m6A mRNA Methylation in Brown Adipose Tissue Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis

Xiao, L.; De Jesus, D. F.; Ju, C.-W.; Wei, J.-B.; Hu, J.; DiStefano-Forti, A.; Tsuji, T.; Cero, C.; Mannisto, V.; Manninen, S. M.; Wei, S.-Y.; Ijaduola, O.; Blueher, M.; Cypess, A. M.; Pihlajamaki, J.; Tseng, Y.-H.; He, C.; Kulkarni, R. N.

doi:10.1101/2023.05.26.542169

bioRxiv · 10.1101/2023.05.26.542169

m6A mRNA Methylation in Brown Adipose Tissue Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis

Xiao, L.·De Jesus, D. F.·Ju, C.-W.·Wei, J.-B.·Hu, J.·DiStefano-Forti, A.·Tsuji, T.·Cero, C.·Mannisto, V.·Manninen, S. M.·Wei, S.-Y.·Ijaduola, O.·Blueher, M.·Cypess, A. M.·Pihlajamaki, J.·Tseng, Y.-H.·He, C.·Kulkarni, R. N.

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Abstract

Brown adipose tissue (BAT) has the capacity to regulate systemic metabolism through the secretion of 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. In this study, we demonstrate that the absence of m6A methyltransferase-like 14 (METTL14), modifies the BAT secretome to initiate inter-organ communication to improve systemic insulin sensitivity. Importantly, these phenotypes are independent of UCP1-mediated energy expenditure and thermogenesis. Using lipidomics, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14KO-BAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a levels are inversely correlated with insulin sensitivity in humans. Furthermore, in vivo administration of PGE2 and PGF2a in high-fat diet-induced insulin-resistant obese mice recapitulates the phenotypes of METTL14 deficient animals. PGE2 or PGF2a improves insulin signaling by suppressing the expression of specific AKT phosphatases. Mechanistically, METTL14-mediated m6A installation promotes decay of transcripts encoding prostaglandin synthases and their regulators in human and mouse brown adipocytes in a YTHDF2/3-dependent manner. Taken together, these findings reveal a novel biological mechanism through which m6A-dependent regulation of BAT secretome regulates systemic insulin sensitivity in mice and humans. HighlightsO_LIMettl14KO-BAT improves systemic insulin sensitivity via inter-organ communication; C_LIO_LIPGE2 and PGF2a are BAT-secreted insulin sensitizers and browning inducers; C_LIO_LIPGE2 and PGF2a sensitize insulin responses through PGE2-EP-pAKT and PGF2a-FP-AKT axis; C_LIO_LIMETTL14-mediated m6A installation selectively destabilizes prostaglandin synthases and their regulator transcripts; C_LIO_LITargeting METTL14 in BAT has therapeutic potential to enhance systemic insulin sensitivity C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/542169v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@16b3393org.highwire.dtl.DTLVardef@1072ae3org.highwire.dtl.DTLVardef@190a6d7org.highwire.dtl.DTLVardef@1b98bce_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Xiao, L., De Jesus, D. F., Ju, C.-W., Wei, J.-B., Hu, J., DiStefano-Forti, A., Tsuji, T., Cero, C., Mannisto, V., Manninen, S. M., Wei, S.-Y., Ijaduola, O., Blueher, M., Cypess, A. M., Pihlajamaki, J., Tseng, Y.-H., He, C., Kulkarni, R. N.. 2023-05-26. m6A mRNA Methylation in Brown Adipose Tissue Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis. https://doi.org/10.1101/2023.05.26.542169

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