Importance of estrogen receptors in adipose tissue function

脂肪组织是一个重要的内分泌系统，参与调节多种过程，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，对脂肪代谢有深远的影响，脂肪代谢是动物主要的能量来源。在哺乳动物中，雌激素促进、维持和控制身体脂肪和白色脂肪组织（WAT）的分布。雌激素的功能是通过核受体超家族的两个成员，雌激素受体（ER）和。内质网是配体诱导的转录因子，由其配体17-雌二醇（E2）结合激活，E2是主要的天然雌激素。内质网结合主要发生在远端调控元件增强子上，而不是近端启动子上。此外，内质网在几个增强子位点的结合需要指示全局染色质结构和直接细胞类型特异性募集和转录程序的先驱因子的存在。

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) and . ER are ligand-inducible transcription factors activated by the binding of their ligands, 17-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 ER and ER 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 (ER) or ESR2 (ER ) 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.