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 雌二醇协调摄食行为和新陈代谢。芳香酶是唯一一种负责 从雄激素中产生雌二醇，它在性腺中高度表达。在人类和啮齿动物中，神经元 大脑中不连续的区域密集表达芳香酶。脑芳香酶和局部新生(脑)的作用- 衍生雌二醇在能量平衡控制中的作用仍然知之甚少。我们的目标是为以下问题提供答案 几个迫在眉睫的基本问题：大脑芳香酶对于进食和能量平衡控制是必要的吗？是 脑芳香酶在神经解剖学和性别分化中的作用？脑和性腺芳香化酶如何相互作用 新陈代谢控制？我们鉴定了两组芳香化酶表达神经元，位于 雌性和雄性大鼠的杏仁核(CEA)和下丘脑腹内侧核(VMH)。我们的预赛 数据表明，CEA中的芳香酶控制着进食行为和随后的性别体重增加-- 具体的方式。相反，VMH中的芳香化酶对棕色脂肪组织的产热起着控制作用 能力和反应，在两性中。因此，在这个项目中，我们将继续研究芳香酶在 CEA对以性别选择的方式控制取食行为至关重要，而VMH中的芳香酶作用具有 控制能量消耗在男性和女性中的主要作用。我们进一步假设，芳香酶在 VMH，而不是CEA，在代谢挑战和病理生理条件下可能特别重要。 拟议的研究结合了行为、代谢、神经解剖学、分子和病毒遗传学策略 成年大鼠通过进行详细的机械实验来支持或反驳这一假说 目标。在目标一中，我们努力确定对喂养控制和下游机制的具体贡献 由杏仁核芳香酶协调。在这里，我们将解决CEA芳香化酶是否是必要和充分的 控制进食动机和进食行为。我们将确定局部的、杏仁核内的和远端的， 下丘脑外侧性特异性通路是否由CEA芳香酶神经元参与，以及这是否丢失 输入可以解除对下丘脑促食欲素通路的抑制。Aim II具体而广泛的目标是测试 下丘脑芳香酶是否在正常代谢状态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 芳香酶在适应代谢挑战方面起着关键作用：肥胖饮食和寒冷暴露，在这两者中 性别。最后，与CEA相反，我们假设VMH芳香酶和由此产生的雌二醇是有反应的 并与性腺类固醇协同工作。如果我们的假设得到支持，我们将证明大脑芳香酶 而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。

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