biostudies-literatureXiao LNIDDK NIH HHSNHGRI NIH HHSAmerican Diabetes AssociationNational Institutes of Health2207-2227.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC11891809biostudies-literatureUnknown36(10)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 m<sup>Cell metabolismm&lt;sup&gt;6&lt;/sup&gt;A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1.PMC11891809K99 DK135927RC2 DK139552UC4 DK116278R01 DK067536P30 DK036836RM1 HG008935Ju CWTsuji THe CMannisto VWei JBBluher MDiStefano-Forti ACypess AMManninen SMXiao LPihlajamaki JHu JTseng YHWei SKulkarni RNCero CIjaduola ODe Jesus DFfalsem&lt;sup&gt;6&lt;/sup&gt;A 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 m<sup>2024-01-01T00:00:00Z2024 Oct2026-06-04T00:16:43.713Z2026-05-03T03:12:00.385ZS-EPMC118918093925579910.1016/j.cmet.2024.08.006