Differential gene regulation by PPARγ agonist and constitutively active PPARγ2
Differential gene regulation by PPARγ agonist and constitutively active PPARγ2
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DOI：
10.1210/me.16.5.1040
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发表时间：
2002-05-01
影响因子：
--
通讯作者：
Lazar, MA
中科院分区：
文献类型：
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作者：
Li, Y;Lazar, MA
pparγ是一个关键的脂肪生成决定因子。PPARgamma的配体如抗糖尿病的噻唑烷二酮（TZD）化合物是脂肪源性的，许多被TZD激活的脂肪细胞基因含有PPARgamma的结合位点。像其他核受体的配体一样，TZDs可以正向或负向调节基因。在这里，我们试图了解PPARgamma在脂肪形成中积极调节基因表达的重要性。强效病毒转录激活因子VP16与PPARgamma2 （VP16- ppargamma）的融合产生了一个转录因子，在缺乏配体的情况下，该转录因子可组成性地显著激活ppargama应答基因的转录。利用逆转录病毒载体在3T3-L1前脂肪细胞中强制表达VP16-PPARgamma，导致在缺乏标准分化培养基或任何外源性PPARgamma配体的情况下发生脂肪形成。基因芯片分析显示，VP16-PPARgamma诱导了许多与脂肪形成和脂肪细胞功能相关的基因。因此，PPARgamma直接上调基因表达足以促进脂肪形成。tzd诱导的脂肪形成上调了许多相同的基因，尽管一些基因受到不同的调控，包括抵抗素，其基因表达在tzd处理的inVP16-PPARgamma脂肪细胞中降低。这些结果表明，尽管异源活化结构域激活PPARgamma足以导致脂肪形成，但它并不等同于TZD处理。这一结论对了解TZDs在脂肪形成和胰岛素增敏中的生物学作用具有重要意义。
The PPARgamma is a key adipogenic determination factor. Ligands for PPARgamma such as antidiabetic thiazolidinedione (TZD) compounds are adipogenic, and many adipocyte genes that are activated by TZDs contain binding sites for PPARgamma. Like ligands for other nuclear receptors, TZDs can regulate genes positively or negatively. Here, we sought to understand the importance of positive regulation of gene expression by PPARgamma in adipogenesis. Fusion of the potent viral transcriptional activator VP16 to PPARgamma2 (VP16-PPARgamma) created a transcription factor that constitutively and dramatically activated transcription of PPARgamma-responsive genes in the absence of ligand. Forced expression of VP16-PPARgamma in 3T3-L1 preadipocytes using retroviral vectors led to adipogenesis in the absence of standard differentiating medium or any exogenous PPARgamma ligand. Gene microarray analysis revealed that VP16-PPARgamma induced many of the genes associated with adipogenesis and adipocyte function. Thus, direct up-regulation of gene expression by PPARgamma is sufficient for adipogenesis. TZD-induced adipogenesis up-regulated many of the same genes, although some were divergently regulated, including resistin, whose gene expression was reduced inVP16-PPARgamma adipocytes treated with TZDs. These results show that, although activation of PPARgamma by a heterologous activation domain is sufficient for adipogenesis, it is not equivalent to TZD treatment. This conclusion has important implications for understanding biological effects of the TZDs on adipogenesis and insulin sensitization.