<br>脂肪 METTL14 诱导的 N6-甲基腺苷通过抑制肾上腺素能信号传导和脂肪分解促进肥胖、胰岛素抵抗和 NAFLD β,Advanced Science

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脂肪 METTL14 诱导的 N6-甲基腺苷通过抑制肾上腺素能信号传导和脂肪分解促进肥胖、胰岛素抵抗和 NAFLD β
Advanced Science ( IF 14.3 ) Pub Date : 2023-08-01 , DOI: 10.1002/advs.202301645
Qianqian Kang _{1,

2} , Xiaorong Zhu _{1,

3} , Decheng Ren ₄ , Alexander Ky ₅ , Ormond A MacDougald _{1,

2,

6} , Robert W O'Rourke _{5,

7} , Liangyou Rui _{1,

2,

6}

Affiliation

白色脂肪组织（WAT）脂肪分解释放游离脂肪酸作为关键能量物质，以支持禁食、寒冷暴露和运动中的新陈代谢。Atgl 与 Cgi-58 协同催化第一个脂解反应。交感神经系统（SNS）通过神经递质去甲肾上腺素刺激脂肪分解，去甲肾上腺素激活脂肪细胞β肾上腺素能受体（Adrb1-3）。在肥胖中，脂肪 Adrb 信号传导和脂肪分解受损，导致致病性 WAT 扩增;然而，人们对底层机制仍然知之甚少。最近的研究强调了基于 N⁶-甲基腺苷（m6A）的 RNA 修饰在健康和疾病中的重要性。METTL14 与 METTL3 异二聚化，形成 RNA 甲基转移酶复合物，将 m6A 安装在转录本中。在这里，这项工作表明脂肪 Mettl3 和 Mettl14 受禁食、再喂养和胰岛素的影响，并在高脂饮食（HFD）诱导的肥胖中上调。肥胖时脂肪 Adrb2 、 Adrb3 、 Atgl 和 Cgi-58 转录本 m6A 含量升高。Mettl14 消融降低这些转录本的 m6A 含量并增加它们在脂肪细胞中的翻译和蛋白质水平，从而增加 Adrb 信号传导和脂肪分解。具有脂肪细胞特异性 Mettl14 缺失的小鼠对 HFD 诱导的肥胖、胰岛素抵抗、葡萄糖耐受不良和非酒精性脂肪肝（NAFLD）具有抵抗力。这些结果揭示了控制 Adrb 信号传导和脂肪分解的 METTL14/m6A/翻译通路。基于 METTL14/m6A 的表观转录组学重编程损害脂肪 Adrb 信号传导和脂肪分解，促进肥胖、NAFLD 和代谢疾病。

"点击查看英文标题和摘要"

Adipose METTL14-Elicited N6-Methyladenosine Promotes Obesity, Insulin Resistance, and NAFLD Through Suppressing β Adrenergic Signaling and Lipolysis

White adipose tissue (WAT) lipolysis releases free fatty acids as a key energy substance to support metabolism in fasting, cold exposure, and exercise. Atgl, in concert with Cgi-58, catalyzes the first lipolytic reaction. The sympathetic nervous system (SNS) stimulates lipolysis via neurotransmitter norepinephrine that activates adipocyte β adrenergic receptors (Adrb1-3). In obesity, adipose Adrb signaling and lipolysis are impaired, contributing to pathogenic WAT expansion; however, the underling mechanism remains poorly understood. Recent studies highlight importance of N⁶-methyladenosine (m6A)-based RNA modification in health and disease. METTL14 heterodimerizes with METTL3 to form an RNA methyltransferase complex that installs m6A in transcripts. Here, this work shows that adipose Mettl3 and Mettl14 are influenced by fasting, refeeding, and insulin, and are upregulated in high fat diet (HFD) induced obesity. Adipose Adrb2, Adrb3, Atgl, and Cgi-58 transcript m6A contents are elevated in obesity. Mettl14 ablation decreases these transcripts’ m6A contents and increases their translations and protein levels in adipocytes, thereby increasing Adrb signaling and lipolysis. Mice with adipocyte-specific deletion of Mettl14 are resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and nonalcoholic fatty liver disease (NAFLD). These results unravel a METTL14/m6A/translation pathway governing Adrb signaling and lipolysis. METTL14/m6A-based epitranscriptomic reprogramming impairs adipose Adrb signaling and lipolysis, promoting obesity, NAFLD, and metabolic disease.

更新日期：2023-08-01

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