Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism.
Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism.
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DOI：
10.1371/journal.pone.0021187
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Kahn CR
中科院分区：
文献类型：
--
作者：
Macotela Y;Emanuelli B;Bång AM;Espinoza DO;Boucher J;Beebe K;Gall W;Kahn CR
环境因素，如饮食中的常量营养素组成，可能对糖尿病和代谢综合征的风险产生深远的影响。在本研究中，我们证明了一个单一的，简单的饮食因素-亮氨酸-可以通过作用于多个组织和多个代谢水平来改变胰岛素抵抗。将小鼠置于正常或高脂肪饮食（HFD）。饮食亮氨酸增加一倍，除了饮用水。在主要的胰岛素敏感组织和血清中评估mRNA、蛋白质和完整代谢组学谱，并将其与葡萄糖稳态和胰岛素信号传导的变化相关联。HFD 8周后，小鼠出现肥胖、脂肪肝、脂肪组织炎症变化和IRS-1磷酸化水平的胰岛素抵抗，以及肝脏、肌肉、脂肪和血清中氨基酸代谢物、TCA循环中间产物、葡萄糖和胆固醇代谢物以及脂肪酸的代谢组学特征的改变。加倍的饮食亮氨酸逆转了许多代谢异常，并导致葡萄糖耐量和胰岛素信号的显着改善，而不改变食物摄入量或体重增加。饮食中亮氨酸的增加也与肝脏脂肪变性的减少和脂肪组织炎症的减少有关。尽管胰岛素刺激的p70 S6激酶磷酸化增加，但仍发生这些变化，表明mTOR活化增强，这是一种通常与胰岛素抵抗相关的现象。这些数据表明，单一环境/营养因素的适度变化可以改变多种代谢和信号传导途径，并通过在全身水平上作用于多种组织来改变HFD诱导的代谢综合征。这些数据还表明，增加饮食中的亮氨酸可以提供一个辅助肥胖相关的胰岛素抵抗的管理。
Environmental factors, such as the macronutrient composition of the diet, can have a profound impact on risk of diabetes and metabolic syndrome. In the present study we demonstrate how a single, simple dietary factor—leucine—can modify insulin resistance by acting on multiple tissues and at multiple levels of metabolism. Mice were placed on a normal or high fat diet (HFD). Dietary leucine was doubled by addition to the drinking water. mRNA, protein and complete metabolomic profiles were assessed in the major insulin sensitive tissues and serum, and correlated with changes in glucose homeostasis and insulin signaling. After 8 weeks on HFD, mice developed obesity, fatty liver, inflammatory changes in adipose tissue and insulin resistance at the level of IRS-1 phosphorylation, as well as alterations in metabolomic profile of amino acid metabolites, TCA cycle intermediates, glucose and cholesterol metabolites, and fatty acids in liver, muscle, fat and serum. Doubling dietary leucine reversed many of the metabolite abnormalities and caused a marked improvement in glucose tolerance and insulin signaling without altering food intake or weight gain. Increased dietary leucine was also associated with a decrease in hepatic steatosis and a decrease in inflammation in adipose tissue. These changes occurred despite an increase in insulin-stimulated phosphorylation of p70S6 kinase indicating enhanced activation of mTOR, a phenomenon normally associated with insulin resistance. These data indicate that modest changes in a single environmental/nutrient factor can modify multiple metabolic and signaling pathways and modify HFD induced metabolic syndrome by acting at a systemic level on multiple tissues. These data also suggest that increasing dietary leucine may provide an adjunct in the management of obesity-related insulin resistance.
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