Oxytocin responses to insulin and glucose: Impact of lactation and obesity

催产素对胰岛素和葡萄糖的反应：哺乳和肥胖的影响

• 批准号: 8243875
• 负责人: CELIA D SLADEK
• 金额: $ 22.69万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243875
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Address; Adult; Alzheimer' s Disease; Anorexia; Appetite Depressants; Appetite Regulation; Blood Circulation; Brain; Calcium; Calcium Channel; Cell Nucleus; Cell physiology; Desire for food; Diabetes Mellitus; Diestrus; Diet; Disease; Eating; Epidemic; Female; Figs - dietary; GLUT-3 protein; GLUT4 gene; Gastric Bypass; Glucokinase; Glucose; Glucose Transporter; Goals; Health; Hormonal; Hormones; Human; Hypothalamic structure; Immunohistochemistry; Individual; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Laboratories; Lactation; Ligands; Lobe; Mediating; Minor; Monitor; Mus; Neurons; Nutrient; Obesity; Oxytocin; Oxytocin Receptor; Peripheral; Play; Potassium Channel; Production; Rattus; Resistance; Risk; Role; Satiation; Signal Transduction; Source; Stimulus; Structure of beta Cell of islet; System; Testing; Vasopressins; Weight Gain; experience; extracellular; feeding; glucokinase receptor; glucose monitor; glucose sensor; glucose uptake; hormone regulation; hypertensive heart disease; indexing; insulin sensitivity; mRNA Expression; magnocellular; male; meetings; novel; paraventricular nucleus; parvocellular; prevent; receptor; relating to nervous system; response; supraoptic nucleus; treatment strategy; voltage

DESCRIPTION (provided by applicant): Glucokinase and insulin receptors (InsR) are abundant in the hypothalamic supraoptic nucleus (SON). The goal of this application is to develop background information to determine if the oxytocin (OT) neurons in SON utilize these molecules to monitor body nutrient status. The presence of glucokinase in other neurons and cells that function as glucose sensors (e.g. pancreatic beta cells and neurons in recognized appetite regulating centers) suggests that glucose-sensitivity may allow the OT neurons to monitor extracellular glucose and thereby respond appropriately to induce anorexia after a meal. Insulin is also recognized as a satiety-inducing signal. Thus, the presence of InsR in OT neurons may provide a second mechanism for the OT neurons to monitor changes in body nutrient status. Since OT is a recognized anorexic agent (e.g. suppresses food intake), alterations in the control of OT secretion may contribute to obesity and/or provide alternate treatment strategies to prevent or reverse obesity. The specific aims of the proposal are: 1. To test the hypothesis that magnocellular OT neurons function as glucose sensors and monitor hormonal indices of body nutrient stores. 2. To test the hypothesis that lactation alters the effect of glucose and insulin on OT release. 3. To test the hypothesis that the role of glucokinase and InsR in SON is altered by diet- induced obesity. Explants of the hypothalamo-neurohypophyseal system (HNS) will be used to determine the effect of glucose and insulin on OT and VP release and to determine if intracellular calcium ([Ca2+]i) signaling is altered in OT and VP SON neurons by glucose and/or insulin. Both hypothalamic and neural lobe hormone release will be monitored, because OT acts centrally to induce anorexia, and dendritic and/or en passant axonal OT release is thought to be the source of ligand for OT receptors (OTR) in 'satiety neurons' of the ventromedial nucleus. Since lactation is associated with both stimulation of OT release and increased food intake, it is possible that the impact of glucose and insulin on OT release is altered during lactation and that similar changes contribute to the difficulty that obese individuals experience in reducing food intake. PUBLIC HEALTH RELEVANCE: Obesity is a significant health concern, because currently more than 30% of adults in the USA are obese and obesity increases the risk for other major diseases including hypertension, heart disease, diabetes, and Alzheimer's disease. In spite of intense efforts, we still lack interventions for preventing or reversing obesity that are helpful to the majority of people. This proposal will evaluate the effect of appetite regulating signals on oxytocin release, an agent know to suppress food intake.

描述（由申请人提供）：葡萄糖激酶和胰岛素受体（InsR）在下丘脑视上核（SON）中丰富。本申请的目标是开发背景信息，以确定SON中的催产素（OT）神经元是否利用这些分子来监测身体营养状态。在其他神经元和作为葡萄糖传感器的细胞（例如胰腺β细胞和公认的食欲调节中心的神经元）中存在葡萄糖激酶表明葡萄糖敏感性可能允许OT神经元监测细胞外葡萄糖，从而适当地响应以诱导餐后厌食症。胰岛素也被认为是一种饱腹感诱导信号。因此，InsR在OT神经元中的存在可能为OT神经元监测身体营养状态的变化提供了第二种机制。由于OT是公认的抗肥胖剂（例如抑制食物摄入），OT分泌控制的改变可能导致肥胖和/或提供替代治疗策略以预防或逆转肥胖。该提案的具体目标是：1。验证大细胞OT神经元作为葡萄糖传感器和监测体内营养物质储存的激素指标的假设。2.为了验证哺乳改变葡萄糖和胰岛素对OT释放的影响的假设。3.验证葡萄糖激酶和InsR在SON中的作用被饮食诱导的肥胖改变的假设。下丘脑-神经垂体系统（HNS）的外植体将用于确定葡萄糖和胰岛素对OT和VP释放的影响，并确定葡萄糖和/或胰岛素是否改变OT和VP SON神经元中的细胞内钙（[Ca 2 +]i）信号传导。下丘脑和神经叶激素释放都将被监测，因为OT在中枢作用以诱导厌食症，并且树突和/或传递轴突OT释放被认为是腹内侧核的“饱腹感神经元”中OT受体（OTR）的配体的来源。由于哺乳与OT释放的刺激和食物摄入量的增加有关，因此可能在哺乳期间葡萄糖和胰岛素对OT释放的影响发生了变化，并且类似的变化导致肥胖个体在减少食物摄入方面遇到困难。 公共卫生相关性：肥胖是一个重要的健康问题，因为目前美国超过30%的成年人肥胖，肥胖增加了其他主要疾病的风险，包括高血压、心脏病、糖尿病和阿尔茨海默病。尽管做出了巨大努力，但我们仍然缺乏对大多数人有帮助的预防或扭转肥胖的干预措施。这项提案将评估食欲调节信号对催产素释放的影响，催产素是一种已知的抑制食物摄入的药物。