Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans
Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans
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DOI：
10.1113/jphysiol.2006.109892
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发表时间：
2006-08-15
影响因子：
5.5
通讯作者：
Bennett, Andrew
中科院分区：
文献类型：
--
作者：
Tsintzas, Kostas;Jewell, Kirsty;Bennett, Andrew
这项研究调查了人类骨骼肌对饥饿和重新进食的生理适应的分子变化。 48 小时的饥饿使全身胰岛素敏感性降低 42%，并使关键碳水化合物 (CHO) 调节基因和蛋白质的表达发生显着变化：SREBP1c 和己糖激酶 II (HKII) 分别下调 2.5 倍和 5 倍，而丙酮酸脱氢酶激酶 4 (PDK4) 上调 4 倍。这些反应不依赖于 Akt 和 FOXO1 的磷酸化状态。另一方面，饥饿和随之而来的循环游离脂肪酸的增加并没有上调参与脂肪代谢的转录因子和基因的表达。重新饲喂富含 CHO 的饮食 24 小时完全逆转了人体骨骼肌中 PDK4、HKII 和 SREBP1c 表达的变化，但未能完全恢复全身胰岛素敏感性。因此，与啮齿动物不同，健康人类在饥饿期间，脂肪代谢的调节不需要转录水平的适应性反应，但需要基因表达的适应性变化来关闭氧化葡萄糖处理。对胰岛素信号传导途径中的关键蛋白质缺乏影响可能表明细胞内底物可用性/通量的变化可能是葡萄糖代谢的这些适应性变化的原因。这可能代表了以能量限制为特征的代谢条件下胰岛素抵抗发展的分子基础的一个重要方面。
This study investigated the molecular alterations underlying the physiological adaptations to starvation and refeeding in human skeletal muscle. Forty-eight hours' starvation reduced whole-body insulin sensitivity by 42% and produced marked changes in expression of key carbohydrate (CHO) regulatory genes and proteins: SREBP1c and hexokinase II (HKII) were downregulated 2.5- and 5-fold, respectively, whereas the pyruvate dexydrogenase kinase 4 (PDK4) was upregulated 4-fold. These responses were not dependent on the phosphorylation status of Akt and FOXO1. On the other hand, starvation and the concomitant increase in circulating free fatty acids did not upregulate the expression of transcription factors and genes involved in fat metabolism. Twenty-four hours' refeeding with a CHO-rich diet completely reversed the changes in PDK4, HKII and SREBP1c expression in human skeletal muscle but failed to fully restore whole-body insulin sensitivity. Thus, during starvation in healthy humans, unlike rodents, regulation of fat metabolism does not require an adaptive response at transcriptional level, but adaptive changes in gene expression are required to switch off oxidative glucose disposal. Lack of effect on key proteins in the insulin-signalling pathway may indicate that changes in intracellular substrate availability/flux may be responsible for these adaptive changes in glucose metabolism. This may represent an important aspect of the molecular basis of the development of insulin resistance in metabolic conditions characterized by energy restriction.