Central neural function of Urocortin 3 in regulating energy balance

项目摘要/摘要 控制食物摄入量和能量消耗对于保持稳定的体重至关重要。 摄入过多的能量会导致肥胖，肥胖是包括糖尿病在内的许多疾病的主要风险因素。 还有高血压素。下丘脑中的神经肽在调节能量平衡方面起着关键作用。一个 详细了解下丘脑多肽及其受体在控制摄食、饱腹感和能量方面的作用 支出是了解肥胖和相关疾病原因的关键。Urocortin 3(UCN 3)是一种新的 在啮齿动物和人类中发现的神经肽，具有强烈的中枢食欲抑制作用。UCN 3是 在包括下丘脑在内的不同脑区高水平表达。大量表达UCN-3的神经元 支配下丘脑腹内侧核(VMH)。UCN 3的受体是2型CRF受体(CRFR2)，它是 在VMH中高度表达，其表达受动物能量状态的调节。重要的是 将UCN_3直接注入VMH可抑制食物摄取，升高血糖水平并激活 下丘脑弓状核内的厌食性POMC神经元。VMH已被公认为 饱腹感中心和它感知血糖水平的能力，然而这个大脑区域 调节摄食和血糖尚不清楚。因此，我们假设UCN 3及其受体是一个关键的 分子介体在VMH中调节能量动态平衡。本项目的主要目标是：(1) 确定介导UCN-3在VMH中作用的神经回路，(2)确定UCN-3的生理作用 内源性UCN_3和CRFR2在VMH调节摄食量和血糖动态平衡中的作用 确定在VMH中调节UCN 3效应的机制。该项目将首先利用一种新的 分子示踪技术与功能解剖学相结合描绘神经通路 UCN_3在VMH中的作用及电生理和药理学方法测定 UCN_3对VMH靶神经元活动的影响然后，该项目将检查POMC神经元 介导UCN_3的食欲抑制作用。最后，在体内将使用小干扰RNA方法 探讨VMH中UCN_3及其受体在调节食物摄入量和能量中的生理作用 动态平衡。拟议的项目将对UCN 3通过哪些机制提供重要的见解 VMH调节摄食，控制能量平衡。

Project Summary / Abstract Regulation of food intake and energy expenditure is crucial in maintaining a stable body weight. Excessive energy intake leads to obesity, which is a leading risk factor in many diseases including diabetes and hypertensin. Neuropeptides in the hypothalamus play a critical role in regulating energy balance. A detailed knowledge of hypothalamic peptides and their receptors in controlling feeding, satiety and energy expenditure is key in understanding the causes of obesity and related disorders. Urocortin 3 (Ucn 3) is a new neuropeptide identified in rodents and humans with strong central appetite suppressive effect. Ucn 3 is expressed at high levels in discrete brain areas including the hypothalamus. Ucn 3-expressing neurons heavily innervate the ventromedial hypothalamus (VMH). The receptor for Ucn 3, the type 2 CRF receptor (CRFR2), is highly expressed in the VMH and its expression is regulated by the energy status of the animals. Importantly, direct injection of Ucn 3 into the VMH suppresses food intake, elevates blood glucose levels and activates anorectic POMC neurons in the arcuate nucleus of the hypothalamus. The VMH has been recognized as a satiety center and for its ability to sense blood glucose levels, yet the mechanism by which this brain area regulates feeding and blood glucose is unknown. Thus, we hypothesize that Ucn 3 and its receptor is a critical molecular mediator in the VMH to regulate energy homeostasis. The major objectives of this project are to (1) identify the neurocircuits that mediate the effect of Ucn 3 in the VMH, (2) determine the physiological role of endogenous Ucn 3 and CRFR2 in the VMH in regulating food intake and glucose homeostasis and (3) determine the mechanisms that mediate the effect of Ucn 3 in the VMH.The project will first utilize a novel molecular tracing technique combined with functional anatomy to delineate the neural pathways that mediate the effect of Ucn 3 in the VMH followed by electrophysiological and pharmacological approaches to determine the effect of Ucn 3 on the activity of VMH target neurons. The project will then examine if POMC neurons mediate the appetite suppressive effect of Ucn 3. Finally in vivo small interference RNA approach will be used to examine the physiological role of Ucn 3 and its receptor in the VMH in regulating food intake and energy homeostasis. The proposed project will provide a significant insight into mechanisms through which Ucn 3 in the VMH regulates feeding and controls energy homeostasis.