Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
J Clin Invest. 2012 Mar;122(3):1010-21. doi: 10.1172/JCI58431. Epub 2012 Feb 13.
The adipocyte-derived hormone leptin is a critical regulator of many physiological functions, ranging from satiety to immunity. Surprisingly, very little is known about the transcriptional pathways that regulate adipocyte-specific expression of leptin. Here, we report studies in which we pursued a strategy integrating BAC transgenic reporter mice, reporter assays, and chromatin state mapping to locate an adipocyte-specific cis-element upstream of the leptin (LEP) gene in human fat cells. Quantitative proteomics with affinity enrichment of protein-DNA complexes identified the transcription factor FOS-like antigen 2 (FOSL2) as binding specifically to the identified region, a result that was confirmed by ChIP. Knockdown of FOSL2 in human adipocytes decreased LEP expression, and overexpression of Fosl2 increased Lep expression in mouse adipocytes. Moreover, the elevated LEP expression observed in obesity correlated well with increased FOSL2 levels in mice and humans, and adipocyte-specific genetic deletion of Fosl2 in mice reduced Lep expression. Taken together, these data identify FOSL2 as a critical regulator of leptin expression in adipocytes.
脂肪细胞衍生的激素瘦素是许多生理功能的关键调节剂，从饱腹感到免疫力。令人惊讶的是，人们对调节脂肪细胞特异性瘦素表达的转录途径知之甚少。在这里，我们报告了一些研究，我们整合了 BAC 转基因报告小鼠、报告基因检测和染色质状态图谱，以定位人类脂肪细胞中瘦素（LEP）基因上游的脂肪细胞特异性顺式元件。通过亲和富集蛋白-DNA 复合物的定量蛋白质组学鉴定了转录因子 FOS 样抗原 2（FOSL2）作为特异性结合所鉴定区域的因子，这一结果得到了 ChIP 的证实。在人脂肪细胞中敲低 FOSL2 会降低 LEP 的表达，而在小鼠脂肪细胞中过表达 Fosl2 会增加 Lep 的表达。此外，肥胖症中观察到的 LEP 表达升高与小鼠和人类中 FOSL2 水平的升高密切相关，并且在小鼠中脂肪细胞特异性遗传敲除 Fosl2 会降低 Lep 的表达。综上所述，这些数据表明 FOSL2 是脂肪细胞中瘦素表达的关键调节因子。
