Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation

Summary Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases. Whether N 6 -methyladenosine (m 6 A) mRNA methylation impacts circadian regulation of lipid metabolism is unclear. Here, we show m 6 A mRNA methylation oscillations in murine liver depend upon a functional circadian clock. Hepatic deletion of Bmal1 increases m 6 A mRNA methylation, particularly of PPaRα . Inhibition of m 6 A methylation via knockdown of m 6 A methyltransferase METTL3 decreases PPaRα m 6 A abundance and increases PPaRα mRNA lifetime and expression, reducing lipid accumulation in cells in vitro . Mechanistically, YTHDF2 binds to PPaRα to mediate its mRNA stability to regulate lipid metabolism. Induction of reactive oxygen species both in vitro and in vivo increases PPaRα transcript m 6 A levels, revealing a possible mechanism for circadian disruption on m 6 A mRNA methylation. These data show that m 6 A RNA methylation is important for circadian regulation of downstream genes and lipid metabolism, impacting metabolic outcomes.