ALTERED SEROTONIN IN OBESITY--ONTOGENY AND MECHANISMS

在美国，人类肥胖仍然是一个严重的健康问题 各州。对人类和动物模型的研究已经证实 肥胖是多方面的，包括改变能量消耗和 改变了能量摄入量。最近的研究还表明，基因 背景有助于人类肥胖的发展和 说明了这种疾病的复杂性。尽管有这种复杂性， 肥胖症中的许多代谢变化是 与交感神经和副交感神经活动改变相一致 神经系统。这份提案关注的是这一变化的一个方面 活动--5-羟色胺能传入大鼠腹内侧核 肥胖的扎克的下丘脑已经被证明是减少的 老鼠。这项建议的两个主要目标与 改变VMN 5-羟色胺能活动的总主题是一个重要的 导致能量平衡发生变化的因素 肥胖。 这项研究的第一个目标是确定改变后的VMN 肥胖大鼠的5-羟色胺能活动发生在肥胖增加之前， 生热作用减弱，或高胰岛素血症。为此，我们将研究 2日龄、4日龄、7日龄和12日龄的Zucker/Brown挪威(ZBN)肥胖(Fafa)与瘦 (发法)幼崽。使用ZBN幼崽，而不是Zucker幼崽，允许 为了在任何年龄区分Fafa和Fafa幼崽，因为 存在紧密连锁的限制性片段长度多态 转到发球区。这是ZBN混合动力车的一大优势，因为 一直不可能可靠地区分Fafa和Fafa幼崽 Zucker菌株在7日龄之前。ZBN的个体发育数据 PUPS将提示Fafa大鼠VMN 5-羟色胺能活动是否改变 发生在由突变的fa基因启动的事件序列的早期。 这项研究的第二个目标是评估三种可能的 Fafa大鼠VMN 5-羟色胺能活动减弱的机制 (1)改变信号的接收和/或传输 中缝(5-羟色胺能投射至VMN的起源部位)；(2) VMN内5-羟色胺释放和/或重摄取的改变；以及(3)改变 输入到背侧中缝。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对Fafa(瘦)大鼠。 这项研究将加深我们对潜在机制的理解 与营养异常相关的自主神经信号的改变 肥胖症的分区特征。

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.