Central neural function of Urocortin 3 in regulating energy balance

描述（由申请方提供）：调节摄食量和能量消耗对于维持稳定的体重至关重要。过量的能量摄入导致肥胖，这是许多疾病包括糖尿病和高血压的主要危险因素。下丘脑中的神经肽在调节能量平衡中起关键作用。详细了解下丘脑肽及其受体在控制进食、饱腹感和能量消耗方面的作用是了解肥胖和相关疾病原因的关键。尿皮质素3（Urocortin 3，UCN 3）是在啮齿动物和人类中发现的一种新的神经肽，具有强烈的中枢食欲抑制作用。表达UCN 3的神经元大量支配下丘脑腹内侧（VMH）。支配VMH的UCN 3神经元受到应激和促性腺激素Leptin的刺激。Ucn 3的受体，2型CRF受体（CRFR 2），在VMH中高度表达，其表达受动物的能量状态调节。将Ucn 3直接注射到VMH抑制食物摄入，升高血糖水平并激活下丘脑弓状核中的厌食POMC神经元。VMH被认为是一个饱腹感中心，并具有感知血糖水平的能力，但该脑区调节进食和血糖的机制尚不清楚。因此，我们推测Ucn 3及其受体是VMH中调节能量稳态的关键分子介质。本研究的主要目的是：（1）确定在VMH中介导Ucn 3作用的神经回路，（2）确定应激和/或瘦素激活投射到VMH的Ucn 3神经元的神经通路，以及（3）确定内源性Ucn 3和CRFR 2在VMH中调节基础和应激条件下摄食的生理作用。该项目将首先利用一些功能性神经解剖学方法来阐明Ucn 3反应神经元（CRFR 2阳性）的传出投射和介导应激和/或瘦素对投射到VMH的Ucn 3神经元的刺激作用的神经通路。最后，将使用Ucn 3敲除小鼠和小干扰RNA方法敲低VMH中的CRFR 2表达来检查Ucn 3及其受体在VMH中调节食物摄入和能量稳态的生理作用。拟议的项目将提供一个重要的洞察机制，通过UCN 3在VMH调节摄食和控制能量稳态。公共卫生相关性：肥胖在美国已达到流行病的程度。因此，迫切需要确定肥胖的原因。Ucn 3肽及其受体是一个未被充分认识的肽系统，在调节机体的安全性方面具有重要作用。对脑Ucn 3在进食和能量稳态中的深入研究将增加我们对肥胖原因的理解，改善肥胖综合征的鉴别诊断，并最终确定药物开发的潜在新靶点，以治疗疾病和代谢相关疾病。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Obesity has reached epidemic proportions in the US. Thus, there is a pressing need to identify the cause of obesity. Ucn 3 peptide and its receptor are a previously underappreciated peptide system in regulating sateity. A thorough study of the brain Ucn 3 in feeding and energy homeostasis will increase our understanding of the causes of obesity, improve differential diagnosis of obesity syndromes, and ultimately identify potential new targets for drug development to treat the disease and metabolic related disorders.