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Xiao, L.* ; De Jesus, D.F.* ; Ju, C.* ; Wei, J.B.* ; Hu, J.* ; DiStefano-Forti, A.* ; Tsuji, T.* ; Cero, C.* ; Maennistoe, V.* ; Manninen, S.M.* ; Wei, S.* ; Ijaduola, O.* ; Blüher, M. ; Cypess, A.M.* ; Pihlajamaeki, J.* ; Tseng, Y.-T.* ; He, C.* ; Kulkarni, R.N.*

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

Cell Metab. 36, 2207–2227 (2024)
DOI
: Publ. Version/Full Text online available 12/2025
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Adipose-tissue; Induced Lipokine; In-vitro; Obesity; Identification; 12,13-dihome; Contributes; Homeostasis; Mice
ISSN (print) / ISBN 1550-4131
e-ISSN 1932-7420
Journal Cell Metabolism
Quellenangaben Volume: 36, Issue: 10, Pages: 2207–2227 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Grants Finnish Cultural Foundation
Finnish Diabetes Research Foundation
Eleanor and Miles Shore Program Award from Harvard Medical School
SUNSTAR Research Fellowship (Hiroo Kaneda Scholarship, Japan)
Mary K. Iacocca Junior Postdoctoral Fellowship
Diabetes Research and Wellness Foundation Endowed Chair