Selective estrogen receptor alpha modulation during body weight cycling

体重循环期间选择性雌激素受体α调节

• 批准号: 225908252
• 负责人: Professor Dr. Ulrich Kintscher
• 金额: --
• 依托单位: Center for Cardiovascular Research (CCM)
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/225908252?language=en
• 关键词: Selective; estrogen; receptor; alpha; modulation

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.

体重（BW）骑自行车在体重减轻后包括BW-Regain与能量消耗（EE）和脂肪组织（AT）代谢的明显变化有关。由于这些过程是对性别特定控制的，因此我们专注于BW-Cycling期间代谢过程中的性二态性，并旨在阐明ER的作用！在AT中的脂肪生成和脂解中。我们建立了饮食诱导的（DIO）小鼠模型，随后通过热量限制（CR）降低了BW，然后进行自适应喂养和重新恢复。我们观察到，雌性小鼠对CR的反应随脂溶作用的增加而反应，并且与雄性动物相比，脂质氧化增加导致体重增加更有效。这些过程可能涉及AT中ATGL和雌激素受体α（ERα）依赖性信号的性二态调节。此外，雌性小鼠在BW周期期间显示出较高的EE水平。这与最近发表的一份报告相符，该报告表明，腹膜下丘脑核us（VMH）的神经元中的ERα脱落导致EE减少。基于这些数据，我们假设ERα在BW-Cycling期间以双峰方式在VMH和AT中介导其代谢作用。这是第二个资金期间本项目的目的是对VMH中的ERα进行详细分析，并作为支持BW还原和预防BW-Regain后重量减肥后的药物目标。我们的研究将集中于选择性雌激素受体调制（SERM）概念的ERα亚型和组织/细胞选择性激活的表征。在第一个融资阶段对AT特异性ERα缺陷小鼠进行表型后，我们将从对BW-Cycling期间VMH特异性ERα缺陷型（ERαLox/ Lox/ SF-1 Cre）小鼠的代谢分析开始。同时，我们将研究VMH和BW-Cycling和Vitro期间的分子Serm component（ERα，核辅助因子，靶基因）。最后，新合成的Serm-Compounds特定于ER！将在体外和体内进行测试。该项目的目的是提高对Serm化合物的理解，作为肥胖症的药物干预。