Laboratory of Molecular Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Development. 2011 Nov;138(21):4709-19. doi: 10.1242/dev.067710.
Obesity is characterized by an expansion of white adipose tissue mass that results from an increase in the size and the number of adipocytes. However, the mechanisms responsible for the formation of adipocytes during development and the molecular mechanisms regulating their increase and maintenance in adulthood are poorly understood. Here, we report the use of leptin-luciferase BAC transgenic mice to track white adipose tissue (WAT) development and guide the isolation and molecular characterization of adipocytes during development using DNA microarrays. These data reveal distinct transcriptional programs that are regulated during murine WAT development in vivo. By using a de novo cis-regulatory motif discovery tool (FIRE), we identify two early gene clusters whose promoters show significant enrichment for NRF2/ETS transcription factor binding sites. We further demonstrate that Ets transcription factors, but not Nrf2, are regulated during early adipogenesis and that Ets2 is essential for the normal progression of the adipocyte differentiation program in vitro. These data identify ETS2 as a functionally important transcription factor in adipogenesis and its possible role in regulating adipose tissue mass in adults can now be tested. Our approach also provides the basis for elucidating the function of other gene networks during WAT development in vivo. Finally these data confirm that although gene expression during adipogenesis in vitro recapitulates many of the patterns of gene expression in vivo, there are additional developmental transitions in pre and post-natal adipose tissue that are not evident in cell culture systems.
肥胖的特征是白色脂肪组织质量的扩张，这是由于脂肪细胞的大小和数量增加所致。然而，负责在发育过程中形成脂肪细胞的机制以及调节其在成年期增加和维持的分子机制还知之甚少。在这里，我们报告使用瘦素-荧光素酶 BAC 转基因小鼠来跟踪白色脂肪组织（WAT）的发育，并使用 DNA 微阵列指导在发育过程中脂肪细胞的分离和分子特征分析。这些数据揭示了在体内调节小鼠 WAT 发育过程中的独特转录程序。通过使用从头 cis-调控基序发现工具（FIRE），我们鉴定了两个早期基因簇，其启动子显示出对 NRF2/ETS 转录因子结合位点的显著富集。我们进一步证明，Ets 转录因子而非 Nrf2 在早期脂肪生成过程中受到调节，并且 Ets2 在体外脂肪细胞分化程序的正常进展中是必不可少的。这些数据表明 ETS2 是脂肪生成中的一个功能重要的转录因子，其在调节成年人脂肪组织质量中的可能作用现在可以进行测试。我们的方法还为阐明体内 WAT 发育过程中其他基因网络的功能提供了基础。最后，这些数据证实，尽管体外脂肪生成过程中的基因表达再现了体内许多基因表达模式，但在细胞培养系统中没有明显的产前和产后脂肪组织的其他发育转变。
