Regulation of Food Intake & Body Adiposity by Peptide YY

食物摄入量的调节

• 批准号: 7016101
• 负责人: ROGER REIDELBERGER
• 金额: $ 24.8万
• 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/7016101
• 关键词: appetite; behavioral /social science research tag; bioenergetics; denervation; gastrointestinal hormones; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; laboratory rat; neuropeptide receptor; nutrient intake activity; nutrition related tag; obesity; peptide hormone; proteomics; satiations; weight control

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，其中近 31%（超过 6100 万人）符合肥胖标准。 肥胖与糖尿病、心脏病、多种癌症和抑郁症的发生之间存在明显的联系。 因此，定义控制食物摄入的生理机制为寻找肥胖的致病机制以及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) 包含一系列结构相关的脑肠肽，具有由四种已知受体（Y1、Y2、Y4、Y5）介导的不同作用。 远端肠道的内分泌细胞是 PYY 的主要来源。 食物摄入至少释放两种形式的 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、[Ser13PO3]PYY(1-36) 和 [Ser13P03]PYY(3-36)。 全身给予 PYY(3-36) 可有效抑制啮齿动物和人类的食物摄入； PYY(1-36) 在大鼠中的效力低 10 倍。 肥胖人群对食物摄入的血浆 PYY 反应似乎减弱；然而，低剂量的 PYY(3-36) 会减少瘦人和肥胖人的食物摄入量。 总之，这些结果表明 PYY(3-36) 可能在生理上发挥作用，以减少食物摄入和身体肥胖，并且 PYY(3-36) 产生不足可能会促进肥胖。 研究将检验这样的假设：肠道响应进餐而分泌的 PYY(3-36) 作为向大脑发出的激素信号，以产生饱腹感并调节能量储备。 留置颈静脉、腹主动脉和/或胃插管的大鼠将用于实现以下具体目标：1) 确定静脉注射时 PYY(3-36) 是否是减少食物的最有效的 PYY 亚型摄入量。 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 同工型厌食反应的 Y 受体亚型。 3) 确定抑制食欲的 PYY 异构体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) 确定当单独给予或与其他 PYY 同工型、饱腹感肽和瘦素联合给予时，每天、间歇性静脉内输注致食欲 PYY 同工型是否可以减少身体肥胖。 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（当通过静脉输注复制时）是否足以减少食物摄入和身体肥胖。 6) 通过研究循环 PYY 的免疫中和是否会增加食物摄入量，确定循环 PYY 亚型是否充当大脑必需的血源性信号以减少食物摄入量。 7) 使用PYY作用拮抗剂（受体拮抗剂和PYY抗体）和腹部迷走神经去神经术来确定厌食性PYY亚型是否通过控制迷走神经信号传导至大脑来减少食物摄入。