The role of adipose tissue estrogen receptors during body weight loss and the maintenance of reduced weight

雌激素受体(ER)、α-和β被认为是体重的重要调节因子。这种调节的潜在机制在很大程度上仍不清楚，但指向脂肪组织代谢(脂肪生成/脂解)调节途径的主要变化。此外，减重过程中ERα/β活性的减弱可能表明，在体重维持阶段保留这种活性可能是防止体重回升的一种有前途的方法。基于内质网的治疗性干预需要全面了解减肥-维持-恢复不同阶段的同型和组织特异性内质网功能。鉴于脂肪组织代谢在ER介导的体重调节中的重要性，本项目旨在研究减肥后体重维持期间和体重恢复期间脂肪组织ERα和ERβ信号的特征。为此，脂肪细胞特异性ERα和ERβ-缺陷小鼠将被代谢表型。ER信号将使用已建立的分子组织分析协议(如EMSA和CHIP)在体外进行全面研究，并将通过脂肪细胞的体外研究加以补充。为了研究我们的假设的临床相关性，我们将从CRG的Z项目中研究脂肪组织活检样本和单核细胞中的ER信号。综上所述，本项目的目的是研究ERα/ERβ信号在体重减轻-维持-恢复过程中的特征，并建立ER作为治疗靶点以维持长期的体重减轻。

Estrogen receptor (ER) α- and β have been identified as important regulators of body weight. The underlying mechanisms of this regulation remain largely unclear, but point towards major changes of regulatory pathways in adipose tissue metabolism (lipogenesis/lipolysis). In addition, attenuated ERα/β activation during weight reduction may suggest that the preservation of this activity during the weight maintenance phase may be a promising approach to prevent weight regain. A therapeutic ER-based intervention requires a comprehensive knowledge of isoform- and tissue-specific ER-function during the different phases of weight reduction – maintenance – regain. Given the importance of adipose tissue metabolism in ER-mediated modulation of body weight, the present project aims for the characterization of adipose tissue ERα- and ERβ- signaling during the maintenance of reduced body weight after weight reduction and during the weight regain period. For this purpose, adipocyte-specific ERα- and ERβ - deficient mice will be metabolically phenotyped. ER signaling will be comprehensively studied ex-vivo using established protocols for molecular tissue analysis such as EMSA and ChIP, which will be complemented by in-vitro studies in adipocytes. To study the clinical relevance of our hypothesis, ER-signaling will be studied in adipose tissue biopsy samples and monocytes from the Z project of the CRG. In summary, the aim of the present project is the characterization of ERα-/ ERβ-signaling during body weight reduction – maintenance - regain, and to establish ERs as therapeutic targets to maintain long-term weight reduction.