A high fat diet impairs stimulation of glucose transport in muscle - Functional evaluation of potential mechanisms
A high fat diet impairs stimulation of glucose transport in muscle - Functional evaluation of potential mechanisms
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DOI：
10.1074/jbc.273.40.26157
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发表时间：
1998-10-02
影响因子：
4.8
通讯作者：
Holloszy, JO
中科院分区：
文献类型：
--
作者：
Hansen, PA;Han, DH;Holloszy, JO
高脂肪饮食会导致骨骼肌葡萄糖转运对胰岛素和收缩产生抵抗。我们测试了这样的假设：脂肪喂养会导致质膜成分发生变化，从而干扰葡萄糖转运蛋白和/或胰岛素受体的功能，连续 8 周喂食高脂肪（50% 卡路里）的大鼠滑车上肌显示，胰岛素和收缩刺激的 3-O-甲基葡萄糖转运减少了 50%。在喂食 4 周脂肪的野生型小鼠的肌肉中，刺激后的葡萄糖转运活性也出现了类似的下降。相比之下，高脂肪饮食喂养的转基因小鼠肌肉过度表达 GLUT1，其高葡萄糖转运率并未下降，这为葡萄糖转运蛋白功能受损提供了证据。在喂食高脂肪饮食 8 周的大鼠肌肉中，胰岛素刺激系统 A 氨基酸转运、胰岛素受体 (IR) 酪氨酸激酶活性以及胰岛素刺激 IR 和 IRS-1 酪氨酸磷酸化均正常。然而，高脂肪饮食 30 周后，肌肉中胰岛素刺激的酪氨酸磷酸化显着减少。用 H-3 标记的 2-N-4-(1-azi-2,2,2-三氟乙基)-苯甲酰基-1,3-双-(D-甘露糖-4-基氧基)-2-丙胺光标记测量，胰岛素或肌肉收缩诱导的细胞表面 GLUT4 增加，与对照大鼠相比，8 周高脂喂养大鼠的肌肉中 GLUT4 减少了 26-36%。我们的研究结果提供了以下证据：(a) 8 周高脂肪喂养导致的肌肉葡萄糖转运受损并非由于质膜组成相关的葡萄糖转运蛋白或胰岛素受体功能减少所致，(b) 胰岛素受体信号传导缺陷是脂肪喂养引起的肌肉胰岛素抵抗的晚期事件，而不是主要原因，(c) GLUT4 向细胞表面易位受损在受刺激的葡萄糖转运减少中起主要作用。
A high fat diet causes resistance of skeletal muscle glucose transport to insulin and contractions. We tested the hypothesis that fat feeding causes a change in plasma membrane composition that interferes with functioning of glucose transporters and/or insulin receptors, Epitrochlearis muscles of rats fed a high (50% of calories) fat diet for 8 weeks showed similar to 50% decreases in insulin- and contraction-stimulated 3-O-methylglucose transport. Similar decreases in stimulated glucose transport activity occurred in muscles of wild-type mice with 4 weeks of fat feeding. In contrast, GLUT1 overexpressing muscles of transgenic mice fed a high fat diet showed no decreases in their high rates of glucose transport, providing evidence against impaired glucose transporter function. Insulin-stimulated system A amino acid transport, insulin receptor (IR) tyrosine kinase activity, and insulin-stimulated IR and IRS-1 tyrosine phosphorylation were all normal in muscles of rats fed the high fat diet for 8 weeks. However, after 30 weeks on the high fat diet, there was a significant reduction in insulin-stimulated tyrosine phosphorylation in muscle. The increases in GLUT4 at the cell surface induced by insulin or muscle contractions, measured with the H-3-labeled 2-N-4-(1-azi-2,2,2-trifluoroethyl) -benzoyl-1,3-bis-(D-mannose-4-yloxy)-2-propylamine photolabel, were 26-36% smaller in muscles of the 8-week high fat-fed rats as compared with control rats. Our findings provide evidence that (a) impairment of muscle glucose transport by 8 weeks of high fat feeding is not due to plasma membrane composition-related reductions in glucose transporter or insulin receptor function, (b) a defect in insulin receptor signaling is a late event, not a primary cause, of the muscle insulin resistance induced by fat feeding, and (c) impaired GLUT4 translocation to the cell surface plays a major role in the decrease in stimulated glucose transport.