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

A.家长资助金摘要 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。脑性类固醇 信号是维持正常体重所必需的。我们先前发现雌激素受体α(ERα)神经元 在杏仁内侧核(Mea)，刺激身体活动和能量消耗，以减轻两种男性的体重。 和雌性。这表明雌激素/ERα途径是先前未确定的大脑代谢的一部分。 雄性和雌性都发出了信号。有趣的是，MEA具有高水平的其他三个关键组成部分 睾酮/雌激素信号，包括雌激素合成的关键酶(芳香酶；ARO)，以及关键的中介作用 睾酮/雌激素信号受体(雄激素受体、雌激素受体α和β；AR、ERα和ERβ)。这些 数据增加了这样一种可能性，即循环中的睾丸素直接与AR结合，或者被Aro芳香化为雌二醇，然后雌二醇 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，以维持正常的能量平衡。为了测试这一点，将产生三只突变小鼠 让这三个成分中的每一个分别在中枢神经元中被特异性地删除。这些小鼠品系(两者 男性和女性)将被用来确定这三种成分在维持能量方面的生理作用 不同性别的动态平衡。这些成分和性激素之间的功能相互作用也将是 检查过了。这些研究的结果将促进我们目前对体重控制和发展的理解。 肥胖症的总体情况。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。

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.