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.

包括雌激素和雄激素在内的性类固醇在调节能量稳态方面起着重要作用。脑正常体重维持需要性类固醇信号传导。我们先前表明雌激素内侧杏仁核（MEA）中的受体α（ERα）神经元刺激体育活动和能量消耗到减轻男性和女性的体重。它表明雌激素/ERαMEA电路构成部分男性和女性的先前未定义的脑代谢信号传导。有趣的是，MEA很高睾丸激素/雌激素信号传导的其他三个关键组成部分的水平，包括用于雌激素合成（芳香酶； ARO）和睾丸激素/雌激素信号的关键介导受体（雄激素受体，雌激素受体α和β； AR，ERα和ERβ）。这些数据增加了流通的可能性睾丸激素直接与AR结合或通过ARO芳香至雌二醇，然后与ERα或ERβ结合以执行代谢功能。我们假设MEA中的神经类睾丸激素/雌激素信号通路互动以维持正常的能量稳态。为了测试这一点，将生成三只突变小鼠在这三个组件中，分别在MEA神经元中专门删除。这些小鼠菌株（都男性和女性）将用于确定这三个组成部分在维护中的身体作用能量稳态在不同的性别中。这些成分与性别之间的功能相互作用还将检查骑兵。这些研究的结果将提高我们当前对身体的理解体重控制和一般肥胖的发展。此外，我们的研究可能会缩小大脑区域以及对调节能量平衡至关重要的骑马/受体，这可能是制定新的抗肥胖策略。