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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：
10649532
负责人：
Pingwen Xu
金额：
$ 43.4万
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/10649532
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.

性激素，包括雌激素和雄激素，在调节能量平衡方面起着重要作用。脑区性类固醇信号是维持正常体重所必需的。我们之前已经证明了雌激素杏仁内侧核受体α(ERα)神经元刺激体力活动和能量消耗减轻男性和女性的体重。提示雌激素/ERα途径途径是雌激素调节的一部分。之前未定义的大脑代谢信号在男性和女性中都存在。有趣的是，MEA有很高睾酮/雌激素信号的其他三个关键成分的水平，包括一种关键的酶雌激素合成(芳香酶；Aro)和睾酮/雌激素信号的关键中介受体(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酮直接与AR结合或被Aro芳构化为雌二醇，雌二醇再与ERα或ERβ结合发挥作用代谢功能。我们推测，神经类固醇睾酮/雌激素信号通路在MEA 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，每只小鼠在这三种成分中，分别在MeA神经元中特异性缺失。这些小鼠品系(两者男性和女性)将被用来确定这三个组成部分在维持不同性别的能量动态平衡。这些成分与性别之间的功能相互作用荷尔蒙也将被检查。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总体发展。此外，我们的研究可能会缩小大脑区域的范围以及对调节能量平衡至关重要的激素/受体，这些激素/受体可能是制定新的反肥胖策略。