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

支持大脑芳香酶控制摄食行为和代谢稳态的神经解剖学基质

• 批准号: 10737130
• 负责人: Karolina P Skibicka
• 金额: $ 53.75万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737130
• 关键词: Adult; Affect; Amygdaloid structure; Androgens; Appetite Stimulants; Aromatase; Aromatase Inhibition; Aromatase Inhibitors; Basic Science; Behavior; Behavior Control; Behavioral; Body Temperature; Body Weight; Brain; Brain region; Brown Fat; Cell Nucleus; Cells; Clinic; Data; Desire for food; Diet; Disease; Disinhibition; Distal; Energy Metabolism; Enzymes; Estradiol; Estrogen Receptors; Estrous Cycle; Feeding behaviors; Female; Food; Functional disorder; Goals; Gonadal Steroid Hormones; Gonadal structure; Health; Homeostasis; Human; Hyperphagia; Hypothalamic structure; Lateral; Ligands; Link; Maintenance; Measurement; Measures; Mediator; Metabolic; Metabolic Control; Metabolism; Molecular; Neuroanatomy; Neurons; Obesity; Pathway interactions; Pharmacologic Substance; Physiologic Thermoregulation; Physiological; Physiology; Plasma; Population; Production; Rattus; Research; Rodent; Role; Self-control as a personality trait; Site; Source; Steroids; System; Testing; Testosterone; Thermogenesis; Viral Vector; Weight Gain; Weight maintenance regimen; Woman; Work; blood-brain barrier crossing; design; energy balance; experimental study; feeding; hypothalamic-pituitary-thyroid axis; knock-down; liquid chromatography mass spectrometry; male; men; motivated behavior; neural; neural circuit; neurochemistry; novel; obesity treatment; obesogenic; overexpression; paraventricular nucleus; receptor; response; sex; translational potential

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.

项目摘要 雌二醇协调喂养行为和代谢。芳香酶是负责的唯一酶 从雄激素中产生雌二醇，并在性腺中高度表达。在人类和啮齿动物中，神经元中 离散的大脑区域不表达芳香酶。大脑芳香酶和从头局部（脑）的作用 - 能量平衡控制中衍生的雌二醇仍然鲜为人知。我们的目标是为 几个紧迫的基本问题： - 喂食和能量平衡控制是否需要脑芳香族？是 脑芳香酶神经解剖学和性别发散的作用？大脑和性腺芳香酶如何相互作用 代谢控制？我们确定了两个表达芳香酶的神经元的种群 杏仁核（CEA）和雌性大鼠的腹膜下丘脑（VMH）中。我们的初步 数据表明，在CEA中特别表明芳香化酶控制喂养行为，并且性别随后的体重增加 具体方式。相反，VMH中的芳香化酶对棕色脂肪组织热施加控制 能力和反应，在两个性别中。因此，在这个项目中，我们将追求一个假设 CEA对于以性选择性方式进行喂养行为控制至关重要，而VMH中的芳香化酶作用具有 能量支出控制在男性和女性中的主要作用。我们进一步将芳香化酶在 在代谢挑战和病理生理学条件下，VMH而不是CEA可能特别重要。 拟议的研究结合了行为，代谢，神经解剖学，分子和病毒式策略 成年大鼠通过进行两次组织的详细机械实验来支持或反驳这一假设 目标。在目的中，我努力确定对喂养控制和下游机制的特定贡献 由杏仁核芳香酶精心策划。在这里，我们将解决CEA芳香化酶是否需要和足够 控制食物动机和摄取行为。我们将确定局部，杏仁核内和远端是否是 下丘脑性特异性途径与CEA芳香化酶神经元相关，以及是否丧失 输入会导致下丘脑原性途径的抑制作用。 AIM II的特定广泛目标是测试 下丘脑芳香化酶是否控制正常和代谢下的喂养和温度调节 具有挑战性的条件。我们将检查VMH中的芳香酶是否需要和足够的能量 两性的支出和体重控制。这里的实验还旨在揭示VMH是否 芳香酶在适应代谢挑战中起着关键作用：肥胖饮食和冷暴露，在 性别。最后，与CEA相反，我们假设VMH芳香化酶和由此产生的雌二醇是响应性的 与性腺类固醇合作并协同工作。如果支持我们的假设，我们将证明大脑芳香酶 并且由此产生的局部产生的雌二醇是维持代谢健康期间能量平衡的关键 疾病。

项目成果

Sex-divergent effects of hindbrain GLP-1-producing neuron activation in rats.

• DOI: 10.3389/fnins.2023.1265080
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Lopez-Ferreras, Lorena;Asker, Mohammed;Krieger, Jean-Philippe;Skibicka, Karolina Patrycja
• 通讯作者: Skibicka, Karolina Patrycja

A vagal influence on schizophrenia? A nationwide retrospective cohort of vagotomized individuals.

迷走神经对精神分裂症的影响？

• DOI: 10.1101/2024.01.30.24301418
• 发表时间: 2024
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Richter,CorneliaF;Skibicka,KarolinaP;Meyer,Urs;Rohrmann,Sabine;Krieger,Jean-Philippe
• 通讯作者: Krieger,Jean-Philippe

From the stomach to locus coeruleus: new neural substrate for ghrelin's effects on ingestive, motivated and anxiety-like behaviors.

• DOI: 10.3389/fphar.2023.1286805
• 发表时间: 2023
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6