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

描述(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)中含量丰富。这项应用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。葡萄糖激酶在其他神经元和作为葡萄糖感受器的细胞中的存在(例如，胰腺β细胞和公认的食欲调节中心的神经元)表明，葡萄糖敏感性可能允许OT神经元监测细胞外葡萄糖，从而适当地反应诱导餐后厌食症。胰岛素也被认为是一种诱导饱腹感的信号。因此，OT神经元中InsR的存在可能为OT神经元监测机体营养状态的变化提供了第二种机制。由于OT是公认的厌食剂(例如抑制食物摄取)，OT分泌控制的改变可能会导致肥胖和/或提供替代治疗策略来预防或逆转肥胖。该提案的具体目的是：1.检验大细胞OT神经元作为血糖感受器的假设，并监测体内营养储存的激素指数。2.验证哺乳改变葡萄糖和胰岛素对催产素释放影响的假说。3.验证饮食诱导肥胖改变葡萄糖激酶和胰岛素受体在SON中作用的假说。下丘脑-神经垂体系统(HNS)的外植体将被用来确定葡萄糖和胰岛素对OT和VP释放的影响，以及葡萄糖和/或胰岛素是否改变了OT和VP SON神经元的细胞内钙([Ca+]i)信号。下丘脑和神经叶激素的释放都将受到监测，因为OT是引起厌食症的中枢作用，树突和/或传递性轴突OT的释放被认为是腹内侧核的饱腹神经元中OT受体(OTR)的配体的来源。由于哺乳期与催产素释放的刺激和食物摄入量的增加有关，葡萄糖和胰岛素对催产素释放的影响在哺乳期可能会发生变化，类似的变化也会导致肥胖者在减少食物摄入量方面遇到困难。 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%的成年人患有肥胖症，肥胖会增加患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。尽管付出了巨大的努力，但我们仍然缺乏对大多数人有帮助的预防或逆转肥胖的干预措施。这项建议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。

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.