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

A.家长补助金摘要 性类固醇包括雌激素和雄激素，在调节能量稳态中起重要作用。脑性类固醇 信号传导是维持正常体重所必需的。我们以前的研究表明，雌激素受体α（ERα）神经元 在内侧杏仁核（MeA）刺激体力活动和能量消耗，以降低雄性动物的体重 和女性。这表明雌激素/ERαMeA回路构成了以前未定义的脑代谢的一部分， 在男性和女性身上都有信号。有趣的是，MeA中其他三种关键成分的含量很高， 睾酮/雌激素信号传导，包括雌激素合成的必需酶（芳香酶; Aro），以及关键的介导 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）。这些 数据表明，循环中的睾酮可能直接与AR结合，或被Aro芳香化为雌二醇， 结合ERα或ERβ发挥代谢功能。我们假设神经类固醇睾酮/雌激素信号 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神经元中删除这三种成分。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能量方面的生理作用 不同性别的体内平衡。这些成分和性激素之间的功能性相互作用也将被 考察这些研究的结果将促进我们目前对体重控制的理解， 肥胖症的症状此外，我们的研究可能会缩小特定的大脑区域和激素/受体， 对于调节能量平衡至关重要，这可能成为开发新的抗肥胖药物的目标。 战略布局

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.