Regulation of Food Intake and Body Adiposity by Peptide YY

肽 YY 对食物摄入和身体肥胖的调节

• 批准号: 7564679
• 负责人: ROGER REIDELBERGER
• 金额: $ 22.92万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-15 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7564679
• 关键词: Abdomen; Address; Adult; Affect; Affinity; Agonist; American; Antibodies; Behavioral; Binding Sites; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Stem; Brain region; Cannulas; Cells; Cholecystokinin; Coupled; Denervation; Development; Diabetes Mellitus; Distal; Dose; Eating; Endocrine; Energy Intake; Environmental Risk Factor; Family; Food Intake Regulation; Genetic Predisposition to Disease; Glycine; Hand; Health Care Costs; Heart Diseases; Hormonal; Human; Hypothalamic structure; Infusion procedures; Intestines; Leptin; Life Style; Ligands; Link; Malignant Neoplasms; Mediating; Medulla Oblongata; Methods; Nerve; Nutrient; Obesity; Obesity associated disease; Overweight; Pancreas; Pancreatic Polypeptide; Peptide YY; Peptides; Peripheral; Phosphorylated Peptide; Physiological; Pituitary Gland; Plasma; Pontine structure; Prevalence; Prevention strategy; Production; Protein Isoforms; Proteomics; Rattus; Reporting; Research Personnel; Rodent; Satiation; Signal Transduction; Site; Source; Stomach; Structure of jugular vein; Testing; Tissues; Visceral; anorexigenic peptide; base; depression; feeding; glucagon-like peptide 1; islet amyloid polypeptide; meetings; neuropeptide Y; novel; obesity in children; paracrine; receptor; response; sedentary

DESCRIPTION (provided by applicant): More than 64% of US adults are overweight or obese, with nearly 31% (over 61 million) meeting criteria for obesity. There is a clear link between obesity and the development of diabetes, heart disease, many cancers, and depression. Defining the physiological mechanisms that control food intake thus provides direction in the search for pathogenic mechanisms of obesity and strategies for prevention and treatment of obesity-related diseases. Peptide YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP) comprise a family of structurally related brain-gut peptides with diverse actions mediated by four known receptors (Y1, Y2, Y4, Y5). Endocrine cells of the distal gut provide a major source of PYY. Food intake releases at least two forms of PYY into the circulation: PYY(1-36) and PYY(3-36); other predicted/detected isoforms include PYY(1-36)-Gly, PYY(3-36)-Gly, [Ser13PO3]PYY(1-36), and [Ser13P03]PYY(3-36). Systemic administration of PYY(3-36) potently inhibits food intake in rodents and humans; PYY(1-36) is 10-fold less potent in rats. Obese humans appear to have a blunted plasma PYY response to food intake; yet, low doses of PYY(3-36) decrease food intake similarly in lean and obese humans. Together, these results suggest that PYY(3-36) may act physiologically to reduce food intake and body adiposity, and that insufficient production of PYY(3-36) may promote obesity. Studies will test the hypothesis that PYY(3-36) secreted by the gut in response to a meal acts as a hormonal signal to the brain to produce satiety and regulate energy reserves. Rats with indwelling jugular vein, abdominal aortic, and/or gastric cannulae will be used to address the following specific aims: 1) Determine whether PYY(3-36), when infused iv, is the most potent and efficacious PYY isoform for reducing food intake. 2) Use selective Y-receptor agonists and antagonists to identify the Y-receptor subtype(s) that mediate anorexic responses to exogenous PYY isoform(s). 3) Determine whether anorexigenic PYY isoform(s) act synergistically with other putative satiety and body energy regulatory signals (CCK, amylin, GLP-1, leptin) to reduce food intake. 4) Determine whether body adiposity is reduced by daily, intermittent iv infusions of anorexigenic PYY isoform(s) when given alone and in combination with other PYY isoform(s), satiety peptides, and leptin. 5) Use novel proteomic methods to determine whether postprandial increases in plasma levels of PYY isoform(s), when reproduced by iv infusion, are sufficient to reduce food intake and body adiposity. 6) Determine whether circulating PYY isoform(s) act as essential blood-borne signals to the brain to reduce food intake, by investigating whether immuneutralization of circulating PYY increases food intake. 7) Use antagonists of PYY action (receptor antagonists and PYY antibodies) and abdominal vagal denervation to determine whether anorexigenic PYY isoform(s) act through control of vagal signaling to the brain to reduce food intake.

描述（由申请人提供）：超过64％的美国成年人超重或肥胖，近31％（超过6100万）满足肥胖标准。 肥胖与糖尿病，心脏病，许多癌症和抑郁症之间存在明确的联系。 因此，定义控制食物摄入的生理机制，因此为寻找肥胖症的致病机制和预防和治疗肥胖相关疾病的策略提供了方向。 肽YY（PYY），神经肽Y（NPY）和胰多肽（PP）组成了一个结构相关的脑肠肽家族，具有由四个已知受体（Y1，Y2，Y4，Y5）介导的各种作用。 远端肠道的内分泌细胞提供了PYY的主要来源。 食物摄入量至少将两种形式的PYY释放到循环中：PYY（1-36）和PYY（3-36）；其他预测/检测到的同工型包括PYY（1-36） - gly，pyy（3-36） - gly，[ser13po3] pyy（1-36）和[ser13p03] pyy（3-36）。 PYY的系统给药（3-36）有效抑制啮齿动物和人类的食物摄入； PYY（1-36）在大鼠中的效力降低了10倍。 肥胖的人类似乎对食物摄入的血浆pyy反应钝。然而，低剂量的PYY（3-36）在瘦和肥胖的人类中类似地降低了食物摄入量。 总之，这些结果表明PYY（3-36）可以在生理上采取行动来减少食物摄入和身体肥胖，而PYY的产生不足（3-36）可能会促进肥胖。 研究将检验以下假设：肠道对饮食的分泌PYY（3-36）是对大脑的激素信号，以产生饱腹感和调节能量储量。 具有留置颈静脉，腹部主动脉和/或胃套管的大鼠将用于解决以下特定目的：1）确定PYY（3-36）（3-36）（3-36）是否是注入IV时是否是最有效，最有效的PYY PYY同工型，用于减少食物摄入量。 2）使用选择性Y受体激动剂和拮抗剂来识别Y受体亚型，这些亚型介导了对外源性PYY同工型（S）的厌食症反应。 3）确定厌食症PYY同工型是否与其他推定的饱腹感和体能调节信号（CCK​​，Amylin，GLP-1，瘦素）协同作用，以减少食物摄入量。 4）确定每天通过单独给出并与其他PYY同工型（S），饱腹肽和瘦素结合的每日间歇性静脉输注厌食性PYY同工型（s）是否会降低体内肥胖。 5）使用新型的蛋白质组学方法来确定餐后血浆同工型的血浆水平是否会在IV输注中再现时是否足以降低食物摄入量和身体肥胖。 6）确定通过研究循环PYY的免疫中和化是否会增加食物摄入量是否会增加循环的PYY同工型（S）作为对大脑降低食物摄入的必不可少的血液传播信号。 7）使用PYY作用（受体拮抗剂和PYY抗体）和腹部迷走神经去神经的拮抗剂来确定是否通过控制对大脑的迷走神经信号传导来减少食物摄入量来确定厌食症PYY同工型（S）作用。