Although significant progress has been made in understanding epigenetic regulation of in vitro adipogenesis, the physiological functions of epigenetic regulators in metabolism and their roles in obesity remain largely elusive. Here, we report that KDM4B (lysine demethylase 4B) in adipose tissues plays a critical role in energy balance, oxidation, lipolysis, and thermogenesis. Loss of KDM4B in mice resulted in obesity associated with reduced energy expenditure and impaired adaptive thermogenesis. Obesity in KDM4B-deficient mice was accompanied by hyperlipidemia, insulin resistance, and pathological changes in the liver and pancreas. Adipocyte-specific deletion of Kdm4b revealed that the adipose tissues were the main sites for KDM4B antiobesity effects. KDM4B directly controlled the expression of multiple metabolic genes, including Ppargc1a and Ppara. Collectively, our studies identify KDM4B as an essential epigenetic factor for the regulation of metabolic health and maintaining normal body weight in mice. KDM4B may provide a therapeutic target for treatment of obesity.

尽管在了解体外脂肪生成的表观遗传调控方面取得了重大进展，但表观遗传调控因子在代谢中的生理功能及其在肥胖中的作用仍然很大程度上难以捉摸。在这里，我们报告脂肪组织中的 KDM4B（赖氨酸去甲基化酶 4B）在能量平衡、氧化、脂肪分解和产热中起关键作用。小鼠中 KDM4B 的缺失导致与能量消耗减少和适应性产热受损相关的肥胖。KDM4B缺陷小鼠的肥胖伴随着高脂血症、胰岛素抵抗以及肝脏和胰腺的病理变化。Kdm4b的脂肪细胞特异性缺失揭示脂肪组织是 KDM4B 抗肥胖作用的主要部位。KDM4B 直接控制多个代谢基因的表达，包括Ppargc1a和Ppara。总的来说，我们的研究将 KDM4B 确定为调节代谢健康和维持小鼠正常体重的重要表观遗传因素。KDM4B 可提供治疗肥胖症的治疗靶点。