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

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。本应用程序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身体营养状况。葡萄糖激酶存在于其他具有葡萄糖传感器功能的神经元和细胞中（如胰腺β细胞和已知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，从而适当地诱导餐后厌食症。胰岛素也被认为是一个诱导饱腹感的信号。因此，在OT神经元中存在InsR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是一种公认的厌食症药物（例如抑制食物摄入），控制OT分泌的改变可能有助于肥胖和/或提供预防或逆转肥胖的替代治疗策略。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机体营养储存激素指标的假说。2. 为了验证哺乳期改变葡萄糖和胰岛素对OT释放影响的假设。3. 为了验证葡萄糖激酶和InsR在SON中的作用被饮食引起的肥胖改变的假设。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神经元的细胞内钙（[Ca2+]i）信号。下丘脑和神经叶的激素释放都将被监测，因为OT的中枢作用是诱导厌食症，树突和/或过路轴突的OT释放被认为是腹内侧核“饱腹感神经元”中OT受体（OTR）配体的来源。由于哺乳期与促排卵和增加食物摄入有关，因此可能在哺乳期葡萄糖和胰岛素对促排卵的影响发生了改变，类似的变化导致肥胖个体在减少食物摄入方面遇到困难。

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.