METTL3 inhibits hepatic insulin sensitivity via N6-methyladenosine modification of Fasn mRNA and promoting fatty acid metabolism.

Type 2 diabetes (T2D) is characterized by lack of insulin, insulin resistance and high blood sugar. However, the underlying mechanisms of insulin resistance during T2D development remains unclear. As the most common mRNAs modification, N6-Methyladenosine (m6A) is involved in many of pathological processes in aging disease. However, it remains unclear whether m6A is involved in T2D development and what is the regulatory mechanism. This study is aimed to illustrate the roles of m6A and its methyltransferase METTL3 in the regulation of blood glucose homeostasis and insulin sensitivity. The results showed that m6A methylated RNA level and its N6-methyladenosine methylase METTL3 were consistently up-regulated in the liver tissues from patients with T2D. Moreover, both m6A methylated RNA and METTL3 levels showed positive correlation with HOMA-IR and negative correlation with HOMA-β. The m6A methylated RNA and METTL3 levels were also up-regulated in mouse with 16 weeks high-fat diet (HFD), compared with mice fed a standard chow diet (CD). Hepatocyte-specific knockout of METTL3 in mice fed a HFD improved insulin sensitivity and decreased fatty acid synthesis. Furthermore, mechanism analysis demonstrates that METTL3 silence decreased the m6A methylated and total mRNA level of Fatty acid synthase (Fasn), subsequently inhibited fatty acid metabolism. Adeno-associated virus mediated Fasn overexpression in METTL3 knockout mice abrogates the improved insulin sensitivity and decreased fatty acid synthesis. Collectively, these results reveal that RNA N6-methyladenosine methylase METTL3 inhibits hepatic insulin sensitivity via N6-methylation of Fasn mRNA and promoting fatty acid metabolism. • The m6A methylated RNA level and its methyltransferase METTL3 are elevated in the liver tissues from patients with T2D. • Hepatocyte-specific METTL3 knockout significantly improved the glucose homeostasis and insulin sensitivity in vitro and in vivo. • METTL3 deletion regulates hepatic fatty acid metabolism. • METTL3 improves the expression of Fasn through its m6A demethylase activity. • AAV mediated Fasn restoration impairs the METTL3-KO improved glucose homeostasis and insulin sensitivity. [ABSTRACT FROM AUTHOR]