Regulation of Hypothalamic POMC by Leptin

描述(申请人提供)：肥胖症和2型糖尿病在美国的发病率令人震惊，总共影响了超过1.2亿人，其中许多是儿童。目前，与营养不良的人数相比，世界上更多的人患有肥胖症和糖尿病。这些疾病每年与数十亿美元的医疗费用有关。常见肥胖/糖尿病的原因尚不清楚，也不存在有效的治疗方法。瘦素是一种荷尔蒙，通常在脂肪组织中产生，释放到循环中，在大脑中发挥作用，减少卡路里摄入量和体重，并改善葡萄糖平衡。在大脑中的许多瘦素反应细胞中有两类神经元，即下丘脑阿片黑质皮质素原(POMC)和刺鼠相关肽(AgRP)神经元。POMC通过大脑中特定的黑素皮质素受体产生多肽，以减少食物摄入量和体重，其表达受到瘦素的刺激。同时，瘦素抑制AgRP的表达和释放，AgRP是一种通过抑制POMC-肽信号来增加卡路里摄入量的肽。缺乏瘦素或瘦素受体，或POMC或黑素皮质素受体基因突变的人类和小鼠，会出现严重的吞噬功能亢进、肥胖和胰岛素抵抗。在这个方案中，我们将使用转基因小鼠来研究瘦素如何通过POMC和AgRP神经元发挥作用，减少卡路里摄入量和减轻体重，并极大地改善葡萄糖平衡。总之，拟议的研究将增加我们对瘦素如何作用于减轻体重和食物摄入量，以及改善葡萄糖平衡的理解。这一发现可能有助于识别新的抗肥胖/糖尿病药物靶点。与公共健康相关：该项目旨在确定荷尔蒙瘦素在大脑中作用的机制，以减轻体重和脂肪质量，减少卡路里摄入量，并改善葡萄糖代谢。具体地说，我们将确定瘦素通过下丘脑POMC和AGRP神经元中的信号影响这些过程的途径。这项资助还将确定瘦素受体在这些特定神经元中的定位调节，因为这与瘦素抵抗肥胖的机制有关。因此，所获得的数据将与未来确定新的抗肥胖/糖尿病药物途径/靶点相关。

DESCRIPTION (provided by applicant): Obesity and Type 2 diabetes occurs with an alarming incidence in the United States, altogether affecting more than 120 million people, many of which are children. Currently, more people are obese and have diabetes in the world as compared to the number of humans who are undernourished. These diseases are associated with billions of dollars in health costs each year. The cause of common obesity/diabetes is unknown and effective treatments do not exist. Leptin is a hormone that is normally produced in fat tissue, released into circulation, and acts in the brain to reduce caloric intake and bodyweight, and to improve glucose balance. Among many leptin-responsive cells in the brain are two neuronal populations, the hypothalamic proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. POMC produce peptides that act via specific melanocortin receptors in the brain to reduce food intake and body weight, and their expression is stimulated by leptin. In parallel, leptin inhibits expression and release of AgRP, a peptide that increases caloric intake by inhibiting POMC-peptide signaling. Humans and mice lacking leptin or leptin receptors, or have mutations in the POMC or the melanocortin receptor genes, suffer from severe hyperphagia, obesity, and insulin resistance. We will in this proposal use transgenic mice to investigate how leptin decreases caloric intake and reduces body weight, and vastly improves glucose balance, by acting via POMC and AgRP neurons. Altogether, the proposed studies will increase our understanding of how leptin acts to decrease body weight and food intake, and to improve glucose balance. The findings may help identification of novel anti-obesity/diabetes drug-targets. PUBLIC HEALTH RELEVANCE: This project aims to identify mechanisms whereby the hormone leptin acts in the brain to reduce body weight and fat mass, reduce caloric intake, and improve glucose metabolism. Specifically, we will identify pathways by which leptin influences these processes, via signaling in hypothalamic POMC and AGRP neurons. The grant will also determine regulation of leptin receptor localization within these specific neurons as this pertains to mechanisms of leptin-resistant obesity. Obtained data will therefore be relevant for future identification of novel anti-obesity/diabetes drug pathways/targets.