Importance of estrogen receptors in adipose tissue function

脂肪组织是一个主要的内分泌系统，参与调节各种过程，包括能量稳态，脂质代谢，免疫反应和生殖。在哺乳动物中，脂肪组织隔室的大小反映了全身能量摄入和消耗之间的平衡。另一方面，繁殖是一个消耗能量的过程，对脂肪代谢有着深远的影响，而脂肪代谢是动物的主要能量来源。在哺乳动物中，雌激素促进、维持和控制体脂和白色脂肪组织（WAT）的分布。雌激素功能通过核受体超家族的两个成员，雌激素受体（ER）α和β介导。ER是配体诱导型转录因子，通过其配体17 β-雌二醇（E2）的结合而激活，17 β-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远端调控元件，而不是近端启动子元件。此外，ER在几个增强子位点的结合需要先锋因子的存在，这些因子决定了全局染色质结构和直接的细胞类型特异性募集和转录程序。这项研究计划的基础假设是ER是WAT特异性基因表达程序的重要调节因子，并且它是生殖系统与哺乳动物最重要的能量来源之间的桥梁。我们的具体目标是：1）确定和比较雌激素受体α和雌激素受体β调节在雌性WAT中响应雌激素的特异性基因表达程序的建立中的分子机制; 2）检查环境异种雌激素对雌性WAT中的雌激素受体信号传导和代谢功能的影响。为了实现这些目标，我们将应用整合转录组学（mRNA-seq）和基因组学（ChIP-seq）方法来确定ER在WAT中建立特定转录程序中的作用。我们将使用小鼠Cre/lox模型，其中通过Cre重组酶诱导WAT特异性ESR 1（ER α）或ESR 2（ER β）基因缺失。此外，我们将通过整合特定染色质标记的重叠层来表征全基因组ER结合位点，更特别地是组蛋白变体H2 A. Z，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WAT，动物的主要能量来源。因此，我们建议还评估这些化合物对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，我们提出了一种新的和全面的调查，使用体内模型和分子和基因组的方法来确定雌激素或异种雌激素调节WAT代谢的动物的机制。

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.