Nillni Eduardo A
The Warren Alpert Medical School, Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
Mol Cell Endocrinol. 2016 Dec 15;438:77-88. doi: 10.1016/j.mce.2016.09.002. Epub 2016 Sep 8.
The last decade had witnessed a tremendous progress in our understanding of the causes of metabolic diseases including obesity. Among the contributing factors regulating energy balance are nutrient sensors such as sirtuins. Sirtuin1 (Sirt1), a NAD + - dependent deacetylase is affected by diet, environmental stress, and also plays a critical role in metabolic health by deacetylating proteins in many tissues, including liver, muscle, adipose tissue, heart, endothelium, and in the complexity of the hypothalamus. Because of its dependence on NAD+, Sirt1 also functions as a nutrient/redox sensor, and new novel data show a function of this enzyme in the maturation of hypothalamic peptide hormones controlling energy balance either through regulation of specific nuclear transcription factors or by regulating specific pro-hormone convertases (PCs) involved in the post-translational processing of pro-hormones. The post-translational processing mechanism of pro-hormones is critical in the pathogenesis of obesity as recently shown that metabolic and physiological triggers affect the biosynthesis and processing of many peptides hormones. Specific regulation of pro-hormone processing is likely another key step where final amounts of bioactive peptides can be tightly regulated. Different factors stimulate or inhibit pro-hormones biosynthesis in concert with an increase in the PCs involved in the maturation of bioactive hormones. Adding more complexity to the system, the new studies describe here suggest that Sirt1 could also regulate the fate of peptide hormone biosynthesis. The present review summarizes the recent progress in hypothalamic SIRT1 research with a particular emphasis on the tissue-specific control of neuropeptide hormone maturation. The series of studies done in mouse and rat models strongly advocate for the first time that a deacetylating enzyme could be a regulator in the maturation of peptide hormones and their processing enzymes. These discoveries are the culmination of the first in-depth understanding of the metabolic role of Sirt1 in the brain. It suggests that Sirt1 behaves differently in the brain than in organs such as the liver and pancreas, where the enzyme has been more commonly studied.
过去十年见证了我们在理解包括肥胖症在内的代谢性疾病病因方面取得的巨大进展。在调节能量平衡的诸多因素中，营养传感器如沉默调节蛋白发挥着作用。沉默调节蛋白1（Sirt1）是一种依赖烟酰胺腺嘌呤二核苷酸（NAD +）的脱乙酰酶，受饮食、环境压力影响，还通过使包括肝脏、肌肉、脂肪组织、心脏、内皮以及下丘脑复合体等多种组织中的蛋白质脱乙酰化，在代谢健康中发挥关键作用。由于其对NAD +的依赖性，Sirt1还充当营养/氧化还原传感器，新的研究数据表明，该酶通过调节特定的核转录因子或参与激素前体翻译后加工的特定激素原转化酶（PCs），在下丘脑肽类激素成熟过程中发挥作用，这些肽类激素控制着能量平衡。激素前体的翻译后加工机制在肥胖症发病机制中至关重要，因为最近研究表明，代谢和生理触发因素会影响许多肽类激素的生物合成和加工过程。激素前体加工的特异性调节可能是另一个关键步骤，通过这一步骤可以严格调控生物活性肽的最终含量。不同因素协同刺激或抑制激素前体的生物合成，同时参与生物活性激素成熟的PCs数量增加。本系统的复杂性还体现在，新研究表明Sirt1也可能调节肽类激素生物合成的命运。本综述总结了下丘脑SIRT1研究的最新进展，特别强调了神经肽激素成熟的组织特异性控制。在小鼠和大鼠模型中进行的一系列研究首次有力地表明，一种脱乙酰酶可能是肽类激素及其加工酶成熟过程中的调节因子。这些发现是首次深入了解Sirt1在大脑中代谢作用的成果。这表明Sirt1在大脑中的行为与在肝脏和胰腺等器官中不同，而在这些器官中对该酶的研究更为普遍。
