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Activation of METTL3 promotes white adipose tissue beiging and combats obesity
Diabetes ( IF 7.7 ) Pub Date : 2023-05-24 , DOI: 10.2337/db22-0775
Renxiang Xie 1, 2 , Sujun Yan 1, 3 , Xiaoling Zhou 1 , Yunyi Gao 1 , Yu Qian 1 , Jingyu Hou 1 , Zhanghui Chen 4 , Kairan Lai 5 , Xiangwei Gao 1, 3 , Saisai Wei 1, 2
Affiliation  

The induction of beige adipocytes in white adipose tissue, also known as WAT beiging, improves glucose and lipid metabolism. However, the regulation of WAT beiging at the posttranscriptional level remains to be studied. Here, we report that METTL3, the methyltransferase of N6-methyladenosine (m6A) mRNA modification, is induced during WAT beiging in mice. Adipose-specific depletion of Mettl3 gene undermines WAT beiging and impairs the metabolic capability of mice fed with a high-fat diet (HFD). Mechanistically, METTL3-catalyzed m6A installation on thermogenic mRNAs, including Krüppel-like factor 9 (Klf9), prevents their degradation. Activation of METTL3 complex by its chemical ligand methyl piperidine-3-carboxylate promotes WAT beiging, reduces body weight, and corrects metabolic disorders in diet-induced obese mice. These findings uncover a novel epitranscriptional mechanism in WAT beiging and identify METTL3 as a potential therapeutic target for obesity-associated diseases.

中文翻译:

METTL3的激活促进白色脂肪组织变黄并对抗肥胖

白色脂肪组织中米色脂肪细胞的诱导(也称为 WAT 米色)可改善葡萄糖和脂质代谢。然而,WAT beiging在转录后水平的调控仍有待研究。在此,我们报道 METTL3(N6-甲基腺苷 (m6A) mRNA 修饰的甲基转移酶)在小鼠 WAT 变黄过程中被诱导。Mettl3 基因的脂肪特异性缺失会破坏 WAT 米色化,并损害高脂饮食 (HFD) 喂养的小鼠的代谢能力。从机制上讲,METTL3 催化的 m6A 安装在产热 mRNA(包括 Krüppel 样因子 9 (Klf9))上,可防止其降解。METTL3 复合物通过其化学配体哌啶-3-甲酸甲酯的激活可促进 WAT 米色化、减轻体重并纠正饮食诱导的肥胖小鼠的代谢紊乱。这些发现揭示了 WAT beiging 中的一种新型表观转录机制,并将 METTL3 确定为肥胖相关疾病的潜在治疗靶点。
更新日期:2023-05-24
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