近日，美国哈佛医学院Rohit N. Kulkarni团队的最新研究探明，褐色脂肪中的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。2024年9月9日出版的《细胞—代谢》杂志发表了这项成果。

研究人员证明m⁶A甲基转移酶样14（METTL14）的缺失改变了褐色脂肪组织(BAT)的分泌组，独立于UCP1改善全身胰岛素敏感性。利用脂质组学，研究团队鉴定出前列腺素E2 (PGE2)和前列腺素F2a (PGF2a)是BAT分泌的胰岛素增敏剂。PGE2和PGF2a与人类胰岛素敏感性呈负相关，并通过抑制特异性AKT磷酸酶，保护小鼠免受高脂肪饮食诱导的胰岛素抵抗。

在机制上，METTL14介导的m⁶A通过YTHDF2/3，促进褐色脂肪细胞中编码PGE2和PGF2a生物合成酶的，基因PTGES2和CBR1的衰变。BAT特异性敲低Ptges2或Cbr1可逆转M14^KO小鼠的胰岛素增敏作用。总的来说，这些发现揭示了一种新的生物学机制，通过m⁶A依赖性的BAT分泌组调节全身胰岛素敏感性。

据介绍，褐色脂肪组织(BAT)通过释放信号脂质调节全身代谢。棕色脂肪组织（BAT）通过释放信号脂质来调节全身代谢。N⁶-甲基腺苷（m⁶A）是最常见且丰富的转录后mRNA修饰，已被报道调控BAT的脂肪生成和能量消耗。

附：英文原文

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

Author: Ling Xiao, Dario F. De Jesus, Cheng-Wei Ju, Jiang Bo Wei, Jiang Hu, Ava DiStefano-Forti, Tadataka Tsuji, Cheryl Cero, Ville Mnnist, Suvi M. Manninen, Siying Wei, Oluwaseun Ijaduola, Matthias Blüher, Aaron M. Cypess, Jussi Pihlajamki, Yu-Hua Tseng, Chuan He, Rohit N. Kulkarni

Issue&Volume: 2024-09-09

Abstract: 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.

DOI: 10.1016/j.cmet.2024.08.006

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00333-4