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: 8394595
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394595
• 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; receptor; tool

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.

肥胖是一种全球流行病，在退伍军人中比在普通公众中更为普遍。的大小 最近，肥胖相关研究 (IL-12-2005-003) 的 RFA 强调了这一流行病 退伍军人事务部。尽管进行了积极的尝试，但迄今为止还没有合适的抗肥胖药物 可用的。因此，我们建议基于以下基础研究开发抗肥胖药物： 内源性食欲和饱腹感信号。在这方面，神经肽 Y (NPY) 是生物体内最丰富的肽。 哺乳动物大脑被认为是迄今为止分离出的最强大的食欲肽。 此外，下丘脑 NPY 还介导瘦素和生长素释放肽对食物摄入和代谢的作用。 此外，NPY 敲除的 ob/ob 小鼠吃得更少，能量消耗增加，因此， 肥胖程度较低。神经性厌食症和贪食症患者的 NPY 水平异常 脑脊液，经治疗后恢复正常。因此，NPY 构成了 控制食物摄入和能量消耗的神经肽能回路。另一方面NPY 同源肽，肽 YY (PYY) 和胰多肽 (PP)，由餐后释放 肠道通过关闭中枢食欲原的作用和/或合成来充当强大的饱腹感信号 信号包括 NPY。因此，四个G蛋白偶联受体分别表示为Y1、Y2、Y4和Y5 调节 NPY、PYY 和 PP 对食物摄入的作用仍然是发展的明显目标 抗肥胖药物。我们针对这一目标的调查已经确定了较低的 分子量三肽 (Y5)、五肽（Y1 和 Y4）和十肽 (Y2) 基序与 NPY 受体。我们现在假设对这些化合物的结构活性研究将导致 开发高效且受体选择性类似物，这对于 基础研究，也许还有临床实用性，特别是治疗肥胖症。这个假设将是 通过三个具体目标进行研究：1）长效有效受体的设计和合成 选择性配体； 2) 使用细胞系专门研究配体的体外特性 表达个体“Y”受体； 3) 研究受体特异性配体对食物摄入的体内影响 和大鼠的新陈代谢。对退伍军人医疗保健的潜在影响：拟议的研究可能会导致 开发新型抗食欲和饱腹感药物。与这些药物一起治疗 饮食和锻炼有望缓解退伍军人的超重问题。此外， NPY 还与焦虑、抑郁和创伤后应激障碍 (PTSD) 的病理生理学有关。 在退伍军人中非常普遍。因此，我们的研究最终可能会导致改善 不仅影响超重退伍军人的生活质量，还影响那些患有各种精神疾病的人的生活质量。这 可以增加召回机会并减轻退伍军人医疗保健费用的负担。