Skp2 controls adipocyte proliferation during the development of obesity
Skp2 controls adipocyte proliferation during the development of obesity
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DOI：
10.1074/jbc.m608144200
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发表时间：
2007-01-19
影响因子：
4.8
通讯作者：
Kasuga, Masato
中科院分区：
文献类型：
--
作者：
Sakai, Tamon;Sakaue, Hiroshi;Kasuga, Masato
在肥胖的发展过程中，脂肪组织质量的增加可能是由于细胞大小的增加，细胞数量的增加，或两者兼而有之。本研究表明，C57BL/6小鼠长期维持高脂饮食（约25周）可诱导脂肪细胞大小初始增加，随后白色脂肪组织中脂肪细胞数量增加。后一种效应被发现伴随着F-box蛋白Skp2基因的表达上调，以及细胞周期蛋白依赖性激酶抑制剂p27（Kip1）的下调，Kip1是SCFSkp2泛素连接酶的主要靶点。Skp2的消融保护小鼠免受高脂肪饮食或致命的黄刺鼠（Ay）突变诱导的肥胖发展，这种保护作用是由于抑制脂肪细胞数量的增加而不影响脂肪细胞肥大。Skp2消融引起的脂肪细胞数量减少也抑制了Ay突变小鼠肥胖相关胰岛素抵抗的发展，尽管Skp2缺陷小鼠的β细胞数量减少和胰岛素分泌水平降低导致葡萄糖耐受不良。因此，我们的观察结果表明，Skp2在肥胖的发展过程中控制脂肪细胞的增殖。
The increase in the mass of adipose tissue during the development of obesity can arise through an increase in cell size, an increase in cell number, or both. Here we show that long term maintenance of C57BL/6 mice on a high fat diet ( for similar to 25 weeks) induces an initial increase in adipocyte size followed by an increase in adipocyte number in white adipose tissue. The latter effect was found to be accompanied by up-regulation of expression of the gene for the F-box protein Skp2 as well as by down-regulation of the cyclin-dependent kinase inhibitor p27(Kip1), a principal target of the SCFSkp2 ubiquitin ligase, in white adipose tissue. Ablation of Skp2 protected mice from the development of obesity induced either by a high fat diet or by the lethal yellow agouti ( Ay) mutation, and this protective action was due to inhibition of the increase in adipocyte number without an effect on adipocyte hypertrophy. The reduction in the number of adipocyte caused by Skp2 ablation also inhibited the development of obesity-related insulin resistance in the Ay mutant mice, although the reduced number of beta cells and reduced level of insulin secretion in Skp2-deficient mice resulted in glucose intolerance. Our observations thus indicate that Skp2 controls adipocyte proliferation during the development of obesity.