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: 7177552
• 负责人: ROGER REIDELBERGER
• 金额: $ 23.49万
• 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/7177552
• 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; Child; Cholecystokinin; Coupled; Daily; 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; Mental Depression; Methods; Nerve; Nutrient; Obesity; Obesity associated disease; Overweight; 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; feeding; glucagon-like peptide 1; islet amyloid polypeptide; neuropeptide Y; novel; 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）符合肥胖标准。 肥胖与糖尿病、心脏病、许多癌症和抑郁症的发展之间存在明显的联系。 因此，确定控制食物摄入的生理机制为寻找肥胖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）包括结构相关的脑肠肽家族，其具有由四种已知受体（Y1、Y2、Y 4、Y 5）介导的不同作用。 肠道远端的内分泌细胞是PYY的主要来源。 食物摄入会释放至少两种形式的PYY进入循环：PYY（1-36）和PYY（3-36）;其他预测/检测到的亚型包括PYY（1-36）-Gly、PYY（3-36）-Gly、[Ser 13 PO 3]PYY（1-36）和[Ser 13 P03]PYY（3-36）。 全身给予PYY（3-36）可有效抑制啮齿类动物和人类的食物摄入; PYY（1-36）在大鼠中的效力低10倍。 肥胖的人似乎对食物摄入具有钝化的血浆PYY响应;然而，低剂量的PYY（3-36）在瘦的和肥胖的人中类似地减少食物摄入。 总之，这些结果表明，PYY（3-36）可能在生理上起到减少食物摄入和身体肥胖的作用，并且PYY（3-36）的产生不足可能会促进肥胖。 研究将测试这一假设，即肠道在进餐时分泌的PYY（3-36）作为大脑的激素信号，产生饱腹感并调节能量储备。 将使用具有留置颈静脉、腹主动脉和/或胃插管的大鼠来解决以下具体目的：1）确定当静脉输注时，PYY（3-36）是否是减少食物摄入的最有效和最有效的PYY同种型。 2)使用选择性Y-受体激动剂和拮抗剂来鉴定介导对外源性PYY亚型的免疫应答的Y-受体亚型。 3)确定产酶PYY亚型是否与其他假定的饱腹感和身体能量调节信号（CCK、胰淀素、GLP-1、瘦素）协同作用以减少食物摄入。 4)确定当单独给药和与其他PYY亚型、饱腹感肽和瘦素联合给药时，每天间歇性静脉输注产脂PYY亚型是否能减少身体肥胖。 5)使用新的蛋白质组学方法来确定餐后PYY亚型血浆水平的增加，当通过静脉输注重现时，是否足以减少食物摄入和身体肥胖。 6)通过研究循环PYY的免疫中和是否增加食物摄入，确定循环PYY同种型是否作为大脑减少食物摄入的必要血液传播信号。 7)使用PYY作用的拮抗剂（受体拮抗剂和PYY抗体）和腹部迷走神经去神经支配，以确定是否通过控制迷走神经信号传导至大脑来减少食物摄入的促氧化PYY亚型。