Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity
Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity
复制标题
神经沉默调节蛋白 6 (Sirt6) 消融会减弱体细胞生长并导致肥胖
DOI：
10.1073/pnas.1016306107
复制
发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Alt, Frederick W.
中科院分区：
文献类型：
--
作者：
Schwer, Bjoern;Schumacher, Bjoern;Alt, Frederick W.
在酵母中，Sir 2家族蛋白（sirtuins）通过组蛋白去乙酰化调节基因沉默、重组、DNA修复和衰老。7种哺乳动物sirtuins（Sirt 1-Sirt 7）中的大多数被认为是NAD（+）依赖的蛋白质脱乙酰酶，其靶点从转录调节因子到代谢酶。我们报告说，神经特异性缺失sirtuin 6（Sirt 6）在小鼠中导致出生后生长迟缓，由于生长激素（GH）和胰岛素样生长因子1（IGF 1）水平低的生长激素衰减。然而，与Sirt 6缺失小鼠不同，神经Sirt 6缺失小鼠不会死于低血糖。相反，随着时间的推移，神经Sirt 6缺失的小鼠达到正常大小并最终变得肥胖。在分子上，Sirt 6缺失导致组蛋白H3赖氨酸9（H3 K9）和赖氨酸56（H3 K56）的显著超乙酰化，这两种染色质标记涉及基因活性和染色质结构的调节，在包括参与神经内分泌调节的那些脑区域中。基于这些发现，我们提出Sirt 6作为躯体生长的中央调节器发挥作用，并通过调节神经染色质结构和基因活性在预防肥胖中发挥重要作用。
In yeast, Sir2 family proteins (sirtuins) regulate gene silencing, recombination, DNA repair, and aging via histone deacetylation. Most of the seven mammalian sirtuins (Sirt1-Sirt7) have been implicated as NAD(+)-dependent protein deacetylases with targets ranging from transcriptional regulators to metabolic enzymes. We report that neural-specific deletion of sirtuin 6 (Sirt6) in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels. However, unlike Sirt6 null mice, neural Sirt6-deleted mice do not die from hypoglycemia. Instead, over time, neural Sirt6-deleted mice reach normal size and ultimately become obese. Molecularly, Sirt6 deletion results in striking hyperacetylation of histone H3 lysine 9 (H3K9) and lysine 56 (H3K56), two chromatin marks implicated in the regulation of gene activity and chromatin structure, in various brain regions including those involved in neuroendocrine regulation. On the basis of these findings, we propose that Sirt6 functions as a central regulator of somatic growth and plays an important role in preventing obesity by modulating neural chromatin structure and gene activity.