Dynamic regulation of N6,2′-O-dimethyladenosine (m6Am) in obesity.

The prevalent m⁶Am mRNA cap modification was recently identified as a valid target for removal by the human obesity gene FTO along with the previously established m⁶A mRNA modification. However, the deposition and dynamics of m⁶Am in regulating obesity are unknown. Here, we investigate the liver m⁶A/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 m⁶Am 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 m⁶Am- but not m⁶A-methylated genes, are found to be highly enriched in metabolic processes. Finally, we deplete all m⁶A background via Mettl3 knockout, and unequivocally uncover the association of m⁶Am methylation with increased mRNA stability, translation efficiency, and higher protein expression. Together, these results strongly implicate a dynamic role for m⁶Am in obesity-related translation regulation. m6A and m6Am are two prevalent mRNA modifications which are target for removal by the fat mass and obesity gene FTO. Here the authors capture the differential profile of these two modifications in the liver of obese mice and identify dynamic translation regulation by the m6Am modification. [ABSTRACT FROM AUTHOR]