Testosterone and estrogen signaling pathways in the medial amygdala interact to control energy homeostasis

内侧杏仁核中的睾酮和雌激素信号通路相互作用以控制能量稳态

基本信息

批准号：
10713363
负责人：
Pingwen Xu
金额：
$ 7.75万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713363
关键词：
Adrenal Glands Age Agonist Amygdaloid structure Androgen Receptor Androgens Aromatase Binding Body Temperature Body Weight Body Weight decreased Body mass index Brain Brain region Castration Central Nervous System Coupled Data Development Diet Dose Electrophysiology (science)Energy Metabolism Enzymes Epidemic Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogens Female Gonadal Steroid Hormones High Fat Diet Homeostasis Hormones Human Hypogonadism Individual Injections Knockout Mice Ligands LoxP-flanked allele Medial Mediating Metabolic Metabolic Pathway Metabolic syndrome Mouse Strains Mus Mutant Strains Mice Mutation Neurons Obesity Obesity associated disease Phenotype Physical Stimulation Physical activity Physiological Play Receptor Signaling Regulation Reporting Research Research Proposals Role Signal Pathway Signal Transduction Stanolone Steroids System Testing Testosterone Weight Gain Weight maintenance regimen Work androgen deprivation therapy androgenic diet-induced obesity energy balance estrogenic male male sex hormones men neural neural circuit neurosteroids novel obesity development obesity prevention overexpression prevent receptor sex side effect weight maintenance

项目摘要

Sex steroids, including estrogens and androgens, play an important role in regulating energy homeostasis. Brain sex steroid signaling is required for normal body weight maintenance. We previously showed that estrogen receptor α (ERα) neurons in the medial amygdala (MeA) stimulate physical activity and energy expenditure to decrease body weight in both males and females. It suggests that the estrogen/ERαMeA circuit constitutes part of a previously undefined brain metabolic signaling in both males and females. Interestingly, the MeA has high levels of other three key components of testosterone/estrogen signaling, including an essential enzyme for estrogen synthesis (aromatase; Aro), and key mediating receptors for testosterone/estrogen signaling (androgen receptor, estrogen receptor α and β; AR, ERα and ERβ). These data raise the possibility that circulating testosterone directly binds to AR or is aromatized by Aro to estradiol, which then binds to ERα or ERβ to exert metabolic functions. We hypothesize that the neurosteroid testosterone/estrogen signaling pathways in the MeA interact to maintain normal energy homeostasis. To test this, three mutant mice will be generated to have each of these three components deleted specifically in the MeA neurons, respectively. These mouse strains (both males and females) will be used to determine the physiological roles of these three components in maintaining energy homeostasis in different sexes. The functional interactions between these components and the sex hormones will also be examined. Results from these studies will advance our current understanding of body weight control and the development of obesity in general. Further, our studies may narrow down the brain regions and hormone/receptors that are critical for the regulation of energy balance, which may serve as targets for the development of new anti-obesity strategies.

性类固醇，包括雌激素和雄激素，在调节大脑能量稳态中发挥着重要作用。性类固醇信号是维持正常体重所必需的我们之前表明雌激素。内侧杏仁核 (MeA) 中的受体 α (ERα) 神经元刺激体力活动和能量消耗男性和女性的体重都会减轻，这表明雌激素/ERαMeA 回路是其中的一部分。先前未定义的男性和女性大脑代谢信号隐含地表明，MeA 具有高水平。睾酮/雌激素信号传导的其他三个关键成分的水平，包括一种必需的酶雌激素合成（芳香酶；Aro）和睾酮/雌激素信号传导的关键受体（雄激素这些数据提出了循环的可能性。睾酮直接与 AR 结合或通过 Aro 芳香化为雌二醇，然后与 ERα 或 ERβ 结合发挥作用我们努力研究 MeA 中的神经类固醇睾酮/雌激素信号通路。相互作用以维持正常的能量稳态为了测试这一点，将产生三只突变小鼠。这三个成分分别在 MeA 神经元中被特异删除。男性和女性）将用于确定这三个成分在维持不同性别的能量稳态这些成分与性别之间的功能相互作用。荷尔蒙也将受到检查，这些研究的结果将增进我们目前对身体的了解。此外，我们的研究可能会缩小大脑区域的范围。以及对能量平衡调节至关重要的激素/受体，它们可以作为制定新的抗肥胖策略。