Impact of tamoxifen on adipocyte lineage tracing: Inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase.
Impact of tamoxifen on adipocyte lineage tracing: Inducer of adipogenesis and prolonged nuclear translocation of Cre recombinase.
复制标题
他莫昔芬对脂肪细胞谱系追踪的影响：脂肪生成的诱导剂和CRE重组酶的长时间核易位。
DOI：
10.1016/j.molmet.2015.08.004
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发表时间：
2015-11
影响因子：
8.1
通讯作者：
Scherer PE
中科院分区：
文献类型：
--
作者：
Ye R;Wang QA;Tao C;Vishvanath L;Shao M;McDonald JG;Gupta RK;Scherer PE
选择性雌激素受体调节剂他莫昔芬与Cre-ERT 2融合蛋白的组合已成为诱导遗传重组的主流方法之一，并在谱系追踪研究中得到广泛应用。在这里，我们报告说，他莫昔芬暴露在广泛使用的浓度仍然可以检测到的质谱分析脂肪组织后，洗脱期为10天。令人惊讶的是，其维持Cre-ERT 2蛋白核转位的能力在2个月的洗脱期后仍保持不变。他莫昔芬治疗急性导致短暂的脂肪萎缩，随后是重新形成脂肪，重建原始脂肪质量。此外，当他莫昔芬治疗与脂肪细胞特异性功能丧失突变体（如脂肪细胞特异性PPARγ敲除）联合使用时，我们发现脂肪细胞的“合成致死”表型。当采用替代诱导方法时，观察到的程度较低。这些发现突出了他莫昔芬诱导的脂肪形成的潜力，以及在谱系追踪研究中使用他莫昔芬的相关缺点，解释了不同系统的谱系追踪结果与基因靶向的时间控制的差异。他莫昔芬治疗诱导小鼠的急性脂肪损失和从头脂肪生成。PPARγ基因敲除可加重他莫昔芬诱导的脂肪萎缩他莫昔芬驱动的Cre-ERT 2核转位在脂肪中持续超过两个月。用mTmG报告基因证实了冷暴露后的从头脂肪形成。
The selective estrogen receptor modulator tamoxifen, in combination with the Cre-ERT2 fusion protein, has been one of the mainstream methods to induce genetic recombination and has found widespread application in lineage tracing studies. Here, we report that tamoxifen exposure at widely used concentrations remains detectable by mass-spectrometric analysis in adipose tissue after a washout period of 10 days. Surprisingly, its ability to maintain nuclear translocation of the Cre-ERT2 protein is preserved beyond 2 months of washout. Tamoxifen treatment acutely leads to transient lipoatrophy, followed by de novo adipogenesis that reconstitutes the original fat mass. In addition, we find a “synthetically lethal” phenotype for adipocytes when tamoxifen treatment is combined with adipocyte-specific loss-of-function mutants, such as an adipocyte-specific PPARγ knockout. This is observed to a lesser extent when alternative inducible approaches are employed. These findings highlight the potential for tamoxifen-induced adipogenesis, and the associated drawbacks of the use of tamoxifen in lineage tracing studies, explaining the discrepancy in lineage tracing results from different systems with temporal control of gene targeting. Tamoxifen treatment induces acute fat loss and de novo adipogenesis in mice. PPARγ knockout exacerbates tamoxifen-induced lipoatrophy. Tamoxifen-driven Cre-ERT2 nuclear translocation lasts beyond two months in adipose. De novo adipogenesis upon cold exposure is confirmed with the mTmG reporter.