Downregulated expression of the secreted glycoprotein follistatin-like 1 (Fstl1) is a robust hallmark of preadipocyte to adipocyte conversion.
Downregulated expression of the secreted glycoprotein follistatin-like 1 (Fstl1) is a robust hallmark of preadipocyte to adipocyte conversion.
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DOI：
10.1016/j.mod.2009.12.003
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发表时间：
2010-04
影响因子：
2.6
通讯作者：
Smas, Cynthia M.
中科院分区：
文献类型：
--
作者：
Wu, Yu;Zhou, Shengli;Smas, Cynthia M.
肥胖是美国的公共健康危机。靶向前脂肪细胞向脂肪细胞转化可能是调节脂肪质量的有效途径。通过鉴别筛选，我们发现Fstl1是一种分泌糖蛋白，在免疫调节、细胞生长、心脏保护和血管化中发挥作用，是一种“前脂肪因子”。Fstl1在3T3-L1前脂肪细胞中高表达，并在其向脂肪细胞分化的早期显著下调。小鼠组织的Northern blot分析显示，白色脂肪组织（WAT）、肺和心脏是Fstl1转录物表达的主要位点。在WAT中，Fstl1转录物仅限于含有前脂肪细胞的基质血管细胞群。多种脂肪形成模型的时间过程研究表明，Fstl1的下调是白色和棕色脂肪细胞转化的标志。通过Western blot，我们发现3T3-L1前脂肪细胞的培养基中含有高水平的Fstl1蛋白，该蛋白在脂肪细胞转化过程中迅速下降。此外，我们观察到前脂肪细胞表型与Fstl1表达之间的相关性，tnf α介导的3T3-L1脂肪细胞去分化伴随着Fstl1转录物和蛋白的重新表达。用18种激素和其他药物治疗3T3-L1前脂肪细胞发现，去甲基化剂5-aza-cytidine可使Fstl1转录物和蛋白水平降低约90%。此外，在另外10个前脂肪细胞表达基因中，我们发现Pref-1、Col1A1、Sca-1/Ly6a、Lox和Thbs2也被5-aza胞苷下调。利用含有791或3922 bp Fstl1 5 '侧区域的荧光素酶报告结构，我们确定了kruppel样因子15的负转录调控。总之，我们的数据表明Fstl1表达的下调可能是前脂肪细胞向脂肪细胞转化的一个重要特征。
Obesity is a public health crisis in The United States. Targeting preadipocyte to adipocyte conversion may be an effective approach to regulate adipose mass. Using differential screening we identified Fstl1, a secreted glycoprotein with roles in immunomodulation, cell growth, cardioprotection, and vascularization, as a “preadipokine”. Fstl1 is highly expressed in 3T3-L1 preadipocytes and dramatically downregulated early in their differentiation to adipocytes. Northern blot analysis of murine tissues reveals white adipose tissue (WAT), lung and heart as primary sites of Fstl1 transcript expression. In WAT, Fstl1 transcript is restricted to the preadipocyte-containing stromal-vascular cell population. Time course studies in multiple adipogenesis models reveal downregulation of Fstl1 is a hallmark of white and brown adipocyte conversion. By Western blot, we show culture media of 3T3-L1 preadipocytes contains high levels of Fstl1 protein that rapidly decline in adipocyte conversion. Moreover, we observe a correlation between preadipocyte phenotype and Fstl1 expression in that TNFα-mediated dedifferentiation of 3T3-L1 adipocytes is accompanied by re-expression of Fstl1 transcript and protein. Treatment of 3T3-L1 preadipocytes with a panel of 18 hormones and other agents revealed the demethylating agent 5-aza-cytidine decreases Fstl1 transcript and protein levels by ~90%. Furthermore, of 10 additional preadipocyte-expressed genes analyzed we find Pref-1, Col1A1, Sca-1/Ly6a, Lox and Thbs2, are also downregulated by 5-aza-cytidine. Using luciferase reporter constructs containing 791 or 3922 bp of the Fstl1 5’-flanking region, we determine negative transcriptional regulation by Kruppel-like factor 15. Together, our data suggest downregulation of Fstl1 expression may be an important feature of preadipocyte to adipocyte conversion.
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