Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea.
1] Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Korea [2] Department of Biophysics and Chemical Biology, Seoul National University, Seoul 151-742, Korea.
Nat Commun. 2015 Jul 3;6:7585. doi: 10.1038/ncomms8585.
Adiponectin plays a key role in the regulation of the whole-body energy homeostasis by modulating glucose and lipid metabolism. Although obesity-induced reduction of adiponectin expression is primarily ascribed to a transcriptional regulation failure, the underlying mechanisms are largely undefined. Here we show that DNA hypermethylation of a particular region of the adiponectin promoter suppresses adiponectin expression through epigenetic control and, in turn, exacerbates metabolic diseases in obesity. Obesity-induced, pro-inflammatory cytokines promote DNMT1 expression and its enzymatic activity. Activated DNMT1 selectively methylates and stimulates compact chromatin structure in the adiponectin promoter, impeding adiponectin expression. Suppressing DNMT1 activity with a DNMT inhibitor resulted in the amelioration of obesity-induced glucose intolerance and insulin resistance in an adiponectin-dependent manner. These findings suggest a critical role of adiponectin gene epigenetic control by DNMT1 in governing energy homeostasis, implying that modulating DNMT1 activity represents a new strategy for the treatment of obesity-related diseases.
脂联素在调节全身能量平衡方面发挥着关键作用，通过调节葡萄糖和脂质代谢。虽然肥胖诱导的脂联素表达减少主要归因于转录调控失败，但潜在机制在很大程度上尚未确定。在这里，我们表明，脂联素启动子的一个特定区域的 DNA 过度甲基化通过表观遗传控制抑制脂联素表达，进而使肥胖中的代谢疾病恶化。肥胖诱导的促炎细胞因子促进 DNMT1 的表达及其酶活性。激活的 DNMT1 选择性地甲基化并刺激脂联素启动子中的致密染色质结构，从而阻碍脂联素的表达。用 DNMT 抑制剂抑制 DNMT1 活性可改善肥胖诱导的葡萄糖不耐受和胰岛素抵抗，这是一种依赖脂联素的方式。这些发现表明 DNMT1 通过 DNA 甲基化在调节能量平衡方面起着关键作用，这表明调节 DNMT1 活性代表了治疗肥胖相关疾病的一种新策略。
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