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：
10093675
负责人：
Roger D. Cone
金额：
$ 33.78万
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/10093675
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 Estrogen receptor positive 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 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 Subfamily lentivirinae 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.

调节进食行为和繁殖的神经系统双向交流栅极生殖事件并调节能量存储，以使生殖状态的变化，此类作为怀孕。黑素皮质素-3受体（MC3R）在调节的多个核中表达繁殖和能量稳态，例如弧形核的AGRP神经元，在人类和小鼠的表达水平上表现出很大的性二态性。损失 MC3R对雌性动物产生了特别深刻的后果。首先，我们证明该MC3R对于禁食诱导女性HPG轴的抑制至关重要。第二，我们在没有MC3R的情况下，已经确定了在喂养行为中引人入胜的性二态性。为了例如，在抑制饲料（NSF）的新颖性中，禁食动物必须进入开放式田地以检索食物，MC3RKO雄性在wt小鼠中吃量等效，而女性则 MC3RKO无法探索，并且完全停止进食。相反，雄性但不是雌性小鼠响应约束应力，表现出增强的厌食症。 AGRP神经元，其中大多数 Express MC3R，直接发送有关营养状态的信息以生殖和代谢控制中心，例如PVH和AVPV，以及像行为控制中心一样腹侧盖区域（VTA），丘脑（PVT）的室室核和侧面副核（PBL），并间接投射到岛状皮质上，参与感觉食物线索的解释，并与神经性厌食症的病理生理有关。这提案将进行MC3R神经元的第一个系统映射和表征参与能量稳态，繁殖和喂养行为的协调，确定MC3R对禁食诱导的要求的基础机制抑制HPG轴，并识别性介导的MC3R神经元和电路双态喂养行为。