Importance of estrogen receptors in adipose tissue function

脂肪组织是主要的内分泌系统，参与多种过程的调节，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，繁殖是一个耗费能量的过程，对脂肪代谢产生深远影响，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、维持和控制体内脂肪和白色脂肪组织（WAT）的分布。雌激素功能是通过核受体超家族的两个成员——雌激素受体 (ER) a 和 ß 介导的。 ER 是配体诱导转录因子，通过其配体 17β-雌二醇 (E2)（主要的天然雌激素）的结合而激活。 ER 结合主要发生在称为增强子的远处调控元件处，而不是近端启动子元件处。此外，几个增强子位点的 ER 结合需要先锋因子的存在，这些先锋因子决定全局染色质结构并指导细胞类型特异性招募和转录程序。拟议的研究计划以这样的假设为基础：ER 是 WAT 特异性基因表达程序的重要调节因子，并且它充当哺乳动物生殖系统与最重要能量来源之间的桥梁。我们的具体目标是： 1) 确定和比较 ERa 和 ERß 调节的分子机制，以建立女性 WAT 响应雌激素的特定基因表达程序； 2) 研究环境异雌激素对女性WAT 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组学 (mRNA-seq) 和基因组学 (ChIP-seq) 方法来体内鉴定 ER 在 WAT 中特定转录程序建立中的作用。我们将使用小鼠 Cre/lox 模型，其中 Cre 重组酶诱导 WAT 特异性去除 ESR1 (ERa) 或 ESR2 (ER ß) 基因。此外，我们将通过整合特定染色质标记的重叠层（尤其是组蛋白变体 H2A.Z）来表征全基因组 ER 结合位点，这将有助于揭示 WAT 中 ER 控制的特定转录程序。由于众所周知，环境中暴露于异雌激素会影响其他组织，因此我们怀疑它也会影响动物的主要能量来源 WAT。因此，我们建议还评估这些化合物对 ER 靶基因调节的分子效应以及它们如何影响 WAT 的生物学功能。 总的来说，我们提出了一项新颖且全面的研究，利用体内模型以及分子和基因组方法来确定雌激素或异雌激素调节动物 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.