ALTERED SEROTONIN IN OBESITY--ONTOGENY AND MECHANISMS

肥胖症在美国仍然是一个严重的健康问题。 States.对人类和动物模型的研究已经证实， 肥胖是多方面的，包括能量消耗的改变， 改变能量摄入。最近的研究还表明， 背景技术导致人类肥胖症的发展， 说明了这种疾病的复杂性。尽管存在这种复杂性， 在肥胖症中发现的许多代谢改变， 与交感神经和副交感神经活动的改变一致 神经系统这一建议的重点是这一改变的一个方面， 活动--向腹内侧核（VMN）的多巴胺能输入， 肥胖Zucker的下丘脑已经被证明是减少的 大鼠这项建议的两个主要目标是： 一般的主题是改变VMN神经递质活性是重要的 导致能量平衡的调节发生改变， 肥胖 本研究的第一个目的是确定改变的VMN是否 肥胖大鼠的肾上腺素能活动发生在肥胖增加之前， 产热减少或高胰岛素血症。为此，我们将研究 2、4、7和12日龄Zucker/Brown Norway（ZBN）肥胖（fafa）与瘦型 小狗。使用ZBN幼仔，而不是Zucker幼仔， 区分任何年龄的Fafa和Fafa同窝仔，因为 限制性片段长度多态性的存在密切相关 到fa位点。这是ZBN混合动力车的一个主要优势， 无法可靠地区分Fafa和Fafa幼仔， Zucker株在7日龄之前。来自ZBN的个体发育数据 幼仔将表明，如果改变的VMN神经递质活性的fafa大鼠 发生在由突变的FA基因启动的事件序列的早期。 本研究的第二个目的是评估三种可能的 在fafa大鼠中减弱VMN神经递质活性的机制： (1)改变的信号接收和/或转导到达 中缝（向VMN投射肾上腺素能的起源部位）;（2） VMN中5-羟色胺的释放和/或再摄取改变;和（3）改变 输入到中缝背侧这些机制将使用 12周龄的体内（微透析）和体外（切片）制剂 Zucker fafa与FaFa（瘦）大鼠。 这项研究将加强我们对潜在机制的理解 与异常营养素相关的自主神经信号改变 肥胖的特征。

Obesity in humans remains a significant health problem in the United States. Research with humans and with animal models has established that obesity is multifaceted, involving altered energy expenditure and altered energy intake. Recent work has also shown that genetic background contributes to the development of obesity in humans and illustrates the complexity of this disorder. Despite this complexity, many of the metabolic alterations that are seen in obesity are consistent with altered activity of the sympathetic and parasympathic nervous systems. This proposal focuses on one aspect of this altered activity -- the serotonergic input to the ventromedial nucleus (VMN) of the hypothalamus which has been shown to be reduced in obese Zucker rats. The two major objectives of this proposal are related to the general theme that altered VMN serotonergic activity is an important contributor to the altered regulation of energy balance that occurs in obesity. The first objective of this study is to determine if the altered VMN serotonergic activity of obese rats occurs before increased adiposity, decreased thermogenesis, or hyperinsulinemia. For this, we will examine 2, 4, 7 and 12 day old Zucker/Brown Norway (ZBN) obese (fafa) vs. lean (Fafa) pups. The use of ZBN pups, rather than Zucker pups, allows one to distinguish fafa from Fafa littermates at any age because of the presence of a restriction fragment length polymorphism closely linked to the fa locus. This is a major advantage of the ZBN hybrids because it has not been possible to reliably distinguish fafa from Fafa pups in the Zucker strain before day 7 of age. The ontogeny data from the ZBN pups will indicate if the altered VMN serotonergic activity of fafa rats occurs early in the sequence of events initiated by the mutant fa gene. The second objective of this study is to evaluate three possible mechanisms for the attenuated VMN serotonergic activity in fafa rats: (1) altered reception and/or transduction of signals arriving at the raphe (site of origin of serotonergic projections to the VMN); (2) altered release and/or reuptake of serotonin in the VMN; and (3) altered input to the dorsal raphe. These mechanisms will be evaluated using in vivo (microdialysis) and in vitro (slice) preparations from 12 wk old Zucker fafa vs. FaFa (lean) rats. This study will enhance our understanding of the mechanisms underlying the altered autonomic signaling associated with the abnormal nutrient partitioning characteristic of obesity.