected to expression changes, which led to an altered homeostasis for energy storage and expenditure in favor of obesity development. Loss of Mbd2 resulted in impaired implementation of above DNA methylation changes associated with altered energy homeostasis, which then protected mice from HFD-induced obesity and insulin resistance. Those data would provide novel insight into the understanding of the pathoetiology underlying obesity with potential for developing effective therapies against obesity in clinical settings.
包括我们的研究在内，以往的研究表明，甲基-CpG结合结构域2（MBD2）作为一种读取器来解读DNA甲基化组编码的信息。因此，在本研究中，我们使用Mbd2基因敲除小鼠作为模型，来剖析高脂饮食（HFD）对与肥胖病理病因相关的DNA甲基化组的影响。有趣的是，我们发现缺乏Mbd2的小鼠对高脂饮食诱导的肥胖和胰岛素抵抗具有抗性。机制研究表明，高脂饮食导致附睾脂肪组织发生DNA甲基化转换，这可通过甲基化水平和模式的变化得到证实。具体而言，与能量消耗相关的基因相比，高脂饮食诱导与能量储存相关基因发生DNA低甲基化的能力更强。结果，一系列基因的表达发生变化，导致能量储存和消耗的内稳态改变，从而有利于肥胖的发展。Mbd2的缺失导致与能量内稳态改变相关的上述DNA甲基化变化的实施受损，进而保护小鼠免受高脂饮食诱导的肥胖和胰岛素抵抗。这些数据将为理解肥胖的病理病因提供新的见解，具有在临床环境中开发有效抗肥胖疗法的潜力。
