Brown adipocyte maturation during postnatal development is essential for brown adipose tissue(BAT)to protect animals against cold.Impaired maturation of brown adipocytes leads to cold intolerance.However,the molecular...Brown adipocyte maturation during postnatal development is essential for brown adipose tissue(BAT)to protect animals against cold.Impaired maturation of brown adipocytes leads to cold intolerance.However,the molecular mechanisms that determine the maturation of brown adipocytes during postnatal development are not fully understood.Here,we identify Wilms’tumor 1-associating protein(WTAP)as an essential regulator in the postnatal development and maturation of BAT.BAT-specific knockout of Wtap(Wtap-BKO)severely impairs maturation of BAT in vivo by decreasing the expression of BAT-selective genes,leading to the whitening of interscapular BAT(iBAT).Single nucleus RNA-sequencing analysis shows the dynamic changes of cell heterogeneity in iBAT of Wtap-BKO mice.Adult mice with WTAP deficiency in BAT display hypothermic and succumb to acute cold challenge.Mechanistically,WTAP deficiency decreases m6A mRNA modification by reducing the protein stability of METTL3.BAT-specific overexpression of Mettl3 partially rescues the phenotypes observed in Wtap-BKO mice.These data demonstrate that WTAP/METTL3 plays an essential role in iBAT postnatal development and thermogenesis.展开更多
基金This study was supported by the National Natural Science Foundation of China grant(92057110,31971083,92057115,and 32071138)National Key R&D Program of China(2020YFA0803800,2019YFA0801900,2020YFA0803601,and 2018YFA0801300).
文摘Brown adipocyte maturation during postnatal development is essential for brown adipose tissue(BAT)to protect animals against cold.Impaired maturation of brown adipocytes leads to cold intolerance.However,the molecular mechanisms that determine the maturation of brown adipocytes during postnatal development are not fully understood.Here,we identify Wilms’tumor 1-associating protein(WTAP)as an essential regulator in the postnatal development and maturation of BAT.BAT-specific knockout of Wtap(Wtap-BKO)severely impairs maturation of BAT in vivo by decreasing the expression of BAT-selective genes,leading to the whitening of interscapular BAT(iBAT).Single nucleus RNA-sequencing analysis shows the dynamic changes of cell heterogeneity in iBAT of Wtap-BKO mice.Adult mice with WTAP deficiency in BAT display hypothermic and succumb to acute cold challenge.Mechanistically,WTAP deficiency decreases m6A mRNA modification by reducing the protein stability of METTL3.BAT-specific overexpression of Mettl3 partially rescues the phenotypes observed in Wtap-BKO mice.These data demonstrate that WTAP/METTL3 plays an essential role in iBAT postnatal development and thermogenesis.
