Feige Jérôme N, Lagouge Marie, Canto Carles, Strehle Axelle, Houten Sander M, Milne Jill C, Lambert Philip D, Mataki Chikage, Elliott Peter J, Auwerx Johan
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, 67404, Illkirch, France.
Cell Metab. 2008 Nov;8(5):347-58. doi: 10.1016/j.cmet.2008.08.017.
The NAD(+)-dependent deacetylase SIRT1 controls metabolic processes in response to low nutrient availability. We report the metabolic phenotype of mice treated with SRT1720, a specific and potent synthetic activator of SIRT1 that is devoid of direct action on AMPK. SRT1720 administration robustly enhances endurance running performance and strongly protects from diet-induced obesity and insulin resistance by enhancing oxidative metabolism in skeletal muscle, liver, and brown adipose tissue. These metabolic effects of SRT1720 are mediated by the induction of a genetic network controlling fatty acid oxidation through a multifaceted mechanism that involves the direct deacetylation of PGC-1alpha, FOXO1, and p53 and the indirect stimulation of AMPK signaling through a global metabolic adaptation mimicking low energy levels. Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation.
烟酰胺腺嘌呤二核苷酸（NAD⁺）依赖性脱乙酰酶SIRT1可根据低营养可用性来控制代谢过程。我们报告了用SRT1720处理的小鼠的代谢表型，SRT1720是一种对SIRT1具有特异性且强效的合成激活剂，对AMPK无直接作用。给予SRT1720可显著提高耐力跑步表现，并通过增强骨骼肌、肝脏和棕色脂肪组织中的氧化代谢，有力地预防饮食诱导的肥胖和胰岛素抵抗。SRT1720的这些代谢作用是通过诱导一个控制脂肪酸氧化的基因网络介导的，该机制涉及多方面，包括对PGC-1α、FOXO1和p53的直接去乙酰化，以及通过模拟低能量水平的整体代谢适应对AMPK信号传导的间接刺激。结合我们之前关于白藜芦醇的研究，本研究进一步验证了SIRT1作为治疗代谢紊乱的靶点，并阐明了SIRT1激活治疗潜力的潜在机制。
