Adipose METTL14-elicited N6-methyladenosine promotes obesity, insulin resistance, and NAFLD by suppressing ß adrenergic signaling and lipolysis

Obesity is associated with impaired ß-adrenergic receptor (Adrb1-3) signaling and lipolysis, leading to aberrant white adipose tissue (WAT) growth. WAT research has been centered on transcriptional and posttranslational regulations, but posttranscriptional regulation and mRNA modifications are poorly understood. Here, we unveil a METTL14/N6-methyladenosine (m6A) paradigm guiding ß-adrenergic signaling and lipolysis. METTL14 complex installs m6A on RNA, regulating mRNA fate and translation. We found that feeding and insulin increased adipose Mettl14 and m6A levels. Adipose Mettl14 and m6A were upregulated in high fat diet (HFD)-induced obesity. Ablation of adipose Mettl14 decreased Adrb2, Adrb3, Atgl (encoding lipase), and Cig-58 (Atgl activator) transcript m6A contents while increasing their translation and protein levels, thereby enhancing adipose ß-adrenergic signaling and lipolysis. Consequently, adipocyte-specific Mettl14 knockout mice were resistant to HFD-induced obesity, insulin resistance, glucose intolerance, and NAFLD. These results unravel a METTL14/m6A-based epitranscriptomic mechanism governing ß-adrenergic signaling, lipolysis, and adipose growth in health and disease. Overall design: We aimed to identify Mettl14 target transcripts. Mettl14?fat and Mettl14f/f male mice were fed an HFD for 20 weeks to increase adipose Mettl14 expression in Mettl14f/f but not Mettl14?fat mice, and eWAT was isolated for RNA-Seq analysis. We used DEseq2 algorithms to detect the DEGs.