Importance of estrogen receptors in adipose tissue function

脂肪组织是一种主要的内分泌系统，参与能量平衡、脂类代谢、免疫反应和生殖等多种过程的调节。在哺乳动物中，脂肪组织隔间的大小反映了全身能量摄入和消耗之间的平衡。另一方面，繁殖是一个耗费能量的过程，对脂肪代谢有深远的影响，这个过程为动物提供了主要的能量来源。在哺乳动物中，雌激素促进、维持和控制体内脂肪和白色脂肪组织(WAT)的分布。雌激素的作用是通过核受体超家族的两个成员--雌激素受体(ER)a和？雌激素受体是一种配体诱导的转录因子，通过与其配体17？雌二醇的结合而被激活，雌二醇是主要的天然雌激素。ER结合主要发生在称为增强子的遥远的调控元件上，而不是在近端的启动子元件上。此外，ER在几个增强子位点的结合需要先驱因子的存在，这些因子决定了全局染色质结构和直接的细胞类型特定的招募和转录程序。所提出的研究计划以这样的假设为基础，即ER是Wat特异性基因表达计划的重要调节因子，并且它在哺乳动物的生殖系统和最重要的能量来源之间起到了桥梁作用。我们的具体目标是：1)确定和比较ERA和ER？调节在雌性WAT中建立响应雌激素的特定基因表达程序中的分子机制；2)检测环境异种雌激素对雌性WAT中ER信号和代谢功能的影响。为了实现这些目标，我们将应用整合转录(mRNA-SEQ)和基因组(CHIP-SEQ)方法在体内确定ER在WAT中建立特定转录程序中的作用。我们将使用Cre重组酶诱导ESR1(Era)或ESR2(ER？)基因Wat特异性缺失的小鼠Cre/lox模型。此外，我们将通过整合重叠的特定染色质标记层，尤其是组蛋白变异体H2A.Z来表征全基因组的ER结合位点，这将有助于揭示Wat中由ER控制的特定转录程序。由于已知环境中暴露于异种雌激素会影响其他组织，我们怀疑它也可能影响动物的主要能量来源WAT。因此，我们还建议评估一系列这些化合物对ER靶基因调控的分子效应，以及它们如何影响WAT的生物学功能。总之，我们提出了一项新颖而全面的研究，利用体内模型以及分子和基因组方法来确定雌激素或异种雌激素调节动物体内Wat代谢的机制。

Adipose tissue is a major endocrine system that participates in the regulation of a variety of processes, including energy homeostasis, lipid metabolism, immune responses and reproduction. In mammals, the size of the adipose tissue compartment reflects the balance between whole-body energy intake and expenditure. On the other side, reproduction is an energetically costly process with profound effects on fat metabolism, the process providing the major energy source in animals. In mammals, estrogens promote, maintain and control the distribution of the body fat and white adipose tissue (WAT). Estrogens functions are mediated via two members of the nuclear receptor superfamily, the estrogen receptors (ER) a and ß. ER are ligand-inducible transcription factors activated by the binding of their ligands, 17ß-estradiol (E2), the predominant naturally-occurring estrogenic hormone. ER binding takes place predominantly at distant regulatory elements called enhancers rather than at proximal promoter elements. Furthermore, ER binding at several enhancer sites requires the presence of pioneer factors that dictates global chromatin structure and direct cell type-specific recruitment and transcriptional programs. The proposed research program uses as a foundation the hypothesis that ER is an essential regulator of WAT-specific gene expression program and that it acts as a bridge between the reproductive system to the most important energy source in mammals. Our specific objectives are: 1) to determine and compare the molecular mechanisms of ERa and ERß regulation in the establishment of specific gene expression programs in female WAT in response to estrogens; 2) to examine the impact of environmental xenoestrogens on ER signalling in female WAT and metabolic functions. To achieve these objectives, we will apply an integrative transcriptomic (mRNA-seq) and genomic (ChIP-seq) approach to identify in vivo the role of ER in the establishment of specific transcriptional programs in WAT. We will use the mice Cre/lox models in which WAT-specific depletion of ESR1 (ERa) or ESR2 (ER ß) gene is induced by the Cre recombinase. Furthermore, we will characterize the genome-wide ER binding sites by integrating overlapping layers of specific chromatin marks, more particularly the histone variant H2A.Z, which will contribute to unveil the specific transcriptional program controlled by ER in WAT. Since environmental exposure to xenoestrogens is known to impinge on other tissues, we suspect that it could also affect WAT, the principal source of energy in animals. Therefore, we propose to also evaluate the molecular effects of a selection of these compounds on the regulation of ER target genes and how they affect the biological functions of WAT. Overall, we propose a novel and comprehensive investigation, using in vivo models and molecular and genomic approaches to determine the mechanisms by which estrogens or xenoestrogens regulates WAT metabolism in animals.