Importance of estrogen receptors in adipose tissue function

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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.