Adipose m⁶A reader YTHDF2 promotes obesity, insulin resistance, and liver steatosis by suppressing β-adrenergic signaling and lipolysis.

IF 6.9 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-10-15 DOI:10.1016/j.celrep.2025.116445

Ruoyu Zhou, Liping Ju, Qianqian Kang, Qiantao Zheng, Decheng Ren, Liangyou Rui

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Abstract

RNA N6-methyladenosine (m⁶A) modification induces catecholamine resistance and lipolysis inhibition in white adipose tissue (WAT), contributing to obesity pathogenesis; however, the responsible m⁶A readers remain elusive. Here, we identify YTHDF2 as a key m⁶A reader governing both β-adrenergic signaling and lipolytic machinery. YTHDF2 binds to m⁶A-marked mRNAs encoding β3-adrenergic receptor (Adrb3), adipose triacylglycerol lipase (Atgl), and comparative gene identification-58 (Cgi-58), promoting their degradation and thereby suppressing β-adrenergic signaling and lipolysis. Deletion of adipose Ythdf2 enhances lipolysis in vivo, in WAT explants ex vivo, and in cultured adipocytes. Conversely, YTHDF2 overexpression suppresses adipocyte lipolysis. High-fat diet feeding upregulates adipose YTHDF2 and increases its binding to Adrb3, Atgl, and Cgi-58 mRNAs. Adipocyte-specific deletion of Ythdf2 protects against diet-induced obesity, insulin resistance, and liver steatosis. Moreover, deletion of adipose Mettl14-but not Ythdf2-disrupts brown adipose tissue development. These results unveil an adipose-intrinsic METTL3/METTL14/m⁶A/YTHDF2 pathway that drives catecholamine resistance and lipolysis suppression in obesity.

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脂肪m6A读取器YTHDF2通过抑制β-肾上腺素能信号和脂肪分解促进肥胖、胰岛素抵抗和肝脏脂肪变性。

RNA n6 -甲基腺苷（m6A）修饰诱导白色脂肪组织（WAT）对儿茶酚胺的抵抗和脂解抑制，参与肥胖发病机制；然而，负责任的m6A阅读器仍然难以捉摸。在这里，我们确定YTHDF2是控制β-肾上腺素能信号和脂肪分解机制的关键m6A读取器。YTHDF2结合m6a标记的mrna，编码β3-肾上腺素能受体（Adrb3）、脂肪三酰甘油脂肪酶（Atgl）和比较基因鉴定-58 (Cgi-58)，促进它们的降解，从而抑制β-肾上腺素能信号传导和脂肪分解。脂肪Ythdf2的缺失在体内、体外WAT外植体和培养脂肪细胞中促进脂肪分解。相反，YTHDF2过表达抑制脂肪细胞脂解。高脂饲料喂养上调脂肪YTHDF2，并增加其与Adrb3、Atgl和Cgi-58 mrna的结合。脂肪细胞特异性缺失Ythdf2可防止饮食引起的肥胖、胰岛素抵抗和肝脏脂肪变性。此外，脂肪mettl14（而非ythdf2）的缺失会破坏棕色脂肪组织的发育。这些结果揭示了肥胖症中驱动儿茶酚胺抵抗和脂肪分解抑制的脂肪内源性METTL3/METTL14/m6A/YTHDF2通路。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

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