Yuan Yangmian, Liu Chengyu, Chen Xingrui, Sun Yuyan, Xiong Mingrui, Fan Yu, Petersen Robert B, Chen Hong, Huang Kun, Zheng Ling
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Mol Nutr Food Res. 2021 Aug;65(16):e2100417. doi: 10.1002/mnfr.202100417. Epub 2021 Jun 23.
DNA methylation contributes to obesity, but the role of the DNA demethylase ten-eleven translocation protein 1 (Tet1) in obesity remains unclear. Vitamin C is a cofactor for the Tet family of proteins, but whether vitamin C can be used to treat obesity via Tet1 awaits clarification.
Tet1 and Tet1 mice are fed a high fat diet (HFD). Higher weight gain and more severe hepatic steatosis, accompanied by reduced 5-hydromethylcytosine (5hmC) levels, are found in the white adipose tissue and liver of Tet1 mice. Accumulated lipids are observed in palmitic acid or oleic acid treated primary hepatocytes derived from Tet1 mice, which are rescued by Tet1 overexpression or vitamin C treatment. Bisulfite sequencing reveals higher DNA methylation levels on lipolysis related genes in the liver of Tet1 mice. Notably, oral intake of vitamin C normalizes DNA methylation levels, promotes lipolysis, and decreases obesity in HFD-fed Tet1 mice.
The results reveal a novel function of Tet1 in obesity and provide a new mechanism for the beneficial role of vitamin C in metabolic diseases through enhanced Tet1 activity.
DNA甲基化与肥胖有关，但DNA去甲基化酶10-11易位蛋白1（Tet1）在肥胖中的作用仍不清楚。维生素C是Tet蛋白家族的辅助因子，但维生素C是否可通过Tet1用于治疗肥胖尚待阐明。
给Tet1基因敲除小鼠和野生型小鼠喂食高脂饮食（HFD）。在Tet1基因敲除小鼠的白色脂肪组织和肝脏中发现体重增加更多且肝脂肪变性更严重，同时伴有5-羟甲基胞嘧啶（5hmC）水平降低。在源自Tet1基因敲除小鼠的原代肝细胞中，经棕榈酸或油酸处理后可观察到脂质积累，而Tet1过表达或维生素C处理可使其得到缓解。亚硫酸氢盐测序显示Tet1基因敲除小鼠肝脏中脂解相关基因的DNA甲基化水平更高。值得注意的是，口服维生素C可使DNA甲基化水平正常化，促进脂解，并减轻喂食HFD的Tet1基因敲除小鼠的肥胖程度。
这些结果揭示了Tet1在肥胖中的新功能，并通过增强Tet1活性为维生素C在代谢疾病中的有益作用提供了新机制。
