棕色脂肪中的 m6A mRNA 甲基化通过独立于 UCP1 的器官间前列腺素信号轴调节全身胰岛素敏感性

IF 27.7 1区 生物学 Q1 CELL BIOLOGY
Ling Xiao, Dario F. De Jesus, Cheng-Wei Ju, Jiang Bo Wei, Jiang Hu, Ava DiStefano-Forti, Tadataka Tsuji, Cheryl Cero, Ville Männistö, Suvi M. Manninen, Siying Wei, Oluwaseun Ijaduola, Matthias Blüher, Aaron M. Cypess, Jussi Pihlajamäki, Yu-Hua Tseng, Chuan He, Rohit N. Kulkarni
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引用次数: 0

摘要

棕色脂肪组织(BAT)通过释放信号脂质调节全身代谢。N6-甲基腺苷(m6A)是最普遍和最丰富的转录后 mRNA 修饰,据报道可调节 BAT 的脂肪生成和能量消耗。在这里,我们证明了 m6A 甲基转移酶样 14(METTL14)的缺失会改变 BAT 的分泌组,从而改善全身胰岛素敏感性,而与 UCP1 无关。利用脂质组学,我们发现前列腺素 E2 (PGE2) 和前列腺素 F2a (PGF2a) 是 BAT 分泌的胰岛素增敏剂。PGE2 和 PGF2a 与人类的胰岛素敏感性成反比,并通过抑制特定的 AKT 磷酸酶保护小鼠免受高脂饮食引起的胰岛素抵抗。从机理上讲,METTL14 介导的 m6A 会通过 YTHDF2/3 促进棕色脂肪细胞中编码 PGE2 和 PGF2a 生物合成酶的基因 PTGES2 和 CBR1 的衰变。同样,特异性敲除 Ptges2 或 Cbr1 可逆转 M14KO 小鼠的胰岛素致敏效应。总之,这些发现揭示了一种新的生物学机制,即依赖于 m6A 的 BAT 分泌组调控系统性胰岛素敏感性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

m6A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1

m6A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1

Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N6-methyladenosine (m6A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. Here, we demonstrate that the absence of m6A methyltransferase-like 14 (METTL14) modifies the BAT secretome to improve systemic insulin sensitivity independent of UCP1. Using lipidomics, we identify prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as BAT-secreted insulin sensitizers. PGE2 and PGF2a inversely correlate with insulin sensitivity in humans and protect mice from high-fat-diet-induced insulin resistance by suppressing specific AKT phosphatases. Mechanistically, METTL14-mediated m6A promotes the decay of PTGES2 and CBR1, the genes encoding PGE2 and PGF2a biosynthesis enzymes, in brown adipocytes via YTHDF2/3. Consistently, BAT-specific knockdown of Ptges2 or Cbr1 reverses the insulin-sensitizing effects in M14KO mice. Overall, these findings reveal a novel biological mechanism through which m6A-dependent regulation of the BAT secretome regulates systemic insulin sensitivity.

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来源期刊
Cell metabolism
Cell metabolism 生物-内分泌学与代谢
CiteScore
48.60
自引率
1.40%
发文量
173
审稿时长
2.5 months
期刊介绍: Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.
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