Lagouge Marie, Argmann Carmen, Gerhart-Hines Zachary, Meziane Hamid, Lerin Carles, Daussin Frederic, Messadeq Nadia, Milne Jill, Lambert Philip, Elliott Peter, Geny Bernard, Laakso Markku, Puigserver Pere, Auwerx Johan
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS / INSERM / ULP, 67404 Illkirch, France.
Cell. 2006 Dec 15;127(6):1109-22. doi: 10.1016/j.cell.2006.11.013. Epub 2006 Nov 16.
Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.
线粒体氧化磷酸化和有氧能力的降低与寿命缩短有关。我们测试了已知能延长寿命的白藜芦醇（RSV）是否会影响线粒体功能和代谢稳态。用RSV处理小鼠显著提高了它们的有氧能力，这从它们增加的跑步时间和肌肉纤维中氧气消耗得到证明。RSV的作用与氧化磷酸化和线粒体生物发生相关基因的诱导有关，并且很大程度上是由RSV介导的PGC-1α乙酰化减少和PGC-1α活性增加所解释的。这一机制与RSV是已知的蛋白质脱乙酰酶SIRT1的激活剂以及RSV对SIRT1(-/-) 小鼠胚胎成纤维细胞无作用相一致。重要的是，RSV处理可保护小鼠免受饮食诱导的肥胖和胰岛素抵抗。RSV的这些药理作用，再加上芬兰人群中三个Sirt1单核苷酸多态性与能量稳态的关联，表明SIRT1是能量和代谢稳态的关键调节因子。
