National Creative Research Initiatives Center for Adipocyte Structure and Function, Seoul National University, Seoul 08826, South Korea.
Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, South Korea.
Proc Natl Acad Sci U S A. 2021 Mar 16;118(11). doi: 10.1073/pnas.2021073118.
White adipose tissue (WAT) is a key regulator of systemic energy metabolism, and impaired WAT plasticity characterized by enlargement of preexisting adipocytes associates with WAT dysfunction, obesity, and metabolic complications. However, the mechanisms that retain proper adipose tissue plasticity required for metabolic fitness are unclear. Here, we comprehensively showed that adipocyte-specific DNA methylation, manifested in enhancers and CTCF sites, directs distal enhancer-mediated transcriptomic features required to conserve metabolic functions of white adipocytes. Particularly, genetic ablation of adipocyte Dnmt1, the major methylation writer, led to increased adiposity characterized by increased adipocyte hypertrophy along with reduced expansion of adipocyte precursors (APs). These effects of Dnmt1 deficiency provoked systemic hyperlipidemia and impaired energy metabolism both in lean and obese mice. Mechanistically, Dnmt1 deficiency abrogated mitochondrial bioenergetics by inhibiting mitochondrial fission and promoted aberrant lipid metabolism in adipocytes, rendering adipocyte hypertrophy and WAT dysfunction. Dnmt1-dependent DNA methylation prevented aberrant CTCF binding and, in turn, sustained the proper chromosome architecture to permit interactions between enhancer and dynamin-1-like protein gene (Drp1) in adipocytes. Also, adipose DNMT1 expression inversely correlated with adiposity and markers of metabolic health but positively correlated with AP-specific markers in obese human subjects. Thus, these findings support strategies utilizing Dnmt1 action on mitochondrial bioenergetics in adipocytes to combat obesity and related metabolic pathology.
白色脂肪组织 (WAT) 是全身能量代谢的关键调节者，而以增大预先存在的脂肪细胞为特征的 WAT 可塑性受损与 WAT 功能障碍、肥胖和代谢并发症有关。然而，保持代谢健康所需的适当脂肪组织可塑性的机制尚不清楚。在这里，我们全面展示了脂肪细胞特异性 DNA 甲基化，表现为增强子和 CTCF 位点，指导远端增强子介导的转录组特征，以维持白色脂肪细胞的代谢功能。特别是，脂肪细胞特异性 Dnmt1（主要的甲基化写入器）的基因缺失导致脂肪量增加，表现为脂肪细胞肥大，同时脂肪细胞前体 (AP) 的扩张减少。Dnmt1 缺乏症的这些影响导致瘦鼠和肥胖鼠的系统性高脂血症和能量代谢受损。在机制上，Dnmt1 缺乏通过抑制线粒体分裂来破坏线粒体生物发生，并促进脂肪细胞中异常的脂质代谢，导致脂肪细胞肥大和 WAT 功能障碍。依赖 Dnmt1 的 DNA 甲基化可防止异常的 CTCF 结合，并维持适当的染色体结构，以允许增强子与 dynamin-1 样蛋白基因 (Drp1) 在脂肪细胞之间相互作用。此外，脂肪组织中的 DNMT1 表达与肥胖和代谢健康标志物呈负相关，但与肥胖人类受试者中 AP 特异性标志物呈正相关。因此，这些发现支持利用 Dnmt1 对脂肪细胞中线粒体生物发生的作用来对抗肥胖和相关代谢病理的策略。
