ALTERED SEROTONIN IN OBESITY--ONTOGENY AND MECHANISMS

肥胖中血清素的改变——个体发生和机制

• 批准号: 2805633
• 负责人: BARBARA Ann HORWITZ
• 金额: $ 3.74万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2805633
• 关键词: RNase protection assay; adipose tissue; bioenergetics; biological signal transduction; body composition; brown fat; developmental genetics; gene expression; genetic models; genetic strain; genotype; hyperinsulinism; hypothalamus; laboratory rat; microdialysis; neural transmission; neurotransmitter metabolism; neurotransmitter transport; newborn animals; nutrition related tag; obesity; serotonin; serotonin receptor; sympathetic nervous system; thermogenesis

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.

人类肥胖仍然是美国的一个重大健康问题 国家。对人类和动物模型的研究表明 肥胖是多方面的，涉及能量消耗的改变和 改变能量摄入。最近的研究还表明，遗传 背景有助于人类肥胖的发展 说明了这种疾病的复杂性。尽管存在这种复杂性， 肥胖中观察到的许多代谢变化是 与交感神经和副交感神经活动的改变一致 神经系统。该提案侧重于这一改变的一个方面 活性——腹内侧核（VMN）的血清素输入 下丘脑已被证明在肥胖的 Zucker 中减少 老鼠。该提案的两个主要目标涉及 改变 VMN 血清素活性的一般主题是一个重要的 造成能量平衡调节改变的因素 肥胖。 本研究的第一个目标是确定改变后的 VMN 是否 肥胖大鼠的血清素活性发生在肥胖增加之前， 生热作用减少，或高胰岛素血症。为此，我们将检查 2、4、7 和 12 天的 Zucker/Brown 挪威 (ZBN) 肥胖 (fafa) 与瘦肉 （发发）小狗。使用 ZBN 幼崽，而不是 Zucker 幼崽，可以让 区分任何年龄的 fafa 和 Fafa 同窝仔鼠，因为 存在密切相关的限制性片段长度多态性 到 fa 轨迹。这是 ZBN 混合动力车的主要优势，因为 目前还无法可靠地区分 fafa 和 Fafa 幼崽 7 天龄前的 Zucker 品系。来自 ZBN 的个体发育数据 幼崽将表明 fafa 大鼠的 VMN 血清素活性是否发生改变 发生在突变 fa 基因引发的一系列事件的早期。 本研究的第二个目标是评估三种可能的情况 fafa 大鼠 VMN 血清素活性减弱的机制： (1) 改变到达信号的接收和/或转换 中缝（VMN 血清素能投射的起源位点）； (2) VMN 中血清素的释放和/或再摄取发生改变； (3) 改变 输入到中缝背侧。这些机制将使用以下方式进行评估： 12 周龄的体内（微透析）和体外（切片）制剂 Zucker fafa 与 FaFa（瘦）大鼠。 这项研究将加深我们对潜在机制的理解 与异常营养相关的自主信号改变 肥胖的划分特征。