FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation

Fat mass and obesity-associated protein (FTO) is a RNA demethylase, whether FTO regulates fat metabolism through its demethylation is unclear. The results of this study confirmed that N6-methyladenosine (m⁶ A) is associated with fat accumulation both in vivo and in vitro. The data showed that FTO down-regulated m⁶ A levels, decreased mitochondrial content, and increased triglyceride (TG) deposition. However, an FTO (R316A) mutant lacking demethylation activity could not regulate mitochondria and TG content, indicating that FTO affects mitochondrial content and fat metabolism by modulating m⁶ A levels in hepatocytes. In addition, the regulatory roles of cycloleucine (methylation inhibitor) and betaine (methyl donor) could regulate m⁶ A levels and fat deposition. This work clarified that the demethylation function of FTO plays an essential role in the fat metabolism of hepatocytes and links the epigenetic modification of RNA with fat deposition, thereby providing a new target (m⁶ A) for regulation of hepatic fat metabolism.