Obesity is a Surgical Problem

摘要 美国社会正在经历一场肥胖症的流行。因为这把钥匙 下丘脑在控制体重中的作用，其长期目标是 研究人员一直在研究下丘脑弓状核与能量有关的基因。 动态平衡。建议的研究集中在下丘脑黑素皮质能。 该系统已成为基础研究和药物开发的重点。那 系统含有α-黑素细胞刺激素(MSH)和黑素皮质素 受体(MCR)亚型MC3R和MC4R。-MSH是一种有效的饱腹感诱导因素 这通过结合和激活MC3R和MC4R来调节其作用。一场持续的 对下丘脑基因表达变化的分析发现，Ankyrin Repeat和 含有蛋白4的SoCS盒(ASB-4)是一个很有前途的研究靶点。ASB-4 是中枢神经系统能量平衡回路中重要的细胞内调节蛋白 在下丘脑神经元中高度调控。 拟议的研究包含四个具体目标：1)审查 可供选择的黑素皮质素信号通路。我们假设MC3R和MC4R 激活丝裂原激活的蛋白激酶信号通路 在下丘脑神经元中识别的环状AMP依赖的过程。2)确定 黑素皮质素信号在c-jun氨基末端激酶(JNK)调节中的作用。我们 推测MC3R和MC4R通过Asb-4调节弓状核JNK活性。3) 阐明Asb-4的转录调控。我们假设Asb-4的表达 下丘脑受黑素皮质素能多肽-MSH的调节。4)至 确定Asb-4在摄食行为中的作用。我们假设Ankyrin重复和 含有蛋白4的SOCS盒是下丘脑神经元中一种重要的细胞内蛋白。 我们推测Asb-4在下丘脑中的定向过表达 原阿片黑素皮质素神经元会减少食物摄入量，增加能量消耗 并能抵抗高脂饮食引起的肥胖。

Abstract 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 (¿-MSH) and melanocortin receptor (MCR) subtypes MC3R and MC4R. ¿-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, ¿-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 confer resistance to high fat diet-induced obesity.