Obesity is a Surgical Problem

描述（由申请人提供）：美国社会正在经历肥胖症的流行。由于下丘脑在控制体重中的关键作用，本研究的长期目标是检查弓状核下丘脑参与能量稳态的基因。下丘脑黑皮质素能系统已成为基础研究和药物开发的重点。该系统包含α黑素细胞刺激激素（1-MSH）和黑皮质素受体（MCR）亚型MC 3R和MC 4 R。1-MSH是一种有效的饱腹感诱导因子，其通过结合和激活MC 3R和MC 4 R来介导其作用。对下丘脑基因表达变化的持续分析已经确定锚蛋白重复序列和SOCS盒蛋白4（Asb-4）是一个非常有前途的研究目标。Asb-4是中枢神经系统能量稳态回路中的重要细胞内调节蛋白，在下丘脑神经元中受到高度调节。本研究的主要目的有四：1）研究黑皮质素信号通路。我们假设MC 3R和MC 4 R除了激活下丘脑神经元中公认的环AMP依赖性过程外，还激活丝裂原活化蛋白激酶信号通路。2)确定黑皮质素信号传导在c-Jun NH 2末端激酶（JNK）调节中的作用。我们推测MC 3R和MC 4 R通过Asb-4调节弓状核JNK活性。3)阐明Asb-4的转录调控。我们推测Asb-4在下丘脑中的表达受黑素皮质素能肽1-MSH的调节。4)探讨Asb-4在摄食行为中的作用。我们推测锚蛋白重复序列和SOCS盒蛋白4是下丘脑神经元中一个重要的细胞内蛋白。我们推测Asb-4在下丘脑前阿黑皮素神经元中的定向过表达将减少食物摄入，增加能量消耗并增强对高脂饮食诱导的肥胖的抵抗。公共卫生相关性：美国社会正在经历肥胖的流行。下丘脑是大脑中控制食欲和食物摄入必不可少的区域，是这些研究的重点。该提案仔细研究了下丘脑黑皮质素信号系统，这是一个重要的能量调节系统，被认为会影响食欲、能量消耗和葡萄糖代谢。

DESCRIPTION (provided by applicant): American society is experiencing an epidemic of obesity. Because of the key role of the hypothalamus in controlling body weight, the long-term objective of this research has been to examine arcuate nucleus hypothalamic genes involved in energy homeostasis. The proposed studies focus upon the hypothalamic melanocortinergic system which has become a focal point for basic research and drug development. That system contains alpha melanocyte-stimulating hormone (1-MSH) and melanocortin receptor (MCR) subtypes MC3R and MC4R. 1-MSH is a potent satiety-inducing factor that mediates its effects by binding and activating MC3R and MC4R. A continuing analysis of hypothalamic gene expression changes has identified ankyrin repeat and SOCS box containing protein 4 (Asb-4) as a very promising investigative target. Asb-4 is an important intracellular regulatory protein in CNS energy homeostatic circuits that is highly regulated in hypothalamic neurons. The proposed research is contained in four specific aims: 1) To examine alternative melanocortin signaling pathways. We hypothesize that MC3R and MC4R activate mitogen-activated protein kinase signaling pathways in addition to well- recognized cyclic AMP-dependent processes in hypothalamic neurons. 2) To determine the role of melanocortin signaling in regulation of c-Jun NH2-terminal kinase (JNK). We hypothesize that MC3R and MC4R, via Asb-4, regulate arcuate nucleus JNK activity. 3) To elucidate transcriptional regulation of Asb-4. We hypothesize that Asb-4 expression in the hypothalamus is regulated by the melanocortinergic peptide, 1-MSH. 4) To determine the role Asb-4 in feeding behavior. We hypothesize that ankyrin repeat and SOCS box containing protein 4 is a crucial intracellular protein in hypothalamic neurons. We hypothesize that directed overexpression of Asb-4 in hypothalamic proopiomelanocortin neurons will decrease food intake, increase energy expenditure and confe resistance to high fat diet-induced obesity. PUBLIC HEALTH RELEVANCE: American Society is experiencing an epidemic of obesity. The hypothalamis, an area in the brain that is essential in control of appetite and food intake, is the focus of these investigations. The proposal examines carefully the hypothalamic melanocortin signaling system, an important energy regulatory system that has postulated to effect appetite, energy expenditure, and glucose metabolism.