Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia
Fra-2/AP-1 controls adipocyte differentiation and survival by regulating PPARγ and hypoxia
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DOI：
10.1038/cdd.2013.198
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发表时间：
2014-04-01
影响因子：
12.4
通讯作者：
Bozec, A.
中科院分区：
文献类型：
--
作者：
Luther, J.;Ubieta, K.;Bozec, A.
脂肪细胞数量是控制体重和代谢功能的关键因素。成年生物体中脂肪细胞数量的调节尚未完全了解，但被认为取决于细胞分化和凋亡的稳态。在本文中，我们表明，在体内脂肪细胞（Fra-2（Delta adip）小鼠）中，激活蛋白（AP-1）相关转录因子Fra-2的靶向缺失诱导了高转换表型，增加了脂肪细胞的分化和凋亡，导致体重和脂肪垫质量下降。重要的是，Fra-2（Delta adip）小鼠的脂肪细胞数量显著减少。在分子水平上，Fra-2直接与PPAR（gamma）2启动子结合并抑制PPAR（gamma）2表达。Fra-2的缺失导致增加的PPAR（gamma）2表达和脂肪细胞分化以及通过上调缺氧诱导因子（HIF）增加的脂肪细胞凋亡。这些发现表明Fra-2是控制脂肪细胞更新的重要检查点。因此，抑制Fra-2可能成为增加脂肪细胞周转和减少体内脂肪细胞数量和脂肪质量的有用策略。
Adipocyte cell number is a crucial factor for controlling of body weight and metabolic function. The regulation of adipocyte numbers in the adult organism is not fully understood but is considered to depend on the homeostasis of cell differentiation and apoptosis. Herein, we show that targeted deletion of the activator protein (AP-1)-related transcription factor Fra-2 in adipocytes in vivo (Fra-2(Delta adip) mice) induces a high-turnover phenotype with increased differentiation and apoptosis of adipocytes, leading to a decrease in body weight and fat pad mass. Importantly, adipocyte cell numbers were significantly reduced in Fra-2(Delta adip) mice. At the molecular level, Fra-2 directly binds to the PPAR(gamma)2 promoter and represses PPAR(gamma)2 expression. Deletion of Fra-2 leads to increased PPAR(gamma)2 expression and adipocyte differentiation as well as increased adipocyte apoptosis through upregulation of hypoxia-inducible factors (HIFs). These findings suggest that Fra-2 is an important checkpoint to control adipocyte turnover. Therefore, inhibition of Fra-2 may emerge as a useful strategy to increase adipocyte turnover and to reduce adipocyte numbers and fat mass in the body.