Selective estrogen receptor alpha modulation during body weight cycling

体重（BW）循环（包括体重减轻后的BW恢复）与能量消耗（EE）和脂肪组织（AT）代谢的显著变化相关。由于这些过程是性别特异性控制，我们专注于在BW周期代谢过程中的性二态性，旨在阐明ER的作用!脂肪生成和脂肪分解。我们建立了饮食诱导（DIO）小鼠模型，随后通过热量限制（CR）降低BW，然后进行适应性喂养和恢复期。我们观察到，雌性小鼠对CR的反应是脂解活性增加，并且与雄性动物相比，增加了脂质氧化，导致更有效的体重减轻。这些过程可能涉及ATGL的性二态调节和AT中的雌激素受体α（ER α）依赖性信号传导。此外，雌性小鼠在BW循环期间表现出更高水平的EE。这与最近发表的一份报告一致，该报告表明下丘脑腹内侧核（VMH）神经元中的ER α缺失导致EE降低。基于这些数据，我们假设ER α在BW循环期间以双峰方式介导其在VMH和AT中的代谢作用。因此，本项目第二个资助期的目的是详细分析VMH和AT中的ER α作为支持BW降低和预防初始体重减轻后BW恢复的药理学靶点。我们的研究将集中在雌激素受体选择性调节（selective estrogen receptor modulation，SERM）概念下ER α亚型和组织/细胞选择性激活的特征。在第一个资助阶段对AT特异性ER α缺陷小鼠进行表型分析后，我们将开始对BW循环期间VMH特异性ER α缺陷（ER α lox/lox/SF-1 Cre）小鼠进行代谢分析。同时，我们将研究BW循环和体外过程中VMH和AT中的分子SERM组分（ER α，核辅因子，靶基因）。最后，新合成的SERM-compounds特异性ER!将在体外和体内进行测试。该项目旨在提高对SERM化合物作为肥胖症药物干预的理解。

Body weight (BW) cycling including BW -regain after weight loss is associated with marked changes in energy expenditure (EE) and adipose tissue (AT) metabolism. Since these processes are sex-specifically controlled, we focus on sexual dimorphisms in metabolic processes during BW-cycling and aimed to elucidate the role of ER! in lipogenesis and lipolysis in the AT. We established a diet-induced (DIO) mouse model with a subsequent reduction of BW by caloric restriction (CR) followed by adaptive feeding, and a regain-period. We observed that female mice responded to CR with an increase in lipolytic activity, and augmented lipid-oxidation leading to more efficient weight loss compared to male animals. These processes likely involve sexual dimorphic regulation of ATGL and estrogen receptor alpha (ERα)-dependent signaling in AT. In addition, female mice showed higher levels of EE during BW-cycling. This is in accordance with a recently published report demonstrating that ERα-deletion in neurons of the ventromedial hypothalamic nucleus (VMH) results in reduced EE. Based on these data we hypothesize that ERα mediates its metabolic action during BW-cycling in a bimodal manner in the VMH and AT. Thus, the aim of the present project for a second funding period is the detailed analysis of ERα in the VMH and AT as a pharmacological target for the support of BW-reduction and prevention of BW-regain after initial weight loss. Our studies will focus on the characterization of subtype- and tissue/ cellselective activation of ERα following the concept of selective estrogen receptor modulation (SERM). After phenotyping of AT-specific ERα-deficient mice during the first funding phase, we will start with the metabolic analysis of VMH-specific ERα-deficient (ERαlox/lox/ SF-1 Cre) mice during BW-cycling. In parallel we will study molecular SERM-components (ERα, nuclear cofactors, target genes) in the VMH and AT during BW-cycling and in-vitro. Finally, newly synthesized SERM-compounds specific for ER! will be tested in-vitro and in-vivo. This projects aims for an improved understanding of SERM compounds as a pharmacological intervention in obesity.