363-OR: Brown Adipose Tissue m6A mRNA Methylation Regulates Systemic Insulin Sensitivity via a Prostaglandin Interorgan Axis

Brown adipose tissue (BAT) has the capacity to regulate peripheral insulin sensitivity via the secretion of signaling lipids. N6-methyladenosine (m⁶A) is among the most prevalent and abundant post-transcriptional RNA modifications in eukaryotes. Recently, m⁶A has been shown to regulate islet and hepatic metabolism as well as BAT adipogenesis and energy expenditure. Here, we demonstrate that deficiency of m⁶A methyltransferase-like 14 (M14) in BAT positively regulates BAT-secretory function to improve systemic insulin sensitivity through inter-organ communication. Using lipidomic approaches, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14^KOBAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a showed significant inverse correlation with HOMA-IR in humans. Furthermore, in vivo administration of PGE2 and PGF2a in HFD-induced insulin resistant obese mice recapitulated the phenotypes of M14^KO mice. Exogenous PGE2 or PGF2a significantly improved insulin stimulated-pAKT by suppressing expression of specific phosphatases in human hepatocyte cell line. Mechanistically, M14-mediated m⁶A installation destabilizes transcripts encoding PGE2 and PGF2a synthases in brown adipocytes in an YTHDF2/3-dependent manner. Collectively, these results unveil a new mechanism by which m⁶A-facilitated BAT-secretory function enables the regulation of whole body insulin sensitivity.