m6A methylation modulates adipogenesis through JAK2-STAT3-C/EBPβ signaling

Abstract

N⁶-methyladenosine (m⁶A), the most abundant internal mRNA modification in eukaryotes, plays a vital role in regulating adipogenesis. However, its underlying mechanism remains largely unknown. Here, we reveal that deletion of m⁶A demethylase FTO in porcine and mouse preadipocytes inhibits adipogenesis through JAK2-STAT3-C/EBPβ signaling. Mechanistically, FTO deficiency suppresses JAK2 expression and STAT3 phosphorylation, leading to attenuated transcription of C/EBPβ, which is essential for the early stage of adipocyte differentiation. Using dual-luciferase assay, we validate that knockdown of FTO reduces expression of JAK2 in an m⁶A-dependent manner. Furthermore, we find that m⁶A "reader" protein YTHDF2 directly targets m⁶A-modified transcripts of JAK2 and accelerates mRNA decay, which results in decreased JAK2 expression and inactivated JAK2-STAT3-C/EBPβ signaling, thereby inhibiting adipogenesis. Collectively, our results provide a novel insight into the molecular mechanism of m⁶A methylation in post-transcriptional regulation of JAK2-STAT3-C/EBPβ signaling axis and highlight the crucial role of m⁶A modification and its modulators in adipogenesis.

Keywords: Adipogenesis; FTO; JAK2; STAT3; YTHDF2; m(6)A.