Landscape of transcriptome‐wide m6A modification in diabetic liver reveals rewiring of PI3K‐Akt signaling after physical exercise

Abstract Aim Type 2 diabetes mellitus (T2DM) is one of the most common diseases, and epigenetic modification N6‐methyladenosine (m 6 A) is essential for transcriptional modulation involved in its development. However, the precise role and landscape of transcriptome‐wide m 6 A alterations in molecular adaptations after physical exercise have yet to be fully elucidated. Methods Four‐week‐old male C57BL/6J mice received a high‐fat diet (HFD) for 12 weeks to establish a diabetic state, and HFD mice were simultaneously subjected to physical exercise (HFD + EX). The hepatic RNA m 6 A methylome was examined, the conjoint MeRIP‐seq and RNA‐seq was performed, and the exercise‐modulated genes were confirmed. Results Physical exercise significantly ameliorates liver metabolic disorder and triggers a dynamic change in hepatic RNA m 6 A. By analyzing the distribution of m 6 A in transcriptomes, an abundance of m 6 A throughout mRNA transcripts and a pattern of conserved m 6 A after physical exercise was identified. It is noteworthy that conjoint MeRIP‐seq and RNA‐seq data revealed that both differentially methylated genes and differentially expressed genes were enriched in all stages of the PI3K‐Akt signaling pathway, in particular the upstream nodes of this pathway, which are considered a valuable therapeutic target for T2DM. Moreover, in vivo and in vitro analyses showed that exercise‐mediated methyltransferase Rbm15 positively regulated the expression of two upstream genes (Itga3 and Fgf21) in an m 6 A‐dependent manner. Conclusion These findings highlight the pivotal role of the exercise‐induced m 6 A epigenetic network and contribute insights into the intricate epigenetic mechanism underlying insulin signaling.