Obesity is a Surgical Problem

摘要 美国社会正在经历肥胖症的流行。因为钥匙 下丘脑在控制体重中的作用，这一长期目标 研究已经检查了弓状核下丘脑基因参与能源 体内平衡拟议的研究集中在下丘脑黑素皮质素能神经元。 该系统已成为基础研究和药物开发的焦点。的 系统包含α黑素细胞刺激激素（<$-MSH）和黑皮质素 受体（MCR）亚型MC 3R和MC 4 R。MSH是一种有效的饱腹感诱导因子 通过结合和激活MC 3R和MC 4 R介导其作用。持续 下丘脑基因表达变化的分析已经鉴定了锚蛋白重复序列， SOCS盒蛋白4（Asb-4）是一个非常有前途的研究目标。抗坏血酸-4 是中枢神经系统能量稳态回路中重要的细胞内调节蛋白， 在下丘脑神经元中高度调节。 本研究的主要目的有四个：1）研究 替代黑皮质素信号通路。我们假设MC 3R和MC 4 R 激活丝裂原活化蛋白激酶信号通路， 识别下丘脑神经元中的环AMP依赖性过程。2)以确定 黑皮质素信号传导在c-Jun氨基末端激酶（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。第三章 阐明Asb-4的转录调控。我们假设Asb-4表达 下丘脑中的黑素皮质素是由黑素皮质素能肽调节的。4)到 Asb-4在摄食行为中的作用我们假设锚蛋白重复序列和 SOCS box containing protein 4是下丘脑神经元中一种重要的胞内蛋白。 我们推测Asb-4在下丘脑中的定向过表达 阿黑皮素原神经元会减少食物摄入，增加能量消耗 并赋予对高脂肪饮食诱导的肥胖症的抵抗力。

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.