Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis
Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis
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DOI：
10.1073/pnas.0906048106
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发表时间：
2009-11-24
影响因子：
11.1
通讯作者：
Jin, Shengkan
中科院分区：
文献类型：
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作者：
Zhang, Yong;Goldman, Scott;Jin, Shengkan
白色脂肪细胞有一个独特的结构，几乎整个细胞体积都被一个大的脂滴占据。然而，产生这种结构所必需的细胞质重塑所涉及的分子和细胞过程还不清楚。自噬是导致溶酶体降解的膜运输过程。在这里，我们研究了一个重要的自噬基因，自噬相关基因7(ATG7)的缺失对脂肪生成的影响。建立了脂肪组织中ATG7靶向缺失的小鼠模型。突变的小鼠很苗条，只含有野生型小鼠白色脂肪组织(WAT)质量的20%。有趣的是，大约50%的突变白色脂肪细胞是多房性的。突变的白色脂肪细胞体积较小，胞浆体积较大，线粒体较多。这些细胞表现出脂肪酸代谢的改变，β-氧化速率增加，激素诱导的脂肪分解速率降低。一贯地，突变小鼠的血浆脂肪酸浓度较低，而且胰岛素刺激后脂肪酸水平下降的速度更快。这些突变的小鼠表现出更高的胰岛素敏感性。突变小鼠的血浆瘦素浓度显著降低，但脂联素浓度没有降低，甘油三酯和胆固醇浓度显著降低，基础体力活动水平更高。引人注目的是，这些突变小鼠对高脂饮食诱导的肥胖具有抵抗力。综上所述，我们的结果表明，ATG7以及由此推断的自噬在正常的脂肪生成中发挥着重要作用，通过破坏ATG7基因来抑制自噬具有独特的抗肥胖和胰岛素增敏作用。
White adipocytes have a unique structure in which nearly the entire cell volume is occupied by one large lipid droplet. However, the molecular and cellular processes involved in the cytoplasmic remodeling necessary to create this structure are poorly defined. Autophagy is a membrane trafficking process leading to lysosomal degradation. Here, we investigated the effect of the deletion of an essential autophagy gene, autophagy-related gene 7 (atg7), on adipogenesis. A mouse model with a targeted deletion of atg7 in adipose tissue was generated. The mutant mice were slim and contained only 20% of the mass of white adipose tissue (WAT) found in wild-type mice. Interestingly, approximate to 50% of the mutant white adipocytes were multilocular. The mutant white adipocytes were smaller with a larger volume of cytosol and contained more mitochondria. These cells exhibited altered fatty acid metabolism with increased rates of beta-oxidation and reduced rates of hormone-induced lipolysis. Consistently, the mutant mice had lower fed plasma concentrations of fatty acids and the levels decreased at faster rates upon insulin stimuli. These mutant mice exhibited increased insulin sensitivity. The mutant mice also exhibited markedly decreased plasma concentrations of leptin but not adiponectin, lower plasma concentrations of triglyceride and cholesterol, and they had higher levels of basal physical activity. Strikingly, these mutant mice were resistant to high-fat-diet-induced obesity. Taken together, our results indicate that atg7, and by inference autophagy, plays an important role in normal adipogenesis and that inhibition of autophagy by disrupting the atg7 gene has a unique anti-obesity and insulin sensitization effect.