Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature. 2010 Mar 25;464(7288):619-23. doi: 10.1038/nature08816. Epub 2010 Mar 3.
The worldwide epidemic of obesity has increased the urgency to develop a deeper understanding of physiological systems related to energy balance and energy storage, including the mechanisms controlling the development of fat cells (adipocytes). The differentiation of committed preadipocytes to adipocytes is controlled by PPARgamma and several other transcription factors, but the molecular basis for preadipocyte determination is not understood. Using a new method for the quantitative analysis of transcriptional components, we identified the zinc-finger protein Zfp423 as a factor enriched in preadipose versus non-preadipose fibroblasts. Ectopic expression of Zfp423 in non-adipogenic NIH 3T3 fibroblasts robustly activates expression of Pparg in undifferentiated cells and permits cells to undergo adipocyte differentiation under permissive conditions. Short hairpin RNA (shRNA)-mediated reduction of Zfp423 expression in 3T3-L1 cells blunts preadipocyte Pparg expression and diminishes the ability of these cells to differentiate. Furthermore, both brown and white adipocyte differentiation is markedly impaired in Zfp423-deficient mouse embryos. Zfp423 regulates Pparg expression, in part, through amplification of the BMP signalling pathway, an effect dependent on the SMAD-binding capacity of Zfp423. This study identifies Zfp423 as a transcriptional regulator of preadipocyte determination.
肥胖症在全球范围内的流行，使得深入了解与能量平衡和能量储存相关的生理系统变得更加紧迫，包括控制脂肪细胞（脂肪细胞）发育的机制。已分化的前脂肪细胞向脂肪细胞的分化受 PPARγ和其他几个转录因子控制，但前脂肪细胞决定的分子基础尚不清楚。我们使用一种新的转录成分定量分析方法，鉴定出锌指蛋白 Zfp423 是前脂肪细胞与非前脂肪成纤维细胞中丰富的因子。Zfp423 在非脂肪生成的 NIH 3T3 成纤维细胞中的异位表达，可在未分化细胞中强烈激活 Pparg 的表达，并允许细胞在允许的条件下进行脂肪细胞分化。3T3-L1 细胞中短发夹 RNA (shRNA)介导的 Zfp423 表达降低，削弱了前脂肪细胞 Pparg 的表达，并降低了这些细胞分化的能力。此外，Zfp423 缺陷型小鼠胚胎中的棕色和白色脂肪细胞分化均明显受损。Zfp423 通过放大 BMP 信号通路来调节 Pparg 的表达，这种作用依赖于 Zfp423 与 SMAD 的结合能力。本研究将 Zfp423 鉴定为前脂肪细胞决定的转录调节剂。
