FTO: linking m6A demethylation to adipogenesis

Abstract

Polymorphism of the FTO gene encoding an N(6)-methyladenosine (m(6)A) RNA demethylase was robustly associated with human obesity; however, the mechanism by which FTO affects metabolism, considering its emerging role in RNA modification, is still poorly understood. A new study published in Cell Research reports novel functions implicating FTO in the regulation of mRNA alternative splicing in the control of adipogenesis.

Figure 1

An illustration of alternative splicing of Runx1t1 mediated by FTO-dependent m⁶A demethylation and Srsf2. The typical removal of m⁶A by FTO (lower panel) minimizes the recruitment of Srsf2, which in its absence prompts the skipping of exon 6, resulting in a short product of Runx1t1. In turn, the short isoform of Runx1t1 induces pre-adipocyte differentiation. Conversely, m⁶A-containing transcripts (enhanced by FTO knockdown) are more likely to recruit Srsf2 and induce exon 6 inclusion, thereby inhibiting pre-adipocyte differentiation.