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Activation of METTL3 promotes white adipose tissue beiging and combats obesity

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posted on 2023-05-24, 18:56 authored by Renxiang Xie, Sujun Yan, Xiaoling Zhou, Yunyi Gao, Yu Qian, Jingyu Hou, Zhanghui Chen, Kairan Lai, Xiangwei Gao, Saisai Wei

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.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82100926 to S.W. and 82073110, 81672847 to X.G.), Natural Science Foundation of Zhejiang Province, China (LQ19H120012 to K.L.), and Zhejiang Youth Talent Support Program (ZJWR0308085 to X.G.).

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