Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC.
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, ROC; Institute of Molecular Medicine, National Taiwan University, Taipei 100, Taiwan, ROC.
Mol Cell. 2019 Nov 7;76(3):500-515.e8. doi: 10.1016/j.molcel.2019.07.026. Epub 2019 Aug 15.
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.
饮食诱导的肥胖可能是由于米色脂肪细胞（白色脂肪组织中的棕色样脂肪细胞）的体温生成受损引起的。促进 WAT 中棕色样特征的形成一直是肥胖治疗的一种有吸引力的方法。然而，米色脂肪细胞形成的机制在很大程度上尚不清楚。N-α-乙酰转移酶 10 蛋白（Naa10p）催化新生蛋白的 N-α-乙酰化，人 Naa10p 的过表达与癌症的发展有关。在这里，我们报告说，在小鼠中，常规和脂肪特异性 Naa10p 的缺失都导致能量消耗、体温生成和米色脂肪细胞分化增加。从机制上讲，Naa10p 乙酰化 Pgc1α 的 N 端，从而阻止 Pgc1α 与 Pparγ 相互作用，激活关键基因，如 Ucp1，参与米色脂肪细胞的功能。一致地，肥胖个体的脂肪组织显示出更高的 NAA10 表达。因此，Naa10p 介导的 Pgc1α N 端乙酰化下调了产热基因的表达，使抑制 Naa10p 的酶活性成为治疗肥胖的一种潜在策略。
