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

被引：3

作者：

Xiao, Ling ^{[1
]}

De Jesus, Dario F. ^{[1
]}

Ju, Cheng-Wei

Wei, Jiang Bo ^{[2
,13
,14
]}

Hu, Jiang ^{[1
]}

DiStefano-Forti, Ava ^{[1
]}

Tsuji, Tadataka ^{[3
]}

Cero, Cheryl ^{[4
]}

Maennistoe, Ville ^{[5
,6
]}

Manninen, Suvi M. ^{[7
]}

Wei, Siying ^{[8
,9
]}

Ijaduola, Oluwaseun ^{[1
]}

Blueher, Matthias ^{[10
,11
]}

Cypess, Aaron M. ^{[4
]}

Pihlajamaeki, Jussi ^{[7
,12
]}

Tseng, Yu-Hua ^{[3
]}

He, Chuan ^{[2
]}

Kulkarni, Rohit N. ^{[1
]}

机构：

[1] Harvard Med Sch, Harvard Stem Cell Inst, Joslin Diabet Ctr, Dept Med,BIDMC,Sect Islet Cell & Regenerat Biol, Boston, MA 02138 USA

[2] Univ Chicago, Howard Hughes Med Inst, Dept Chem, Chicago, IL USA

[3] Harvard Med Sch, Harvard Stem Cell Inst, Joslin Diabet Ctr, Dept Med,BIDMC,Sect Integrat Physiol & Metab, Boston, MA USA

[4] NIDDKD, NIH, Diabet Endocrinol & Obes Branch, Intramural Res Program, Bethesda, MD USA

[5] Univ Eastern Finland, Dept Med, Kuopio, Finland

[6] Kuopio Univ Hosp, Kuopio, Finland

[7] Univ Eastern Finland, Fac Hlth Sci, Inst Publ Hlth & Clin Nutr, Kuopio, Finland

[8] Harvard Med Sch, Sect Islet Cell & Regenerat Biol, Boston, MA USA

[9] Harvard Med Sch, Joslin Diabet Ctr, Dept Med, CRISPR Screen Core Lab, Boston, MA USA

[10] Univ Leipzig, Helmholtz Inst Metab Obes & Vasc Res HI MAG, Leipzig, Germany

[11] Univ Hosp Leipzig, Leipzig, Germany

[12] Kuopio Univ Hosp, Endocrinol & Clin Nutr, Kuopio, Finland

[13] Natl Univ Singapore, Dept Chem, Singapore, Singapore

[14] Natl Univ Singapore, Dept Biol Sci, Singapore, Singapore

来源：

CELL METABOLISM | 2024年 / 36卷 / 10期

基金：

芬兰科学院;

关键词：

ADIPOSE-TISSUE; INDUCED LIPOKINE; IN-VITRO; OBESITY; IDENTIFICATION; 12,13-DIHOME; CONTRIBUTES; HOMEOSTASIS; MICE;

D O I：

10.1016/j.cmet.2024.08.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N6-methyladeno- sine (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.

引用

页码：2207 / 2227.e9

页数：31