Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance
Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance
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DOI：
10.1038/nm1662
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发表时间：
2007-10-01
期刊：
影响因子：
82.9
通讯作者：
Yamada, Nobuhiro
中科院分区：
文献类型：
--
作者：
Matsuzaka, Takashi;Shimano, Hitoshi;Yamada, Nobuhiro
胰岛素抵抗通常与肥胖有关，并可导致2型糖尿病。迄今为止，大多数已知的改善胰岛素抵抗的方法必须先改善肥胖和脂肪肝。在这里，我们表明，这一规定是不是强制性的，胰岛素抵抗和高血糖症的改善肝脏脂肪酸组成的修改，即使在存在持续性肥胖和脂肪肝。产生Elov 16（编码催化棕榈酸酯转化为硬脂酸酯的延长酶的基因）缺陷的小鼠，并显示当喂食高脂肪饮食或与瘦素缺陷的ob/ ob小鼠交配时变得肥胖并发展成脂肪肝.然而，它们显示出对高胰岛素血症、高血糖症和高瘦素血症的显著保护。胰岛素抵抗的改善与肝脏胰岛素受体底物2的恢复和肝脏蛋白激酶C e活性的抑制有关，导致Akt磷酸化的恢复。总的来说，这些数据表明肝脏脂肪酸组成是胰岛素敏感性的新决定因素，其作用独立于细胞能量平衡和压力。这种延长酶的抑制可能是一种新的治疗方法，用于改善胰岛素抵抗，糖尿病和心血管风险，即使在存在持续的肥胖状态。
Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high- fat diet or mated to leptin- deficient ob/ ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate- 2 and suppression of hepatic protein kinase C e activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.