Abnormalities of methyl-CpG binding protein 2 (Mecp2) cause neurological disorders with metabolic dysfunction; however, its role in adipose tissues remains unclear. Here, we report upregulated Mecp2 in white adipose tissues (WAT) of obese humans, as well as in obese mice and during in vitro adipogenesis. Normal chow–fed adipocyte-specific Mecp2 knockout mice (Mecp2Adi KO mice) showed a lean phenotype, with downregulated lipogenic genes and upregulated thermogenic genes that were identified using RNA sequencing. Consistently, the deficiency of Mecp2 in adipocytes protected mice from high-fat diet (HFD)–induced obesity and inhibited in vitro adipogenesis. Furthermore, Mecp2Adi KO mice showed increased browning under different stimuli, including cold treatment. Mechanistically, Mecp2 bound to the promoter of secretory leukocyte protease inhibitor (Slpi) and negatively regulated its expression. Knockdown of Slpi in inguinal WAT of Mecp2Adi KO mice prevented cold-induced browning. Moreover, recombinant SLPI treatment reduced the HFD-induced obesity via enhancing browning. Together, our results suggest a novel non–central nervous system function of Mecp2 in obesity by suppressing browning, at least partially, through regulating adipokine Slpi.

中文翻译：

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Mecp2 的脂肪特异性敲除通过增强褐变上调 Slpi 以减少肥胖

甲基-CpG 结合蛋白 2 (Mecp2) 的异常导致代谢功能障碍的神经系统疾病；然而，其在脂肪组织中的作用仍不清楚。在这里，我们报告了肥胖人类白色脂肪组织 (WAT) 以及肥胖小鼠和体外脂肪生成过程中 Mecp2 的上调。正常饲料喂养的脂肪细胞特异性 Mecp2 敲除小鼠（Mecp2Adi KO 小鼠）表现出瘦弱表型，脂肪生成基因下调，产热基因上调，这些基因使用 RNA 测序鉴定。一致地，脂肪细胞中 Mecp2 的缺乏保护小鼠免受高脂肪饮食 (HFD) 诱导的肥胖并抑制体外脂肪生成。此外，Mecp2Adi KO 小鼠在包括冷处理在内的不同刺激下显示出更多的褐变。从机制上讲，Mecp2 与分泌型白细胞蛋白酶抑制剂 (Slpi) 的启动子结合并负调控其表达。在 Mecp2Adi KO 小鼠的腹股沟 WAT 中敲除 Slpi 可防止冷诱导的褐变。此外，重组 SLPI 治疗通过增强褐变减少了 HFD 诱导的肥胖。总之，我们的结果表明 Mecp2 在肥胖症中具有一种新的非中枢神经系统功能，通过调节脂肪因子 Slpi 至少部分抑制褐变。