The role of AGRP neurons in mediating food intake, valence, and obesity

AGRP 神经元在介导食物摄入、效价和肥胖中的作用

• 批准号: 9257690
• 负责人: Amber L Alhadeff
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257690
• 关键词: ART protein; Acute; Affective; American; Animals; Area; Attenuated; Automobile Driving; Axon; Behavior Therapy; Behavioral Assay; Biological; Body Weight decreased; Brain; Brain region; Calcium; Characteristics; Chronic; Data; Development; Diet; Eating; Feeding behaviors; Feeling; Food; Functional disorder; Goals; Human; Hunger; Hyperphagia; Hypothalamic structure; Image; Individual; Knowledge; Lateral; Lateral Hypothalamic Area; Literature; Measures; Mediating; Monitor; Mus; Negative Valence; Neurons; Nutrient; Obese Mice; Obesity; Pharmacological Treatment; Physiological; Plant Roots; Population; Prevalence; Public Health; Recruitment Activity; Regulation; Role; Signal Transduction; Site; Structure of nucleus infundibularis hypothalami; Structure of paraventricular nucleus of thalamus; Structure of terminal stria nuclei of preoptic region; Testing; Thinness; United States; Weight; Weight Gain; Work; base; design; energy balance; experimental study; feeding; innovation; insight; negative affect; neural circuit; novel; obesity treatment; paraventricular nucleus; prevent; relating to nervous system; tool; weight maintenance

PROJECT SUMMARY The recent increase in obesity prevalence is a major public health concern in the United States. Since energy balance regulation is rooted in the brain, understanding the neural feeding circuits that impede weight loss and maintenance is necessary for the development of novel obesity treatments. Agouti-related protein-expressing neurons in the hypothalamic arcuate nucleus (ARCAGRP) are both necessary and sufficient for food intake. Indeed, acute stimulation of ARCAGRP neurons drives food intake, and chronic stimulation leads to dramatic hyperphagia and weight gain. ARCAGRP neurons can be divided into distinct subpopulations that project to one of several target regions. Independent stimulation of four of these distinct projection subpopulations [ARCAGRP- bed nucleus of the stria terminalis (BNST), -paraventricular hypothalamic nucleus (PVH), -lateral hypothalamic area (LHA) and paraventricular thalamic nucleus (PVT)] is sufficient to drive food intake. We have also shown that ARCAGRP neurons transmit a negative valence that may be likened to the negative affect that is associated with hunger. Here, we take advantage of the one-to-one neuron connectivity to test the affective, functional and physiological relevance of ARCAGRP neuron subpopulations. The main goal of this proposal is to test the hypothesis that ARCAGRP neurons contribute to diet-induced obesity by driving food intake and negative valence through distinct neuron subpopulations. Specific Aim I experiments will examine the valence of the four ARCAGRP neuron subpopulations that increase feeding upon stimulation to provide insight into the specific neural projections that mediate negative affect associated with dieting for weight loss. Specific Aim II examines the neural activity dynamics of feeding-sufficient ARCAGRP neuron subpopulations during the gradual onset of hunger and feeding in lean and obese mice to better understand the endogenous role of feeding-sufficient ARCAGRP subpopulations in hunger and weight gain. Finally, given that persistent ARCAGRP neuron firing is associated with obesity, Specific Aim III experiments will directly examine the role of ARCAGRP neurons in the development and treatment of diet-induced obesity. Overall, results from these experiments will identify ARCAGRP neuron subpopulations, target regions, and mechanisms that can be leveraged to develop novel treatments for obesity.

项目摘要 最近，肥胖症患病率的增加是美国的主要公共卫生问题。自能量以来 平衡调节植根于大脑，了解阻碍体重减轻和 维护对于开发新型肥胖治疗是必要的。与Agouti相关的蛋白质表达 下丘脑弓形核（Arcagrp）中的神经元既需要食物摄入量。 实际上，急性刺激Arcagrp神经元驱动食物摄入，慢性刺激导致戏剧性 肥大和体重增加。 Arcagrp神经元可以分为不同的亚群，将其投射到一个 几个目标区域。独立刺激这些独特的投影亚群[Arcagrp- 质末端（BNST）的床核， - 脑室下丘脑核（PVH），侧丘脑下丘脑 面积（LHA）和旁腔丘脑核（PVT）]足以驱动食物摄入量。我们也显示了 Arcagrp神经元传递了可能比作负面影响的负价 饥饿。在这里，我们利用一对一的神经元连接来测试情感，功能和 Arcagrp神经元亚群的生理相关性。该提议的主要目的是测试 假设Arcagrp神经元通过驱动食物摄入和阴性有助于饮食引起的肥胖症 通过不同的神经元亚群的价。具体目的I实验将检查 四个Arcagrp神经元亚群，它们会增加刺激以洞察特定的刺激 介导与减肥节食相关的负面影响的神经预测。特定目标II检查 在逐渐开始逐渐发作的喂养弧形神经元亚群的神经活动动力学 饥饿和进食瘦和肥胖的小鼠，以更好地了解喂养充足的内源性作用 饥饿和体重增加中的Arcagrp亚群。最后，鉴于持续的Arcagrp神经元的射击是 与肥胖相关，特定的目标III实验将直接检查Arcagrp神经元在 饮食引起的肥胖症的发展和治疗。总体而言，这些实验的结果将确定 Arcagrp神经元亚群，目标区域和可以利用的机制发展为新型 肥胖的治疗。