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）：下丘脑上核核（SON）中葡萄糖酶和胰岛素受体（INSR）丰富。该应用的目的是开发背景信息，以确定SON中的催产素（OT）神经元是否利用这些分子来监测人体养分状态。在其他充当葡萄糖传感器的神经元和细胞中存在葡萄糖酶（例如，在公认的食欲调节中心中的胰腺β细胞和神经元）表明，葡萄糖敏感性可能使OT神经元可以使细胞外葡萄糖可监测外部葡萄糖，从而在一餐后诱导厌食。胰岛素也被认为是饱腹感信号。因此，OT神经元中INSR的存在可能为OT神经元监测身体养分状态的变化提供第二种机制。由于OT是公认的厌食剂（例如抑制食物摄入量），因此OT分泌控制的改变可能有助于肥胖和/或提供替代的治疗策略以预防或逆转肥胖。该提案的具体目的是：1。测试巨细胞OT神经元充当葡萄糖传感器并监测体内营养储存的激素指标的假设。 2。测试泌乳的假设会改变葡萄糖和胰岛素对OT释放的影响。 3。为了检验脂肪动物酶和INSR在SON中的作用的假设会因饮食诱导的肥胖而改变。下丘脑 - 神经型植物学系统（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，并确定细胞内钙（[Ca2+] i）信号是否通过葡萄糖和/或胰岛素在OT和VP SON神经元中改变了葡萄糖和胰岛素。下丘脑和神经叶激素的释放将受到监测，因为OT在集中诱导厌食症中，而树突状和/或EN传递轴突释放被认为是OT受体（OTR）在腹膜核核中的satietie神经元中的配体来源。由于泌乳既与刺激OT释放和食物摄入量增加有关，因此葡萄糖和胰岛素对OT释放的影响可能会改变泌乳期间，并且类似的变化导致肥胖个体在减少食物摄入量方面经历的困难。 公共卫生相关性：肥胖是一个重大的健康问题，因为目前，美国超过30％的成年人是肥胖，肥胖会增加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氏病。尽管做出了巨大的努力，但我们仍然缺乏预防或逆转对大多数人有帮助的肥胖症的干预措施。该提案将评估调节信号对催产素释放的影响，该特工知道可以抑制食物摄入量。