Introduction & Objective: White adipose tissue (WAT) releases free fatty acids (FFAs) via lipolysis to meet metabolic demand in a negative energy state. Excessive WAT growth imposes risk for type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), but mechanism for aberrant WAT growth is poorly understood. We previously reported that adipose METTL14, a m6A writer installing m6A methylation on RNA, promotes obesity by suppressing lipolysis. The objective of this work is to identify m6A readers mediating METTL14’s action.
Methods: Adipocyte-specific Ythdf2 knockout mice (Ythdf2Δfat) were generated by crossing Ythdf2f/f with Adipoq-Cre mice and fed high fat diet (HFD) for 12 weeks. Lipolysis assays were performed in mice and in WAT explants. RNA immunoprecipitation was used to assess m6A levels and YTHDF2-binding to RNA.
Results: We found that Ythdf2Δfat mice, both males and females, were resistant to HFD-induced obesity. Fat content was significantly lower in Ythdf2Δfat than in Ythdf2f/f littermates. Ablation of adipose Ythdf2 mitigated insulin resistance and MASLD. β-agonist treatment increased plasma FFAs to a higher level in Ythdf2Δfat than in Ythdf2f/f mice. β-agonists also stimulated lipolysis to a higher level in Ythdf2Δfat WAT ex vivo. Adipose triglyceride lipase (ATGL) and CGI-58 (ATGL cofactor) levels were markedly higher in Ythdf2Δfat than in Ythdf2f/f WAT. YTHDF2 bound to Atgl and Cgi-58 mRNAs, and ablation of METTL14 suppressed YTHDF2 interactions with these transcripts. These results suggest that YTHDF2 binds to m6A-marked transcripts to inhibit ATGL and CGI-58 syntheses, thereby suppressing lipolysis.
Conclusion: Our results unveil YTHDF2-based epitranscriptomic reprogramming that governs lipolysis and WAT growth.
R. Zhou: None. L. Rui: None. Q. Kang: None.
National Institutes of Health (R01DK130111)
