Central Neural Function of Urocortin 3 in Regulating Energy Balance

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。过份 摄入能量会导致肥胖，肥胖是许多疾病的主要风险因素，包括糖尿病和 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。一个详细的 下丘脑肽及其受体在控制摄食、饱腹感和能量消耗中的知识 是理解肥胖和相关疾病的原因的关键。尿皮质激素3(UCN 3)是一种新的神经肽 在啮齿动物和人类中发现，具有强烈的中枢性食欲抑制作用。UCN-3表达神经元 严重支配下丘脑腹内侧核(VMH)。支配VMH的UCN-3神经元是 在压力和厌食激素的刺激下，瘦素。UCN 3受体，2型CRF受体(CRFR2)， 在VMH中高度表达，其表达受动物能量状态的调节。直接 VMH注射UCN_3抑制摄食，升高血糖，激活厌食 下丘脑弓状核内的POMC神经元。VMH已经被认为是一个饱餐中心 以及它感知血糖水平的能力，然而这个大脑区域调节摄食的机制 而血糖则不得而知。因此，我们假设UCN 3及其受体是一个关键分子 调节VMH中的能量动态平衡。这个项目的主要目标是：(1)确定 在VMH中介导UCN 3效应的神经回路，(2)决定应激和/或 Leptin激活投射到VMH的UCN-3神经元；(3)确定内源性 UCN 3和CRFR2在VMH调节基础和应激条件下的摄食。该项目将首先 利用多种功能神经解剖学方法阐明UCN-3的传出投射 反应性神经元(CRFR2阳性)与介导应激刺激效应的神经通路 和/或瘦素在投射到VMH的UCN-3神经元上。最后UCN 3空鼠和一个小干扰 RNA方法敲除CRFR2在VMH中的表达将被用来检测其生理作用 UCN-3及其受体在调节食物摄入量和能量平衡中的作用。拟议的项目将 对VMH中的UCN 3调节饲料和控制的机制提供了重要的见解 能量平衡。

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 expressing neurons heavily innervate the ventromedial hypothalamus (VMH). Ucn 3 neurons that innervates the VMH are stimulated by stress and anoretic hormone, leptin. 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. 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 neuropahtwys by which stress and/or leptin activate Ucn 3 neurons that project to the VMH and (3) ascertain the physiological role of endogenous Ucn 3 and CRFR2 in the VMH in regulating feeding under basal and stress conditions.The project will first utilize a number of functional neuroanatomical approaches to elucidate the efferent projections of Ucn 3- responsive neurons (CRFR2 positive) and the neuropathways that mediate the stimulatory effect of stress and/or leptin on Ucn 3 neurons that project into the VMH. Finally Ucn 3 null mice and a small interference RNA approach to knockdown CRFR2 expression in the VMH 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.