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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：
10262923
负责人：
Pingwen Xu
金额：
$ 51.74万
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/10262923
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 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 Hormone Receptor Human Hypogonadism Individual Injections Knockout Mice Ligands Medial Mediating Metabolic Metabolic Pathway Metabolic syndrome Mouse Strains Mus Mutant Strains Mice Mutation Neuraxis Neurons Obesity Obesity associated disease Phenotype 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 base diet-induced obesity energy balance estrogenic male male sex hormones men neural circuit neurosteroids novel obesity development obesity prevention overexpression prevent receptor relating to nervous system 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，在调节能量稳态中起重要作用。大脑性类固醇信号传导是维持正常体重所必需的。我们之前的研究表明雌激素内侧杏仁核（MeA）中的ERα受体神经元刺激身体活动和能量消耗，降低雄性和雌性的体重。提示雌激素/ERα-MeA通路是雌激素受体的重要组成部分，一种以前未定义的大脑代谢信号在男性和女性中的作用。有趣的是，MeA具有高睾酮/雌激素信号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）。这些数据提出了一种可能性，睾酮直接与AR结合或被Aro芳香化为雌二醇，然后雌二醇与ERα或ERβ结合，代谢功能我们假设，在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平衡。为了测试这一点，将产生三只突变小鼠，这三种成分分别在MeA神经元中特异性缺失。这些小鼠品系（两者雄性和雌性）将用于确定这三种组分在维持不同性别的能量平衡。这些成分和性别之间的功能性相互作用激素也将被检查。这些研究的结果将促进我们目前对身体的理解体重控制和肥胖症的发展。此外，我们的研究可能会缩小大脑区域以及对于调节能量平衡至关重要的激素/受体，其可以作为制定新的抗肥胖战略。