Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Rd., Baton Rouge, LA 70808, USA.
Am J Physiol Endocrinol Metab. 2011 May;300(5):E877-85. doi: 10.1152/ajpendo.00626.2010. Epub 2011 Feb 22.
The transcription factor HIF-1α activity is increased in adipose tissue to contribute to chronic inflammation in obesity. However, its upstream and downstream events remain to be characterized in adipose tissue in obesity. We addressed this issue by investigating adipocyte HIF-1α activity in response to obesity-associated factors, such as adipogenesis, insulin, and hypoxia. In adipose tissue, both HIF-1α mRNA and protein were increased by obesity. The underlying mechanism was investigated in 3T3-L1 adipocytes. HIF-1α mRNA and protein were augmented by adipocyte differentiation. In differentiated adipocytes, insulin further enhanced HIF-1α in both levels. Hypoxia enhanced only HIF-1α protein, not mRNA. PI3K and mTOR activities are required for the HIF-1α expression. Function of HIF-1α protein was investigated in the regulation of VEGF gene transcription. ChIP assay shows that HIF-1α binds to the proximal hypoxia response element in the VEGF gene promoter, and its function is inhibited by a corepressor composed of HDAC3 and SMRT. These observations suggest that of the three obesity-associated factors, all of them are able to augment HIF-1α protein levels, but only two (adipogenesis and insulin) are able to enhance HIF-1α mRNA activity. Adipose tissue HIF-1α activity is influenced by multiple signals, including adipogenesis, insulin, and hypoxia in obesity. The transcriptional activity of HIF-1α is inhibited by HDAC3-SMRT corepressor in the VEGF gene promoter.
转录因子 HIF-1α 的活性在脂肪组织中增加，有助于肥胖症中的慢性炎症。然而，其在肥胖症脂肪组织中的上游和下游事件仍有待描述。我们通过研究肥胖相关因素（如脂肪生成、胰岛素和缺氧）对脂肪细胞 HIF-1α 活性的影响来解决这个问题。在脂肪组织中，肥胖会增加 HIF-1α 的 mRNA 和蛋白水平。我们在 3T3-L1 脂肪细胞中研究了这种机制。脂肪细胞分化会增加 HIF-1α 的 mRNA 和蛋白水平。在分化的脂肪细胞中，胰岛素在这两个水平上进一步增强了 HIF-1α。缺氧仅增强 HIF-1α 蛋白，而不增强其 mRNA。PI3K 和 mTOR 活性是 HIF-1α 表达所必需的。我们还研究了 HIF-1α 蛋白在 VEGF 基因转录调节中的作用。ChIP 实验表明，HIF-1α 结合到 VEGF 基因启动子的近端缺氧反应元件上，其功能受到由 HDAC3 和 SMRT 组成的核心抑制因子的抑制。这些观察结果表明，在三种肥胖相关因素中，所有因素都能够增加 HIF-1α 蛋白水平，但只有两种（脂肪生成和胰岛素）能够增强 HIF-1α mRNA 活性。肥胖症中的脂肪组织 HIF-1α 活性受到多种信号的影响，包括脂肪生成、胰岛素和缺氧。HIF-1α 的转录活性受到 VEGF 基因启动子上的 HDAC3-SMRT 核心抑制因子的抑制。
