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：
10632260
负责人：
Pingwen Xu
金额：
$ 6.46万
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/10632260
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 Equilibrium Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogens Female Glucose Gonadal Steroid Hormones High Fat Diet Homeostasis Hormone Receptor Human Hypogonadism Individual Injections Knockout Mice Ligands Medial Mediating Metabolic Metabolic Pathway Metabolic syndrome Metabolism 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 hormone regulation male male sex hormones men neural circuit neurosteroids novel obesity development obesity prevention overexpression parent grant prevent receptor relating to nervous system sex side effect weight maintenance

项目摘要

A. Abstract of Parent Grant 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 specific 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.

A. 家长补助金摘要性类固醇，包括雌激素和雄激素，在调节能量稳态方面发挥着重要作用。我们之前表明雌激素受体α（ERα）神经元需要信号传导。内侧杏仁核 (MeA) 刺激身体活动和能量消耗，以减轻男性的体重这表明雌激素/ERαMeA 回路构成了先前未定义的大脑代谢的一部分。 MeA 的其他三个关键成分的水平都很高。睾酮/雌激素信号传导，包括雌激素合成的必需酶（芳香酶；Aro）和关键介导睾酮/雌激素信号传导受体（雄激素受体、雌激素受体 α 和 β；AR、ERα 和 ERβ）。数据提出了循环睾酮直接与 AR 结合或被 Aro 芳香化为雌二醇的可能性，然后我们发现神经类固醇睾酮/雌激素信号传导与 ERα 或 ERβ 结合以发挥代谢功能。 MeA 中的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。分别在 MeA 神经元中专门删除这三个组件。男性和女性）将用于确定这三个成分在维持能量方面的生理作用这些成分与性激素之间的功能相互作用也将是不同性别的体内平衡。这些研究的结果将增进我们目前对体重控制和发展的理解。此外，我们的研究可能会缩小特定的大脑区域和激素/受体的范围。对于能量平衡的调节至关重要，这可以作为开发新的抗肥胖药物的目标策略。