Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes
Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes
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DOI：
10.1016/j.cell.2007.08.047
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发表时间：
2007-11-02
期刊：
影响因子：
64.5
通讯作者：
Penninger, Josef M.
中科院分区：
文献类型：
--
作者：
Pospisilik, J. Andrew;Knauf, Claude;Penninger, Josef M.
2 型糖尿病是由胰岛素抵抗的发展和随之而来的胰岛素分泌受损引起的。最近的研究将线粒体氧化磷酸化（OxPhos）的改变视为胰岛素抵抗的潜在遗传因素。然而，这些 OxPhos 变化的因果或代偿性质尚未得到证实。在这里，我们表明，小鼠肌肉和肝脏特异性 AIF 消融会引发一种与人类胰岛素抵抗非常相似的 OxPhos 缺乏模式，并且与目前的预期相反，导致葡萄糖耐量增加、脂肪量减少和胰岛素敏感性增加。这些结果在高脂肪喂养以及遗传嵌合体和普遍存在的 OxPhos 缺陷突变体中得以维持。重要的是，AIF 对葡萄糖代谢的影响是急性诱导且可逆的。这些发现证实，小鼠体内组织特异性以及整体的 OxPhos 缺陷可以抵消胰岛素抵抗、糖尿病和肥胖的发展。
Type-2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Recent studies place altered mitochondrial oxidative phosphorylation (OxPhos) as an underlying genetic element of insulin resistance. However, the causative or compensatory nature of these OxPhos changes has yet to be proven. Here, we show that muscle-and liver-specific AIF ablation in mice initiates a pattern of OxPhos deficiency closely mimicking that of human insulin resistance, and contrary to current expectations, results in increased glucose tolerance, reduced fat mass, and increased insulin sensitivity. These results are maintained upon high-fat feeding and in both genetic mosaic and ubiquitous OxPhos-deficient mutants. Importantly, the effects of AIF on glucose metabolism are acutely inducible and reversible. These findings establish that tissue-specific as well as global OxPhos defects in mice can counteract the development of insulin resistance, diabetes, and obesity.