Amino acids require glucose to enhance, through phosphoinositide-dependent protein kinase 1, the insulin-activated protein kinase B cascade in insulin-resistant rat adipocytes
Amino acids require glucose to enhance, through phosphoinositide-dependent protein kinase 1, the insulin-activated protein kinase B cascade in insulin-resistant rat adipocytes
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DOI：
10.1007/s00125-006-0201-z
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发表时间：
2006-05-01
期刊：
影响因子：
8.2
通讯作者：
Van Obberghen, E
中科院分区：
文献类型：
--
作者：
Hinault, C;Mothe-Statney, I;Van Obberghen, E
目的/假设：众所周知，氨基酸与胰岛素协同激活雷帕霉素（mTOR）通路的哺乳动物靶标以调节细胞功能。尽管最近取得了重要进展，但对mTOR信号通路的了解甚少。我们之前的结果揭示了一种新的途径，其中当磷脂酰肌醇3-激酶（PI 3 K）受到抑制时，氨基酸允许新鲜分离的脂肪细胞中胰岛素诱导的蛋白激酶B（PK B）/mTOR途径的激活。本研究的目的是在分子水平上进一步研究这一途径。研究方法：我们研究了氨基酸对PKB磷酸化的影响，在不同的细胞模型或新鲜分离的脂肪细胞孵育在不同的缓冲液中，胰岛素和氨基酸的时间过程后，在药理学抑制剂的存在下。为了研究氨基酸在胰岛素作用中的潜在作用，评估了高脂饮食对肥胖大鼠脂肪细胞中葡萄糖转运的影响。结果如下：在脂肪组织外植体和新鲜分离的脂肪细胞中，在渥曼青霉素存在下，胰岛素诱导的PKB磷酸化被氨基酸恢复，但在培养的脂肪细胞或肝细胞中不恢复。此外，氨基酸需要葡萄糖的存在以磷酸化PKB并以PI 3 K非依赖性方式部分拯救葡萄糖转运。结果还表明，氨基酸通过磷酸肌醇依赖性蛋白激酶1起作用。此外，氨基酸被认为是改善胰岛素刺激的葡萄糖转运脂肪细胞从高脂肪喂养的大鼠。结论/解释：这项研究表明，氨基酸可以增强脂肪细胞胰岛素信号在病理生理情况下，如胰岛素抵抗与肥胖症。
Aims/hypothesis: Amino acids are well known to activate the mammalian target of the rapamycin (mTOR) pathway in synergy with insulin to regulate cell functions. Despite recent important advances, the mTOR signalling pathway is poorly understood. Our previous results revealed a new pathway in which amino acids permit insulin-induced activation of the protein kinase B (PKB)/mTOR pathway in freshly isolated adipocytes when phosphatidylinositol 3-kinase (PI3K) is inhibited. The aim of this study was to further investigate this pathway at the molecular level. Methods: We studied the effect of amino acids on PKB phosphorylation in different cellular models or in freshly isolated adipocytes incubated in different buffers, after a time course of insulin and amino acids and in the presence of pharmacological inhibitors. To investigate the potential role of amino acids in insulin action, the effect on glucose transport in obese rat adipocytes following a high-fat diet was assessed. Results: Insulin-induced PKB phosphorylation is restored by amino acids in the presence of wortmannin in adipose tissue explants and freshly isolated adipocytes, but not in cultured adipocytes or hepatocytes. Moreover, amino acids require the presence of glucose to phosphorylate PKB and to partially rescue glucose transport in a PI3K-independent manner. The results also suggest that the amino acids act through the phosphoinositide-dependent protein kinase 1. In addition, amino acids were seen to improve insulin-stimulated glucose transport in adipocytes from high-fat-fed rats. Conclusions/interpretation: This study suggests that amino acids could enhance adipocyte insulin signalling in pathophysiological situations such as insulin resistance associated with obesity.