Sir2 mutants versus Controls at 2 weeks of age

Although SIRT1 plays a central role in maintaining metabolic homeostasis, the molecular mechanisms remain unclear. Here we show that loss of the Drosophila SIRT1 homolog sir2 leads to the progressive onset of diabetic phenotypes, similar to studies of SIRT1 in mice. Sir2 function is both necessary and sufficient in the fat body to maintain peripheral insulin sensitivity. This activity is mediated by the Drosophila HNF4 nuclear receptor, which is deacetylated and stabilized through protein interactions with Sir2. This study demonstrates that the key metabolic activities of SIRT1 have been conserved through evolution and establishes HNF4 as a critical downstream target. 4 sir2 mutant, 4 control samples, independent biological replicates

尽管沉默信息调节因子1（SIRT1）在维持代谢稳态中发挥核心作用，但其具体分子机制仍未明确。本研究发现，果蝇中SIRT1同源基因sir2的缺失会导致糖尿病表型的渐进性发作，这与小鼠体内SIRT1的相关研究结果一致。Sir2在脂肪体中的功能对于维持外周胰岛素敏感性既是必需的，也是充分的。该调控活性由果蝇肝细胞核因子4（HNF4）核受体介导，Sir2通过与HNF4的蛋白质相互作用使其发生去乙酰化并维持其稳定性。本研究证实了SIRT1的关键代谢调控功能在进化过程中具有保守性，并确立了HNF4作为其关键下游靶标的地位。本研究包含4份sir2突变体样本与4份对照样本，均为独立生物学重复。