Dynamic regulation of N,2'-O-dimethyladenosine (mAm) in obesity.

The prevalent mAm mRNA cap modification was recently identified as a valid target for removal by the human obesity gene FTO along with the previously established mA mRNA modification. However, the deposition and dynamics of mAm in regulating obesity are unknown. Here, we investigate the liver mA/m methylomes in mice fed on a high fat Western-diet and in ob/ob mice. We find that FTO levels are elevated in fat mice, and that genes which lost mAm marking under obesity are overly downregulated, including the two fatty-acid-binding proteins FABP2, and FABP5. Furthermore, the cellular perturbation of FTO correspondingly affect protein levels of its targets. Notably, generally mAm- but not mA-methylated genes, are found to be highly enriched in metabolic processes. Finally, we deplete all mA background via Mettl3 knockout, and unequivocally uncover the association of mAm methylation with increased mRNA stability, translation efficiency, and higher protein expression. Together, these results strongly implicate a dynamic role for mAm in obesity-related translation regulation.