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
{"title":"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","authors":"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","doi":"10.1016/j.cmet.2024.08.006","DOIUrl":null,"url":null,"abstract":"<p>Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) 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 m<sup>6</sup>A 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 m<sup>6</sup>A promotes the decay of <em>PTGES2</em> and <em>CBR1</em>, the genes encoding PGE2 and PGF2a biosynthesis enzymes, in brown adipocytes via YTHDF2/3. Consistently, BAT-specific knockdown of <em>Ptges2</em> or <em>Cbr1</em> reverses the insulin-sensitizing effects in M14<sup>KO</sup> mice. Overall, these findings reveal a novel biological mechanism through which m<sup>6</sup>A-dependent regulation of the BAT secretome regulates systemic insulin sensitivity.</p>","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"17 1","pages":""},"PeriodicalIF":27.7000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"m6A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1\",\"authors\":\"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\",\"doi\":\"10.1016/j.cmet.2024.08.006\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) 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 m<sup>6</sup>A 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 m<sup>6</sup>A promotes the decay of <em>PTGES2</em> and <em>CBR1</em>, the genes encoding PGE2 and PGF2a biosynthesis enzymes, in brown adipocytes via YTHDF2/3. Consistently, BAT-specific knockdown of <em>Ptges2</em> or <em>Cbr1</em> reverses the insulin-sensitizing effects in M14<sup>KO</sup> mice. Overall, these findings reveal a novel biological mechanism through which m<sup>6</sup>A-dependent regulation of the BAT secretome regulates systemic insulin sensitivity.</p>\",\"PeriodicalId\":9840,\"journal\":{\"name\":\"Cell metabolism\",\"volume\":\"17 1\",\"pages\":\"\"},\"PeriodicalIF\":27.7000,\"publicationDate\":\"2024-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell metabolism\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.cmet.2024.08.006\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell metabolism","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.cmet.2024.08.006","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
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.
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.