Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice
Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice
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DOI：
10.1152/ajpendo.00198.2012
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发表时间：
2012-11-01
影响因子：
5.1
通讯作者：
Xie, Zhonglin
中科院分区：
文献类型：
--
作者：
Li, Hongliang;Xu, Mingjiang;Xie, Zhonglin
李宏，徐明，李杰，何春，谢志。补充亮氨酸可增加SIRT 1表达并预防高脂饮食诱导的肥胖小鼠的线粒体功能障碍和代谢紊乱Am J Physiol Endocrinol Metab 303：E1234-E1244，2012。首次发表于2012年9月11日; doi：10.1152/ajpendo.00198.2012.-在动物模型中，亮氨酸补充剂已被证明可以预防高脂饮食（HFD）诱导的肥胖、高血糖和血脂异常，但其潜在机制尚未完全了解。最近的研究表明，Sirtuin 1（SIRT 1）的激活是维持能量和代谢稳态的重要机制。因此，我们研究了SIRT 1在亮氨酸代谢预防肥胖和胰岛素抵抗中的作用。为了实现这一目标，雄性C57 BL/6 J小鼠被喂食正常饮食或HFD，补充有或没有亮氨酸。治疗2个月后，分析SIRT 1表达、胰岛素信号传导和能量代谢的变化。八周的HFD诱导小鼠肥胖、脂肪肝、线粒体功能障碍、高血糖和胰岛素抵抗。在HFD中添加亮氨酸与SIRT 1和NAMPT（烟酰胺磷酸核糖转移酶）的表达增加以及细胞内NAD（+）水平升高相关，这降低了过氧化物酶体增殖物激活受体-γ辅激活因子1 α（PGC 1 α）和叉头盒O 1（FoxO 1）的乙酰化。PGC 1 α的去乙酰化可能有助于控制线粒体生物合成和脂肪酸氧化的基因的上调，从而改善线粒体功能并预防HFD诱导的小鼠肥胖。此外，FoxO 1乙酰化的降低伴随着假激酶tribble 3（TRB 3）表达的降低，并减少了TRB 3和Akt之间的关联，从而增强了胰岛素敏感性并改善了葡萄糖代谢。最后，显性失活AMPK的转染阻止了HFD-Leu小鼠中SIRT 1信号的激活。这些数据表明，亮氨酸补充后SIRT 1表达增加可能导致PGC 1 α和FoxO 1乙酰化减少，这与HFD诱导的线粒体功能障碍、胰岛素抵抗和肥胖的减弱有关。
Li H, Xu M, Lee J, He C, Xie Z. Leucine supplementation increases SIRT1 expression and prevents mitochondrial dysfunction and metabolic disorders in high-fat diet-induced obese mice. Am J Physiol Endocrinol Metab 303: E1234-E1244, 2012. First published September 11, 2012; doi:10.1152/ajpendo.00198.2012.-Leucine supplementation has been shown to prevent high-fat diet (HFD)-induced obesity, hyperglycemia, and dyslipidemia in animal models, but the underlying mechanisms are not fully understood. Recent studies suggest that activation of Sirtuin 1 (SIRT1) is an important mechanism to maintain energy and metabolic homeostasis. We therefore examined the involvement of SIRT1 in leucine supplementation-prevented obesity and insulin resistance. To accomplish this goal, male C57BL/6J mice were fed normal diet or HFD, supplemented with or without leucine. After 2 mo of treatment, alterations in SIRT1 expression, insulin signaling, and energy metabolism were analyzed. Eight weeks of HFD induced obesity, fatty liver, mitochondrial dysfunction, hyperglycemia, and insulin resistance in mice. Addition of leucine to HFD correlated with increased expression of SIRT1 and NAMPT (nicotinamide phosphoribosyltransferase) as well as higher intracellular NAD(+) levels, which decreased acetylation of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1 alpha) and forkhead box O1 (FoxO1). The deacetylation of PGC1 alpha may contribute to upregulation of genes controlling mitochondrial biogenesis and fatty acid oxidation, thereby improving mitochondrial function and preventing HFD-induced obesity in mice. Moreover, decreased acetylation of FoxO1 was accompanied by decreased expression of pseudokinase tribble 3 (TRB3) and reduced the association between TRB3 and Akt, which enhanced insulin sensitivity and improved glucose metabolism. Finally, transfection of dominant negative AMPK prevented activation of SIRT1 signaling in HFD-Leu mice. These data suggest that increased expression of SIRT1 after leucine supplementation may lead to reduced acetylation of PGC1 alpha and FoxO1, which is associated with attenuation of HFD-induced mitochondrial dysfunction, insulin resistance, and obesity.