Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance
Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance
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DOI：
10.1074/jbc.m801824200
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发表时间：
2008-07-25
影响因子：
4.8
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Inoue, Noriyuki;Yahagi, Naoya;Shimano, Hitoshi
脂肪细胞增生和肥大是肥胖发生发展过程中脂肪细胞分化的决定性因素。p21（WAF 1/CIP 1）是一种细胞周期蛋白依赖性激酶抑制剂，在脂肪细胞分化过程中被诱导;然而，其对这一过程的确切贡献尚不清楚。使用体外和体内系统，我们表明，p21是至关重要的维持脂肪细胞肥大和肥胖诱导的胰岛素抵抗。3 T3-L1成纤维细胞通过RNA介导的干扰敲低或来自p21（-/-）小鼠的胚胎成纤维细胞中p21的缺失损害脂肪细胞分化，导致较小的脂肪细胞。尽管正常饮食的脂肪组织质量正常，但喂食高能量饮食的p21（-/-）小鼠脂肪组织质量和脂肪细胞大小减少，胰岛素敏感性显著改善。在饮食诱导的肥胖小鼠的增大的附睾脂肪中，以及在完全分化的3 T3-L1脂肪细胞中，p21的敲低通过激活p53而引起强烈的细胞凋亡。因此，p21参与脂肪细胞分化和保护肥大脂肪细胞免于凋亡。通过这两种机制，p21在高脂肪饮食喂养期间促进脂肪组织扩张，导致下游病理生理学后果增加，如胰岛素抵抗。
Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of obesity. p21(WAF1/CIP1), a cyclin-dependent kinase inhibitor, is induced during adipocyte differentiation; however, its precise contribution to this process is unknown. Using both in vitro and in vivo systems, we show that p21 is crucial for maintaining adipocyte hypertrophy and obesity-induced insulin resistance. The absence of p21 in 3T3-L1 fibroblasts by RNA-mediated interference knockdown or in embryonic fibroblasts from p21(-/-) mice impaired adipocyte differentiation, resulting in smaller adipocytes. Despite normal adipose tissue mass on a normal diet, p21(-/-) mice fed high energy diets had reduced adipose tissue mass and adipocyte size accompanied by a marked improvement in insulin sensitivity. Knockdown of p21 in enlarged epididymal fat of diet-induced obese mice and also in fully differentiated 3T3-L1 adipocytes caused vigorous apoptosis by activating p53. Thus, p21 is involved in both adipocyte differentiation and in protecting hypertrophied adipocytes against apoptosis. Via both of these mechanisms, p21 promotes adipose tissue expansion during high fat diet feeding, leading to increased downstream pathophysiological consequences such as insulin resistance.