Regulation of Hypothalamic POMC by Leptin

描述（由申请人提供）：肥胖和2型糖尿病在美国的发病率惊人，总共影响了超过1.2亿人，其中许多是儿童。目前，世界上肥胖和糖尿病患者的人数比营养不良的人数要多。这些疾病每年造成数十亿美元的医疗费用。常见肥胖/糖尿病的病因尚不清楚，也没有有效的治疗方法。瘦素是一种激素，通常在脂肪组织中产生，释放到血液循环中，在大脑中起作用，减少热量摄入和体重，改善葡萄糖平衡。在大脑中许多对瘦素有反应的细胞中有两个神经元群，即下丘脑促黑素皮质素（POMC）和刺痛素相关肽（AgRP）神经元。POMC通过大脑中特定的黑素皮质素受体产生肽，减少食物摄入和体重，瘦素刺激它们的表达。同时，瘦素抑制AgRP的表达和释放，AgRP是一种通过抑制pomc肽信号传导增加热量摄入的肽。人类和小鼠缺乏瘦素或瘦素受体，或在POMC或黑素皮质素受体基因中有突变，患有严重的贪食、肥胖和胰岛素抵抗。我们将在本提案中使用转基因小鼠来研究瘦素如何通过POMC和AgRP神经元减少热量摄入和减轻体重，并极大地改善葡萄糖平衡。总的来说，拟议的研究将增加我们对瘦素如何减少体重和食物摄入以及改善葡萄糖平衡的理解。这一发现可能有助于确定新的抗肥胖/糖尿病药物靶点。公共卫生相关性：本项目旨在确定瘦素激素在大脑中的作用机制，以减少体重和脂肪量，减少热量摄入，并改善葡萄糖代谢。具体来说，我们将通过下丘脑POMC和AGRP神经元的信号传导来确定瘦素影响这些过程的途径。该基金还将确定瘦素受体在这些特定神经元中的定位调节，因为这与瘦素抵抗性肥胖的机制有关。因此，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.