Fat-Specific Knockout of Mecp2 Upregulates Slpi to Reduce Obesity by Enhancing Browning
Fat-Specific Knockout of Mecp2 Upregulates Slpi to Reduce Obesity by Enhancing Browning
复制标题
Mecp2 的脂肪特异性敲除可上调 Slpi，通过增强褐变来减少肥胖
DOI：
10.2337/db19-0502
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发表时间：
2020-01-01
期刊：
影响因子：
7.7
通讯作者：
Huang, Kun
中科院分区：
文献类型：
--
作者：
Liu, Chengyu;Wang, Jiao;Huang, Kun
甲基-CpG结合蛋白2（Mecp 2）的缺失导致神经系统疾病和代谢功能障碍;然而，其在脂肪组织中的作用尚不清楚。在这里，我们报告上调Mecp 2在白色脂肪组织（WAT）的肥胖的人，以及在肥胖小鼠和在体外脂肪形成。正常饮食喂养的脂肪细胞特异性Mecp 2敲除小鼠（Mecp 2（Adi）KO小鼠）显示出瘦的表型，使用RNA测序鉴定出脂肪生成基因下调和产热基因上调。因此，脂肪细胞中Mecp 2的缺乏保护小鼠免于高脂饮食（HFD）诱导的肥胖，并抑制体外脂肪形成。此外，Mecp 2（Adi）KO小鼠在不同的刺激（包括冷处理）下表现出增加的布朗宁。机制上，Mecp 2结合到分泌性白细胞蛋白酶抑制剂（Slpi）的启动子，并负调控其表达。Mecp 2（Adi）KO小鼠腹股沟WAT中Slpi的敲低防止了冷诱导的布朗宁。此外，重组SLPI处理通过增强布朗宁来减少HFD诱导的肥胖。总之，我们的研究结果表明，一种新的非中枢神经系统功能的Mecp 2在肥胖症中抑制布朗宁，至少部分，通过调节脂肪因子Slpi。
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 (Mecp2(Adi) 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, Mecp2(Adi) 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 Mecp2(Adi) 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.