Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity
Augmenting muscle diacylglycerol and triacylglycerol content by blocking fatty acid oxidation does not impede insulin sensitivity
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DOI：
10.1073/pnas.1206868109
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发表时间：
2012-07-17
影响因子：
11.1
通讯作者：
Schrauwen, Patrick
中科院分区：
文献类型：
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作者：
Timmers, Silvie;Nabben, Miranda;Schrauwen, Patrick
低脂肪氧化能力与肌肉二酰甘油 (DAG) 积累和胰岛素抵抗有关。或者，低脂肪氧化率可能会刺激葡萄糖氧化，从而增强葡萄糖的处理。在这里，我们研究了乙基-2-[6-(4-氯苯氧基)己基]-环氧乙烷-2-羧酸酯（依托莫克西）诱导的脂肪氧化抑制是否会导致肌肉脂肪储存和胰岛素抵抗。对健康男性受试者的干预与对人类原代肌管的研究相结合。此外，在依托莫克西治疗的 C57bl6 小鼠中检查了肌肉 DAG 和三酰甘油 (TAG)、线粒体功能和胰岛素信号传导。在人类中，依托莫克西的给药增加了葡萄糖氧化，但以脂肪氧化为代价。这种效应伴随着肌膜处 GLUT4 丰度的增加和血浆葡萄糖水平的降低，表明葡萄糖稳态的改善。在小鼠中，注射依托莫克西会导致肌肉 TAG 和 DAG 的积累，同时改善胰岛素刺激的 GLUT4 易位。同样在人类肌管中，在肌细胞内脂质积累增加的情况下，依托莫克西也改善了胰岛素信号传导。小鼠和人类肌管中的这些胰岛素增敏作用伴随着 AMP 激活蛋白激酶 (AMPK) 磷酸化的增加。我们的结果表明，脂肪氧化减少导致肌肉 DAG 积累并不一定会导致胰岛素抵抗，因为脂肪氧化减少可能会激活 AMPK。
A lowfat oxidative capacity has been linked to muscle diacylglycerol (DAG) accumulation and insulin resistance. Alternatively, a low fat oxidation rate may stimulate glucose oxidation, thereby enhancing glucose disposal. Here, we investigated whether an ethyl-2-[6-(4-chlorophenoxy)hexyl]-oxirane-2-carboxylate (etomoxir)-induced inhibition of fat oxidation leads to muscle fat storage and insulin resistance. An intervention in healthy male subjects was combined with studies in human primary myotubes. Furthermore, muscle DAG and triacylglycerol (TAG), mitochondrial function, and insulin signaling were examined in etomoxir-treated C57bl6 mice. In humans, etomoxir administration increased glucose oxidation at the expense of fat oxidation. This effect was accompanied by an increased abundance of GLUT4 at the sarcolemma and a lowering of plasma glucose levels, indicative of improved glucose homeostasis. In mice, etomoxir injections resulted in accumulation of muscle TAG and DAG, yet improved insulin-stimulated GLUT4 translocation. Also in human myotubes, insulin signaling was improved by etomoxir, in the presence of increased intramyocellular lipid accumulation. These insulin-sensitizing effects in mice and human myotubes were accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK). Our results show that a reduction in fat oxidation leading to accumulation of muscle DAG does not necessarily lead to insulin resistance, as the reduction in fat oxidation may activate AMPK.