Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi-shi, Gunma 371-8512, Japan.
Endocrinology. 2010 Jun;151(6):2556-66. doi: 10.1210/en.2009-1319. Epub 2010 Apr 7.
Silent information regulator (SIR)2 is an nicotinamide adenine dinucleotide dependent deacetylase implicated in the regulation of life span in species as diverse as yeast, worms, and flies. Mammalian Sirt1 is the most closely related homolog of the SIR2 gene. Pharmacological activators of Sirt1 have been reported to increase the life span and improve the health of mice fed a high-fat diet and to reverse diabetes in rodents. Sirt1 links the energy availability status with cellular metabolism in peripheral organs including liver, pancreas, muscle, and white adipose tissue. Insulin and leptin signaling regulate food intake by controlling the expression of orexigenic and anorexigenic neuropeptides in the arcuate nucleus of the hypothalamus via Forkhead box O (Foxo)-1 and signal transducer and activator of transcription-3. Sirt1 has been reported to improve insulin sensitivity in vitro, but the role of hypothalamic Sirt1 in regulating feeding has not been addressed. We found that hypothalamic Sirt1 protein levels increase on feeding, and this induction is abrogated in diet-induced obese mice and db/db mice. We also demonstrate for the first time that Sirt1 protein turnover is regulated by the proteasome and ubiquitination in a hypothalamic cell line and in vivo by feeding, and this regulation is not seen in a pituitary cell line AtT20. Forced expression of wild-type Sirt1 in the mediobasal hypothalamus by adenovirus microinjection suppressed Foxo1-induced hyperphagia, a model for central insulin resistance. Moreover, Sirt1 suppressed Foxo1-dependent expression of the orexigenic neuropeptide Agouti-related peptide in vitro. We propose that on feeding, Sirt1 protein is stabilized in the hypothalamus, leading to decreased Foxo1-dependent expression of orexigenic neuropeptide Agouti-related peptide and cessation of feeding.
沉默信息调节因子 (SIR)2 是一种烟酰胺腺嘌呤二核苷酸依赖性去乙酰化酶，参与调节从酵母、蠕虫和苍蝇等不同物种的寿命。哺乳动物 Sirt1 是 SIR2 基因最密切相关的同源物。据报道，Sirt1 的药理学激活剂可以延长高脂肪饮食喂养的小鼠的寿命并改善其健康状况，并在啮齿动物中逆转糖尿病。Sirt1 将能量可用性状态与外周器官（包括肝脏、胰腺、肌肉和白色脂肪组织）中的细胞代谢联系起来。胰岛素和瘦素信号通过 Forkhead box O (Foxo)-1 和信号转导和转录激活因子-3 控制弓状核中食欲肽和厌食肽的表达来调节食物摄入。据报道，Sirt1 可以提高体外胰岛素敏感性，但下丘脑 Sirt1 在调节摄食中的作用尚未得到解决。我们发现，进食时下丘脑 Sirt1 蛋白水平增加，而这种诱导在饮食诱导肥胖小鼠和 db/db 小鼠中被阻断。我们还首次证明，Sirt1 蛋白周转受蛋白酶体和泛素化调节，在下丘脑细胞系和体内通过进食进行调节，而在垂体细胞系 AtT20 中则没有这种调节。腺病毒微注射在中脑基底部强制表达野生型 Sirt1 可抑制 Foxo1 诱导的过度进食，这是中枢性胰岛素抵抗的模型。此外，Sirt1 抑制了 Foxo1 依赖性食欲肽 Agouti 相关肽的表达。我们提出，在进食时，Sirt1 蛋白在下丘脑稳定，导致 Foxo1 依赖性食欲肽 Agouti 相关肽表达减少并停止进食。
