M⁶A mRNA methylation in brown fat regulates systemic insulin sensitivity via an inter-organ prostaglandin signaling axis independent of UCP1.

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 m

SUBMITTER: Xiao L 

PROVIDER: S-EPMC11891809 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature