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

项目摘要 最近肥胖患病率的增加是美国主要的公共卫生问题。因为能源 平衡调节植根于大脑，了解阻碍减肥的神经营养回路， 维持对于开发新的肥胖症治疗是必要的。Agouti相关蛋白表达 下丘脑弓状核（ARCAGRP）中的神经元对于食物摄取是必要的和足够的。 事实上，急性刺激ARCAGRP神经元驱动食物摄入，慢性刺激导致戏剧性的 食欲过盛和体重增加。ARCAGRP神经元可以分为不同的亚群， 几个目标区域。这些不同的投射亚群中的四个的独立刺激[ARCAGRP-2010]。 终纹床核（BNST），下丘脑室旁核（PVH），下丘脑外侧核 丘脑室旁核（PVT）和丘脑腹侧区（LHA）足以驱动食物摄入。我们还表明 ARCAGRP神经元传递负效价，这可能与相关的负面影响有关， 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。本提案的主要目标是测试 假设ARCAGRP神经元通过驱动食物摄入和负反馈来促进饮食诱导的肥胖 通过不同的神经元亚群。具体目标I实验将检查 四个ARCAGRP神经元亚群，增加刺激后的进食，以提供对特定 调节与节食减肥相关的负面影响的神经投射。具体目标II检查 进食充足的ARCAGRP神经元亚群的神经活动动力学在逐渐发作的 饥饿和喂养瘦和肥胖小鼠，以更好地了解内源性作用的喂养充足 饥饿和体重增加的ARCAGRP亚群。最后，考虑到持续的ARCAGRP神经元放电是 与肥胖相关，特异性目标III实验将直接研究ARCAGRP神经元在肥胖中的作用。 饮食诱导的肥胖症的发展和治疗。总的来说，这些实验的结果将确定 ARCAGRP神经元亚群、靶区域和可用于开发新的 肥胖症的治疗方法

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.