Transcriptional regulation of N 6 -methyladenosine orchestrates sex-dimorphic metabolic traits

Males and females exhibit striking differences in the prevalence of metabolic traits including hepatic steatosis, a key driver of cardiometabolic morbidity and mortality. RNA methylation is a widespread regulatory mechanism of transcript turnover. Here, we show that presence of the RNA modification N 6 -methyladenosine (m 6 A) triages lipogenic transcripts for degradation and guards against hepatic triglyceride accumulation. In male but not female mice, this protective checkpoint stalls under lipid-rich conditions. Loss of m 6 A control in male livers increases hepatic triglyceride stores, leading to a more ‘feminized’ hepatic lipid composition. Crucially, liver-specific deletion of the m 6 A complex protein Mettl14 from male and female mice significantly diminishes sex-specific differences in steatosis. We further surmise that the m 6 A installing machinery is subject to transcriptional control by the sex-responsive BCL6–STAT5 axis in response to dietary conditions. These data show that m 6 A is essential for precise and synchronized control of lipogenic enzyme activity and provide insights into the molecular basis for the existence of sex-specific differences in hepatic lipid traits.