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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要雌二醇协调进食行为和新陈代谢。从雄激素中产生雌二醇，它在人类和啮齿动物的性腺、神经元中高度表达。离散的大脑区域密集地表达芳香酶大脑芳香酶的作用和局部从头（大脑）- 衍生雌二醇在能量平衡控制中的作用仍然知之甚少，我们的目标是提供答案。几个紧迫的基本问题： – 大脑芳香酶对于喂养和能量平衡控制是必需的吗？大脑芳香酶在神经解剖学和性别方面的作用不同？大脑和性腺芳香酶如何相互作用？代谢控制？我们在神经元的中央核中发现了两个表达芳香酶的神经元群体。我们初步研究了雌性和雄性大鼠的杏仁核（CeA）和下丘脑腹内侧（VMH）。数据表明，CeA 中的芳香酶控制着性别动物的摄食行为和随后的体重增加。相反，VMH 中的芳香酶以特定的方式控制棕色脂肪组织的产热。因此，在这个项目中，我们将追求芳香酶在两性中的假设。 CeA 对于以性别选择性方式控制摄食行为至关重要，而 VMH 中的芳香酶作用我们进一步认为芳香酶在男性和女性中都起着控制能量消耗的主要作用。在代谢挑战和病理生理学条件下，VMH（而非 CeA）可能特别重要。拟议的研究结合了行为、代谢、神经解剖学、分子和病毒发生策略成年大鼠通过进行分为两部分的详细机械实验来支持或反驳这一假设在目标 I 中，我们努力确定对饲喂控制和下游机制的具体贡献。在这里，我们将解决 CeA 芳香酶是否是必要且充分的。我们将确定是否是局部的、杏仁核内的和远端的。下丘脑外侧性别特异性通路由 CeA 芳香酶神经元参与，并且该通路是否丧失输入导致下丘脑食欲通路的去抑制。Aim II 的具体目标是测试。正常代谢情况下下丘脑芳香酶是否控制摄食和体温调节我们将研究 VMH 中的芳香酶对于能量是否是必要且充足的。这里的实验也旨在揭示 VMH 是否对男女都有影响。芳香酶在适应代谢挑战方面发挥着关键作用：肥胖饮食和寒冷暴露，在这两个方面最后，与 CeA 相比，我们发现 VMH 芳香酶和由此产生的雌二醇具有反应性。如果我们的假设得到支持，我们将证明大脑芳香酶与性腺类固醇协同工作。由此产生的本地产生的雌二醇是代谢健康和维持能量平衡的关键疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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.