Central Neural Function of Urocortin 3 in Regulating Energy Balance

调节食物摄入和能量消耗对维持稳定的体重至关重要。过度 能量摄入导致肥胖，肥胖是许多疾病的主要危险因素，包括糖尿病和 高血压下丘脑中的神经肽在调节能量平衡中起关键作用。详细 下丘脑肽及其受体在控制进食、饱腹感和能量消耗方面的知识 是理解肥胖和相关疾病的关键。尿皮质素3（Urocortin 3，UCN 3）是一种新的神经肽 在啮齿类动物和人类中发现具有强烈的中枢食欲抑制作用。UCN 3表达神经元 下丘脑腹内侧（VMH）。支配VMH的UCN 3神经元是 受到压力和促性腺激素瘦素的刺激。Ucn 3的受体，2型CRF受体（CRFR 2）， 在VMH中高度表达，其表达受动物能量状态的调节。直接 将Ucn 3注射到VMH中抑制食物摄入，升高血糖水平并激活厌食症。 下丘脑弓状核的POMC神经元。VMH被认为是一个饱腹感中心 以及感知血糖水平的能力，但这一大脑区域调节进食的机制 血糖未知。因此，我们假设Ucn 3及其受体是一个关键的分子， 调节VMH中的能量稳态。本项目的主要目标是：（1）确定 神经回路，介导VMH中的Ucn 3的作用，（2）确定神经通路，通过该神经通路，应激和/或 瘦素激活投射到VMH的Ucn 3神经元;（3）确定内源性瘦素的生理作用， Ucn 3和CRFR 2在VMH中调节基础和应激条件下的摄食。 利用一些功能性神经解剖学方法来阐明Ucn 3的传出投射， 反应神经元（CRFR 2阳性）和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神经元上的作用。最后Ucn 3敲除小鼠和小干扰 将使用RNA方法敲低VMH中的CRFR 2表达，以检查CRFR 2在VMH中的生理作用。 UCN 3及其受体在VMH中调节摄食和能量平衡。拟议项目将 提供了一个重要的洞察机制，通过UCN 3在VMH调节进食和控制 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.