Sexually Dimorphic Expression and Function of the Melanocortin-3 Receptor

Melanocortin-3 受体的性别二态性表达和功能

基本信息

批准号：
10262943
负责人：
Roger D. Cone
金额：
$ 35.09万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10262943
关键词：
Androgen Receptor Animals Anorexia Anorexia Nervosa Axon Behavior Behavior Control Biological Assay Brain region Candidate Disease Gene Cell Nucleus Cells Cues Data Defect Dependence Disease Eating Electrophysiology (science)Estrogen Receptors Estrogens Event Exhibits Exposure to Fasting Feeding behaviors Female Food Foundations Functional disorder GNRH1 gene Gap Junctions Gene Expression Gestational Diabetes Glutamates Gonadal Steroid Hormones Gonadotropins Homeostasis Hormones Human Image Analysis Immunohistochemistry In Situ Hybridization Lateral Lentivirus Leptin Masculine Mediating Medical Melanocortin 3 Receptor Metabolic Metabolic Control Metabolism Methods Mus Neurons Nutritional Pattern Phenotype Population Pregnancy Regulation Reproduction RiboTag Role Sensory Sex Differences Signal Transduction Slice Steroids Stress Structure of nucleus infundibularis hypothalami Structure of paraventricular nucleus of thalamus System Testing Three-Dimensional Image Time Tracer Ventral Tegmental Area Woman alpha-Melanocyte stimulating hormone fascinate feeding hypothalamic pituitary gonadal axis knock-down leptin receptor male parabrachial nucleus paraventricular nucleus postnatal postnatal development receptor expression relating to nervous system reproductive response restoration restraint stress sexual dimorphism small hairpin RNA transcriptomics

项目摘要

Neural systems regulating feeding behavior and reproduction communicate bidirectionally to gate reproductive events and to regulate energy stores for changes in reproductive states, such as pregnancy. The melanocortin-3 receptor (MC3R) is expressed in multiple nuclei that regulate reproduction and energy homeostasis such as the AgRP neurons of the arcuate nucleus, and exhibits a large sexual dimorphism in its level of expression in both humans and mice. Loss of the MC3R has particularly profound consequences for female animals. First, we demonstrate that MC3R is essential for fasting-induced suppression of the HPG axis in females. Second, we have identified fascinating sexual dimorphisms in feeding behavior in the absence of MC3R. For example, In the novelty suppressed feeding (NSF) assay in which fasted animals must enter an open field to retrieve food, MC3RKO males eat equivalent amounts to WT mice, while female MC3RKO fail to explore, and cease feeding entirely. In contrast, male but not female mice exhibit enhanced anorexia in response to restraint stress. AgRP neurons, the majority of which express MC3R, send information regarding nutritional state directly to reproductive and metabolic control centers, like the PVH and AVPV, and to behavioral control centers like the ventral tegmental area (VTA), paraventricular nucleus of the thalamus (PVT), and lateral parabrachial nucleus (PBl), and project indirectly to the insular cortex, involved in sensory interpretation of food cues and implicated in the pathophysiology of anorexia nervosa. This proposal will conduct the first systematic mapping and characterization of the MC3R neurons involved in the coordination of energy homeostasis, reproduction and feeding behavior, determine the mechanism(s) underlying the requirement of MC3R for fasting-induced suppression of the HPG axis, and identify the MC3R neurons and circuits mediating sexually dimorphic feeding behaviors.

调节摄食行为和繁殖的神经系统与控制生殖事件并调节生殖状态变化的能量储存，例如作为怀孕。黑皮质素 3 受体 (MC3R) 在多个细胞核中表达，调节生殖和能量稳态，例如弓状核的 AgRP 神经元，以及在人类和小鼠中的表达水平表现出巨大的性别二态性。损失 MC3R 对雌性动物有着特别深远的影响。首先，我们演示 MC3R 对于禁食引起的女性 HPG 轴抑制至关重要。第二，我们已经发现在缺乏 MC3R 的情况下进食行为中令人着迷的性别二态性。为了例如，在新奇抑制进食 (NSF) 测定中，禁食的动物必须进入开放场地取回食物时，MC3RKO 雄性小鼠吃的食物量与 WT 小鼠相当，而雌性小鼠 MC3RKO 无法探索并完全停止进食。相比之下，雄性小鼠而非雌性小鼠表现出对约束压力的反应增强的厌食症。 AgRP 神经元，其中大部分表达 MC3R，将有关营养状态的信息直接发送给生殖和代谢控制中心，如 PVH 和 AVPV，以及行为控制中心，如腹侧被盖区 (VTA)、丘脑室旁核 (PVT) 和外侧被盖区臂旁核（PBl），间接投射到岛叶皮质，参与感觉食物线索的解释及其与神经性厌食症病理生理学的关系。这该提案将对 MC3R 神经元进行首次系统绘图和表征参与能量稳态、繁殖和进食行为的协调，确定 MC3R 对禁食引起的需求的潜在机制 HPG 轴的抑制，并识别介导性的 MC3R 神经元和电路二态性摄食行为。