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.

人类的肥胖仍然是曼联的重大健康问题 国家。与人类和动物模型的研究已经确定 肥胖是多方面的，涉及能量消耗的改变和 能量摄入改变。最近的工作还表明了遗传 背景有助于人类肥胖的发展 说明了这种疾病的复杂性。尽管这种复杂性， 肥胖症中看到的许多代谢改变是 与交感神经和副交感神经的活性改变 神经系统。该提案重点是这一改变的一个方面 活性 - 对腹侧核（VMN）的血清素能输入 在肥胖的扎克中已显示出降低的下丘脑 老鼠。该提案的两个主要目标与 改变VMN血清素能活动的一般主题是重要的 贡献了改变能量平衡的调节的贡献者 肥胖。 这项研究的第一个目的是确定VMN是否改变 肥胖大鼠的血清素能活性发生在肥胖增加之前， 减少的热生成或高胰岛素血症。为此，我们将检查 2、4、7和12天大的Zucker/Brown Norway（ZBN）肥胖（FAFA）与精益 （fafa）幼崽。 ZBN幼崽而不是Zucker幼崽的使用允许一个 在任何年龄段 限制片段长度多态性的存在紧密联系 到FA基因座。这是ZBN混合动力车的主要优势，因为 不可能可靠地将FAFA与FAFA幼崽区分开 年龄第7天之前的扎克菌株。来自ZBN的个体发育数据 幼崽将指示FAFA大鼠的VMN血清素能活性是否改变 发生在突变FA基因引发的事件序列的早期。 这项研究的第二个目标是评估三个可能 FAFA大鼠中VMN血清素能活性减弱的机制： （1）到达的信号的接收和/或转导的改变 Raphe（VMN的血清素能预测的起源部位）； （2） VMN中5-羟色胺的释放和/或再摄取的释放和/或再摄取； （3）改变 输入背面raphe。这些机制将使用 体内（微透析）和体外（切片）从12周旧 Zucker Fafa vs. Fafa（瘦）大鼠。 这项研究将增强我们对基本机制的理解 与养分异常相关的自主信号的改变 分配肥胖的特征。