Role of Neuropeptide Y in Obesity-Receptor Specific Analogs

神经肽 Y 在肥胖受体特异性类似物中的作用

• 批准号: 7789830
• 负责人: AMBIKAIPAKAN BALASUBRAMANIAM
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789830
• 关键词: Agonist; Anorexia Nervosa; Anti-Obesity Agents; Anxiety; Arthritis; Body Weight; Brain; Bulimia; Cell Line; Cerebrospinal Fluid; Clinical; Clinical Trials; Coronary Arteriosclerosis; Development; Diabetes Mellitus; Disease; Eating; Energy Metabolism; Epidemic; Exhibits; Family; Food Energy; Functional disorder; G-Protein-Coupled Receptors; General Population; Goals; Health Care Costs; Healthcare; Hormones; Hypertension; Hypothalamic structure; In Vitro; Individual; Interleukin-12; Intestines; Investigation; Knock-out; Lead; Leptin; Ligands; Marketing; Mediating; Mental Depression; Metabolic Control; Metabolism; Molecular Weight; Neuropeptide Y Receptor; Obesity; Overweight; Pancreatic Polypeptide; Patients; Peptide YY; Peptides; Peripheral; Pharmaceutical Preparations; Population; Post-Traumatic Stress Disorders; Property; Psychiatry; Quality of life; Rattus; Research; Rodent; Role; Satiation; Signal Transduction; Structure; Testing; Veterans; analog; base; design; diet and exercise; feeding; ghrelin; improved; in vivo; neuropeptide Y; neuropeptide Y4 receptor; novel; peptide analog; public health relevance; receptor; tool

DESCRIPTION (provided by applicant): Obesity, a global epidemic, is more prevalent among veterans than in the general public. The magnitude of this epidemic is highlighted by a recent RFA for obesity-related research (IL-12-2005-003) by the Department of Veteran Affairs. Despite vigorous attempts, to date no suitable anti-obesity drugs are available. We therefore propose investigations towards the development of anti-obesity drugs based on endogenous orexigenic and satiety signals. In this regard, neuropeptide Y (NPY), most abundant peptide in the mammalian brain, has been characterized as the most powerful orexigenic peptide isolated to date. Moreover, hypothalamic NPY also mediates the actions of leptin and ghrelin on food intake and metabolism. In addition, NPY knock-out ob/ob mice ate less and exhibited increased energy expenditure, and therefore, were less obese. Patients with anorexia nervosa and bulimia had abnormal levels of NPY in the cerebrospinal fluid, which returned to normal on treatment. Thus, NPY constitutes a critical component of neuropeptidergic circuitary controlling food intake and energy expenditure. On the other hand NPY homologous peptides, peptide YY (PYY) and pancreatic polypeptide (PP), released postprandially by the intestine act as powerful satiety signals via shutting off the actions and/or synthesis of central orexigenic signals including NPY. Therefore, the four G-protein coupled receptors denoted as Y1, Y2, Y4, and Y5 mediating the actions of NPY, PYY and PP on food intake remain obvious targets for the development of anti-obesity drugs. Our investigations towards this goal have already led to the identification of lower molecular weight tri-peptide (Y5), pentapeptide (Y1 and Y4) and decapeptide (Y2) motifs for interaction with NPY receptors. We now hypothesize that structure-activity studies with these compounds will lead to the development of highly potent and receptor selective analogs which would have great significance for fundamental investigations and perhaps for clinical utility, especially to treat obesity. This hypothesis will be investigated through three specific aims: 1) Design and synthesis of long acting and potent receptor selective ligands; 2) Investigation of the in vitro properties of the ligands using cell lines specifically expressing individual "Y" receptors; 3) Investigating in vivo effects of receptor specific ligands on food intake and metabolism in rats. Potential Impact on Veterans Health Care: The proposed study may lead to the development of novel class of anti-orexigenic and satiety drugs. Treatment with these drugs together with diet and exercise can be expected to alleviate the overweight problem among the veterans. In addition, NPY have also been implicated NPY in the pathophysiology of anxiety, depression and PTSD, conditions highly prevalent among the veterans. Therefore, our studies may eventually lead to the betterment of the quality of life of not only the overweight veterans, but also those with a variety of psychiatry disorders. This could enhance recall opportunities and reduce the burden on the Veterans Health Care cost. PUBLIC HEALTH RELEVANCE: Significance & Relevance to the Veteran Population: The understanding of the mechanism of action of the most powerful orexigenic peptide, NPY, on food intake may eventually lead to the development of novel classes of anti-orexigenic and satiety drugs. Since 70% of the veterans are already overweight or obese, treatment with these drugs together with diet and exercise can be expected to alleviate the overweight problem among veterans. This may improve the quality of life of veterans and reduce the burden on health care costs.

描述（由申请人提供）： 肥胖症是一种全球流行病，在退伍军人中比在公众中更普遍。近期与肥胖有关的研究（IL-12-2005-003）的RFA强调了这种流行病的大小。尽管有剧烈的尝试，但迄今为止尚无合适的抗肥胖药物。因此，我们提出了基于内源性染料和饱腹感信号的抗肥胖药物的研究。在这方面，哺乳动物大脑中最丰富的肽的神经肽Y（NPY）被描述为迄今为止分离的最强大的甲状腺素肽。此外，下丘脑NPY还介导了瘦素和生长素素对食物摄入和代谢的作用。此外，NPY敲除ob/ob小鼠吃的少，表现出增加的能量消耗，因此肥胖较少。神经性厌食症和贪食症患者在脑脊液中的NPY水平异常，治疗后恢复正常。因此，NPY构成了控制食物摄入和能量消耗的神经肽循环的关键组成部分。另一方面，NPY同源肽，肽YY（PYY）和胰多肽（PP），通过肠道行为后在餐后释放，通过关闭包括NPY在内的中央或过肌信号的动作和/或合成。因此，四种G蛋白偶联受体表示为Y1，Y2，Y4和Y5，介导NPY，PYY和PP对食物摄入的作用仍然是抗肥胖药物发展的明显靶标。我们对该目标的研究已经导致鉴定出较低的分子量三肽（Y5），五肽（Y1和Y4）和脱肽（Y2）基序，以与NPY受体相互作用。现在，我们假设使用这些化合物的结构活性研究将导致高度有效和受体选择性类似物的发展，这对基本研究和临床效用可能具有重要意义，尤其是治疗肥胖症。该假设将通过三个特定目的进行研究：1）长作用和有效受体选择性配体的设计和合成； 2）使用专门表达个体“ Y”受体的细胞系研究配体的体外特性； 3）研究受体特异性配体对大鼠食物摄入和代谢的体内影响。对退伍军人卫生保健的潜在影响：拟议的研究可能导致新型抗毒和饱腹药的发展。可以期望用这些药物与饮食和运动进行治疗，以减轻退伍军人之间的超重问题。此外，NPY在焦虑，抑郁和PTSD的病理生理学中也被牵涉到退伍军人中高度普遍的疾病。因此，我们的研究最终可能会改善不仅超重退伍军人的生活质量，而且还提高了患有各种精神病障碍的人的生活质量。这可以增加召回机会并减轻退伍军人医疗保健成本的负担。 公共卫生相关性： 与退伍军人人口的意义和相关性：对食物摄入量最强大的肽肽NPY的作用机理的理解最终可能导致新型的抗厌食和饱腹药的新型。由于70％的退伍军人已经超重或肥胖，因此可以预期用这些药物与饮食和运动进行治疗，以减轻退伍军人之间的超重问题。这可能会改善退伍军人的生活质量，并减轻医疗保健成本的负担。