Naa10p Inhibits Beige Adipocyte-Mediated Thermogenesis through N-α-acetylation of Pgc1α

Diet-induced obesity can be caused by impaired thermogenesis of beige adipocytes, the brown-like adipocytes in white adipose tissue (WAT). Promoting brown-like features in WAT has been an attractive therapeutic approach for obesity. However, the mechanism underlying beige adipocyte formation is largely unknown. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and overexpression of human Naa10p is linked to cancer development. Here, we report that both conventional and adipose-specific Naa10p deletions in mice result in increased energy expenditure, thermogenesis, and beige adipocyte differentiation. Mechanistically, Naa10p acetylates the N terminus of Pgc1α, which prevents Pgc1α from interacting with Pparγ to activate key genes, such as Ucp1, involved in beige adipocyte function. Consistently, fat tissues of obese human individuals show higher NAA10 expression. Thus, Naa10p-mediated N-terminal acetylation of Pgc1α downregulates thermogenic gene expression, making inhibition of Naa10p enzymatic activity a potential strategy for treating obesity. [Display omitted] •Adipose-specific Naa10p depletion prevents diet-induced obesity•Naa10p depletion increases Ucp1 expression and thermogenesis in beige adipocytes•N-terminal acetylation of Pgc1α by Naa10p suppresses thermogenic gene expression•Higher NAA10 expression correlates with human obesity Lee et al. reveal that Naa10p-mediated N-terminal acetylation of Pgc1α inhibits beige thermogenesis and promotes diet-induced obesity (DIO) in mice. Together with the fact that NAA10 expression positively correlates with human obesity, their results suggest that inhibiting the enzymatic activity of Naa10p in adipose tissues may suppress DIO.