309-OR: Adipose RNA N6-Methyladenosine (m6A) Modification Promotes Obesity and Insulin Resistance through Suppressing Lipolysis

Excessive white adipose tissue (WAT) promotes insulin resistance and nonalcoholic fatty liver disease (NAFLD) in obesity; however, the WAT expansion mechanism remains poorly understood. We reported that WAT lipolysis is suppressed in obesity, likely contributing to WAT growth. Adipose triglyceride lipase (Atgl) catalyzes the lipolysis reaction, and its lipolytic activity is increased by phosphorylation and binding to cofactor Cgi58. The sympathetic nervous system activates adipocyte β adrenergic receptor (Adrb)/cAMP/PKA pathway to stimulate lipolysis via Atgl and Cgi58. In this study, we have identified a novel m6A modification of Adrb, Atgl, and Cgi58 transcripts that promotes obesity and metabolic disorders. We found that obesity was associated with increased expression of adipose Mettl3 and Mettl14 and elevated m6A levels in WAT. Mettl14 directly binds to Mettl3 to form a methyltransferase complex that catalyzes m6A on RNA. Insulin also increased Mettl14 expression and m6A levels in adipocytes. We generated adipocyte-specific Mettl14 knockout mice (Mettl14 Δfat) and placed mice on a high fat diet (HFD). Remarkably, Mettl14 Δfat mice, both males and females, were resistant to HFD-induced obesity, insulin resistance, and NAFLD. Adipose Adrb2/3, Atgl, and Cgi58 protein levels were significantly upregulated in Mettl14 Δfat mice and consequently, adipose β adrenergic signaling and lipolysis were significantly higher in Mettl14 Δfat than in Mettl14f/f mice. Mettl14 deficiency dramatically decreased the m6A content of Adrb2/3, Atgl, and Cgi58 transcripts in WAT; strikingly, m6A inhibition markedly increased translational rates of these transcripts in adipocytes. Collectively, these results unravel a previously unrecognized adipose Mettl14/m6A/translation axis that promotes obesity, insulin resistance, and NAFLD by suppressing adipose β adrenergic signaling, lipolysis, and fatty acid oxidation.