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

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 PPaR alpha. Inhibition of m(6)A methylation via knockdown of m(6)A methyltransferase METTL3 decreases PPaR alpha m(6)A abundance and increases PPaR alpha mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. Mechanistically, YTHDF2 binds to PPaR alpha to mediate its mRNA stability to regulate lipid metabolism. Induction of reactive oxygen species both in vitro and in vivo increases PPaR alpha 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.