Central neural function of Urocortin 3 in regulating energy balance

描述（由申请人提供）：调节食物摄入和能量消耗对维持稳定体重至关重要。过多的能量摄入导致肥胖，这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着关键作用。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，是理解肥胖和相关疾病原因的关键。尿皮质素3 （Ucn 3）是一种在啮齿动物和人类中发现的具有强烈中枢食欲抑制作用的新神经肽。表达ucn3的神经元大量支配下丘脑腹内侧（VMH）。控制下颌下颌骨的ucn3神经元受到压力和厌食性激素瘦素的刺激。ucn3的受体，2型CRF受体（CRFR2）在VMH中高表达，其表达受动物能量状态的调节。在下丘脑弓状核直接注射ucn3可以抑制食物摄入，提高血糖水平，激活下丘脑弓状核的POMC厌食神经元。下丘脑下丘脑被认为是一个饱腹感中枢，它具有感知血糖水平的能力，但这个大脑区域调节进食和血糖的机制尚不清楚。因此，我们假设ucn3及其受体是VMH调节能量稳态的关键分子介质。该项目的主要目标是：(1)确定介导ucn3在下颌下颌骨中的作用的神经回路，(2)确定应激和/或瘦素激活投射到下颌下颌骨的ucn3神经元的神经通路，(3)确定内源性ucn3和CRFR2在基础和应激条件下调节下颌下颌骨摄食的生理作用。该项目将首先利用一些功能性神经解剖学方法来阐明ucn3 -反应神经元（CRFR2阳性）的传出投射，以及介导应激和/或瘦素对投射到VMH的ucn3神经元的刺激作用的神经通路。最后，将使用ucn3缺失小鼠和小干扰RNA方法来敲低VMH中CRFR2的表达，以研究ucn3及其受体在VMH中调节食物摄入和能量稳态的生理作用。拟议的项目将为VMH中ucn3调节摄食和控制能量稳态的机制提供重要的见解。公共卫生相关性：肥胖在美国已经达到流行病的程度。因此，迫切需要确定肥胖的原因。ucn3肽及其受体是一个以前未被充分认识的调节安全性的肽系统。深入研究大脑ucn3在喂养和能量稳态中的作用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，并最终确定治疗疾病和代谢相关疾病的药物开发的潜在新靶点。

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.