NADP modulates RNA m⁶A methylation and adipogenesis via enhancing FTO activity

Metabolism is often regulated by the transcription and translation of RNA. In turn, it is likely that some metabolites regulate enzymes controlling reversible RNA modification, such as N⁶-methyladenosine (m⁶A), to modulate RNA. This hypothesis is at least partially supported by the findings that multiple metabolic diseases are highly associated with fat mass and obesity-associated protein (FTO), an m⁶A demethylase. However, knowledge about whether and which metabolites directly regulate m⁶A remains elusive. Here, we show that NADP directly binds FTO, independently increases FTO activity, and promotes RNA m⁶A demethylation and adipogenesis. We screened a set of metabolites using a fluorescence quenching assay and NADP was identified to remarkably bind FTO. In vitro demethylation assays indicated that NADP enhances FTO activity. Furthermore, NADP regulated mRNA m⁶A via FTO in vivo, and deletion of FTO blocked NADP-enhanced adipogenesis in 3T3-L1 preadipocytes. These results build a direct link between metabolism and RNA m⁶A demethylation.