SirT1 gain of function increases energy efficiency and prevents diabetes in mice.
SirT1 gain of function increases energy efficiency and prevents diabetes in mice.
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DOI：
10.1016/j.cmet.2008.08.014
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发表时间：
2008-10
期刊：
影响因子：
29
通讯作者：
Accili D
中科院分区：
文献类型：
--
作者：
Banks AS;Kon N;Knight C;Matsumoto M;Gutiérrez-Juárez R;Rossetti L;Gu W;Accili D
在酵母、蠕虫和苍蝇中，编码Sirtuin Sir2的基因的额外拷贝增加了代谢效率，就像服用多酚类物质如白藜芦醇一样，认为通过Sirtuins起作用。但是，Sirtuin功能获得导致哺乳动物代谢效率增加的证据有限。我们产生的转基因小鼠与中度过度表达的SirT1，旨在模仿Sirtuin获得的功能，改善代谢秀丽隐杆线虫。这些小鼠表现出正常的胰岛素敏感性，但食物摄入和运动活动减少，导致能量消耗减少。然而，在胰岛素抵抗和糖尿病的各种模型中，SirT1转基因显示出改善的葡萄糖耐量，这是由于肝葡萄糖产生减少和脂联素水平增加，而体重或组成没有变化。我们的结论是，SirT1功能获得性启动机体对胰岛素抵抗的代谢适应，增加肝脏胰岛素敏感性，降低全身能量需求。这些发现对基于Sirtuin的人类疗法具有重要意义。
In yeast, worms and flies, an extra copy of the gene encoding the Sirtuin Sir2 increases metabolic efficiency, as does administration of polyphenols like resveratrol, thought to act through Sirtuins. But evidence that Sirtuin gain-of-function results in increased metabolic efficiency in mammals is limited. We generated transgenic mice with moderate overexpression of SirT1, designed to mimic the Sirtuin gain-of-function that improves metabolism in C.elegans. These mice exhibit normal insulin sensitivity, but decreased food intake and locomotor activity, resulting in decreased energy expenditure. However, in various models of insulin resistance and diabetes, SirT1 transgenics display improved glucose tolerance due to decreased hepatic glucose production and increased adiponectin levels, without changes in body weight or composition. We conclude that SirT1 gain-of-function primes the organism for metabolic adaptation to insulin resistance, increasing hepatic insulin sensitivity and decreasing whole-body energy requirements. These findings have important implications for Sirtuin-based therapies in humans.
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