摘要
N6-methyladenosine(m^(6)A)is one of the most abundant modifications on m RNAs and plays important roles in various biological processes.The formation of m^(6)A is catalyzed by a methyltransferase complex(MTC)containing a key factor methyltransferase-like 3(Mettl3).However,the functions of Mettl3 and m^(6)A modification in hepatic lipid and glucose metabolism remain unclear.Here,we showed that both Mettl3 expression and m^(6)A level increased in the livers of mice with high fat diet(HFD)-induced metabolic disorders.Overexpression of Mettl3 aggravated HFDinduced liver metabolic disorders and insulin resistance.In contrast,hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain,reducing lipid accumulation,and improving insulin sensitivity.Mechanistically,Mettl3 depletion-mediated m^(6)A loss caused extended RNA half-lives of metabolism-related genes,which consequently protected mice against HFD-induced metabolic syndrome.Our findings reveal a critical role of Mettl3-mediated m^(6)A in HFD-induced metabolic disorders and hepatogenous diabetes.
基金
Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDA16030000)
the National Key R&D Program(Grant Nos.2017YFA0103803,2018YFA0107703,and 2018YFA0801200)
the National Natural Science Foundation of China(Grant Nos.31621004 and 31770872)
the Key Research Projects of the Frontier Science of the Chinese Academy of Sciences(Grant Nos.QYZDY-SSW-SMC002 and QYZDB-SSW-SMC022)
the Youth Innovation Promotion Association of Chinese Academy of Sciences(Grant No.CAS2018133)
