Neuroanatomical substrates underpinning brain aromatase control of feeding behavior and metabolic homeostasis

项目摘要 雌激素协调摄食行为和新陈代谢。芳香化酶是唯一负责 从雄激素产生雌二醇，并且在性腺中高度表达。在人类和啮齿动物中， 离散的脑区域密集地表达芳香化酶。脑芳香化酶和局部从头（脑）的作用- 衍生的雌二醇在能量平衡控制中的作用仍然知之甚少。我们的目标是提供答案 几个紧迫的基本问题：-脑芳香化酶是喂养和能量平衡控制所必需的吗？是 脑芳香化酶的作用神经解剖学和性别分歧？大脑和性腺芳香化酶如何相互作用 代谢控制？我们鉴定了两个表达芳香化酶的神经元群体，在中央核， 杏仁核（CeA）和腹内侧下丘脑（VMH）。我们的初步 数据表明，CeA中的芳香化酶特异性地控制性别中的进食行为和随后的体重增加， 具体方式。相反，VMH中的芳香化酶控制棕色脂肪组织的产热， 能力和反应，在两个性别。因此，在本项目中，我们将继续研究芳香化酶在 CeA对性别选择性的摄食行为控制至关重要，而VMH中的芳香化酶作用 男性和女性能量消耗控制的主要作用。我们进一步证实， VMH，而不是CeA，可能是特别重要的代谢挑战和病理生理条件下。 拟议的研究结合了联合收割机的行为，代谢，神经解剖，分子和病毒发生学策略， 成年大鼠进行详细的机械实验，支持或反驳这一假设，组织在两个 目标。在目标I中，我们努力确定对摄食控制和下游机制的具体贡献 由杏仁核芳香化酶控制在这里，我们将解决CeA芳香化酶是否是必要的和足够的， 控制食物动机和摄食行为。我们将确定是否局部杏仁核内和远端， 外侧下丘脑性别特异性通路参与了CeA芳香化酶神经元，以及是否失去了这一点， 输入导致下丘脑食欲途径的去抑制。Aim II的具体广泛目标是测试 下丘脑芳香化酶是否在正常和代谢条件下控制摄食和体温调节 具有挑战性的条件。我们将研究VMH中的芳香化酶是否是能量的必要和充分条件。 在两种性别中的支出和体重控制。这里的实验也旨在揭示VMH是否 芳香化酶在适应代谢挑战中起着关键作用：肥胖饮食和寒冷暴露， 性别最后，与CeA相反，我们假设VMH芳香化酶和产生的雌二醇是反应性的， 并与性腺类固醇协同作用。如果我们的假设得到支持，我们将证明大脑芳香酶 并且由此产生的本地产生的雌二醇是代谢健康期间维持能量平衡的关键， 疾病

Project Summary Estradiol orchestrates feeding behavior and metabolism. Aromatase is the sole enzyme responsible for producing estradiols from androgens, and it is highly expressed in gonads. In humans and rodents, neurons in discrete brain regions densely express aromatase. The role of brain aromatase and locally de novo (brain)- derived estradiols in energy balance control remains poorly understood. Our goal is to provide answers for several pressing basic questions: – is brain-aromatase necessary for feeding and energy balance control? Is the role of brain aromatase neuroanatomically and sex divergent? How do brain and gonadal aromatase interact in metabolic control? We identified two populations of aromatase-expressing neurons, in the central nucleus of the amygdala (CeA) and in the ventromedial hypothalamus (VMH), in female and male rats. Our preliminary data suggest aromatase specifically in the CeA controls feeding behavior and subsequent weight gain in a sex- specific manner. In contrast, aromatase in the VMH, exerts control over the brown adipose tissue thermogenic capacity and response, in both sexes. Therefore, in this project we will pursue the hypothesis that aromatase in the CeA is critical to feeding behavior control in a sex-selective manner, while aromatase action in the VMH has the primary role of energy expenditure control in both males and females. We further posit that aromatase in the VMH, but not CeA, may be particularly important under conditions of metabolic challenges and pathophysiology. The proposed studies combine behavioral, metabolic, neuroanatomical, molecular, and virogenetic strategies in adult rats to support or refute this hypothesis by conducting detailed mechanistic experiments organized in two aims. In Aim I we strive to identify the specific contribution to feeding control and downstream mechanisms orchestrated by amygdala aromatase. Here we will resolve whether CeA aromatase is necessary and sufficient to control food-motivated and ingestive behavior. We will determine whether local, intra-amygdala, and distal, lateral hypothalamic sex-specific pathways are engaged by CeA aromatase neurons, and whether loss of this input leads to disinhibition of hypothalamic orexigenic pathways. The specific broad goal of Aim II is to test whether hypothalamic aromatase controls feeding and thermoregulation under normal and metabolically challenging conditions. We will examine whether aromatase in the VMH is necessary and sufficient for energy expenditure and body weight control in both sexes. Experiments here are also designed to reveal whether VMH aromatase has a critical role in adaptation to metabolic challenges: obesogenic diet and cold exposure, in both sexes. Finally, and in contrast to CeA, we hypothesize that VMH aromatase and resulting estradiol are responsive to and work in concert with gonadal steroids. If our hypothesis is supported, we will show that brain aromatase and resulting locally produced estradiols are key to maintenance of energy balance during metabolic health and disease.