Synphilin-1 and obesity

Synphilin-1 与肥胖

• 批准号: 7992235
• 负责人: WANLI W SMITH
• 金额: $ 40.15万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992235
• 关键词: 5' -AMP-activated protein kinase; Affect; Behavioral; Biological; Biological Process; Body Weight; Calories; Cardiovascular Diseases; Cell Culture System; Cell Nucleus; Cells; Co-Immunoprecipitations; Cytoplasmic Protein; Cytosol; Data; Disease; Eating; Event; Fasting; Future; Gene Expression; Genetic; Goals; Homeostasis; Hormonal; Human; Hyperphagia; Hypothalamic structure; In Vitro; Ingestion; Intake; Knowledge; Metabolic; Metabolic Diseases; Modeling; Molecular; Mus; NPY gene; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Outcome; Parkinson Disease; Pathogenesis; Pattern; Peptide Receptor; Peptides; Peripheral; Phenotype; Phosphorylation; Physiological; Play; Prevalence; Proteins; Research; Role; Signal Transduction; Site; Small Interfering RNA; Taste Perception; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; Transgenic Organisms; Weight Gain; Weight maintenance regimen; Work; alpha synuclein; base; energy balance; feeding; human SNCAIP protein; in vivo; insight; novel; overexpression; paraventricular nucleus; parkin gene/protein; preference; protein aggregation; public health relevance; response; sensor

DESCRIPTION (provided by applicant): Obesity is the most common metabolic disease, resulting from the ingestion of calories in excess of ongoing requirements. Increased prevalence of obesity has resulted in rapidly accelerating rates of obesity related disorders such as type 2 diabetes and cardiovascular disease. The pathogenesis of obesity remains incompletely understood. In the current application, we propose to investigate a novel role for synphilin-1 in food intake and body weight control. Synphilin-1, a cytoplasmic protein, interacts with alpha-synuclein and parkin and has implications in Parkinson's disease pathogenesis related to protein aggregation. Through work examining the phenotype of a synphillin-1 transgenic mouse (SP1), we have evidence that synphilin-1 over- expression significantly increases body weight and does so through increasing food intake. We have found that synphilin-1 is highly expressed in neurons of hypothalamic nuclei involved in energy balance, suggesting that synphilin-1 may be affecting energy balance by modulating hypothalamic signaling. Our preliminary data suggest that synphilin-1 may affect food intake and body weight through increases in orexigenic genes: NPY and AgRP expression in hypothalamic neurons. Recently, studies have suggested that AMP-activated kinase (AMPK) is a central neuronal energy sensor that plays a major role in maintaining energy homeostasis. Our preliminary data showed that expression of human synphilin-1 increased AMPK phosphorylation in cultured N1E-115 cells and at the PVN site, and further showed that synphilin-1 interacted with AMPK as indicated by co-immunoprecipitation. Thus, in this proposal, we will test the hypothesis that synphilin-1 modulates hypothalamic feeding related gene expression and AMPK signaling cascades resulting in hyperphagia and obesity. In Aim 1, we will characterize changes in food intake, body weight and patterns of hypothalamic gene expression in responses to overexpression of synphilin-1. We will specifically assess the bases for the increased meal size that characterizes the hyperphagia in SP1 mice by testing responses to central and peripheral peptide administration and characterizing their taste preferences. In Aim 2, we will investigate the role of endogenous hypothalamic synphilin-1 in response to alterations in metabolic status. In Aim 3, we will test the hypothesis that synphilin-1 alters AMPK signaling cascades and its related cell energy events in an in vitro cell culture system. In Aim 4, we will test the hypothesis that synphilin-1 activates AMPK signaling in hypothalamus resulting in hyperphagia and obesity in vivo using overexpression and siRNA knockdown approaches. These studies will provide insight into the molecular mechanisms underlying synphilin-1-induced hyperphagia and obesity, will enlarge our knowledge of the biological functions of synphilin-1, and may provide a unique genetic obesity model for future studies of the pathogenesis of obesity. PUBLIC HEALTH RELEVANCE: We propose to investigate the role and the molecular mechanisms of synphilin-1 protein in regulating food intake and body weight using behavioral, pharmacological and cell biological approaches. These studies will greatly increase our understanding of the biological functions of synphilin-1 and will provide new insights into the molecular mechanisms underlying obesity and related disorders.

描述（由申请人提供）：肥胖是最常见的代谢疾病，这是由于超出持续需求的卡路里摄入的卡路里而产生的。肥胖症患病率的增加导致肥胖相关疾病的速度迅速加速，例如2型糖尿病和心血管疾病。肥胖的发病机理仍然不完全理解。在当前的应用中，我们建议研究Synphilin-1在食物摄入和体重控制中的新作用。 Synphilin-1是一种细胞质蛋白，与α-突触核蛋白和帕金蛋白相互作用，对与蛋白质聚集有关的帕金森氏病发病机理具有影响。通过检查Synphillin-1转基因小鼠（SP1）的表型的工作，我们有证据表明Synphilin-1过度表达显着增加了体重，并通过增加食物摄入量而进行。我们发现，Synphilin-1在与能量平衡有关的下丘脑核神经元中高度表达，这表明Synphilin-1可能通过调节下丘脑信号传导来影响能量平衡。我们的初步数据表明，Synphilin-1可能通过增加甲状腺素基因的增加而影响食物摄入和体重：下丘脑神经元中的NPY和AGRP表达。最近，研究表明，AMP激活激酶（AMPK）是一种中心神经元能量传感器，在维持能量稳态中起着重要作用。我们的初步数据表明，人类Synphilin-1的表达增加了培养的N1E-115细胞和PVN位点中AMPK磷酸化的表达，并进一步表明Synphilin-1与AMPK相互作用，如共免疫注射所示。因此，在此提案中，我们将检验以下假设：Synphilin-1调节下丘脑喂养相关的基因表达和AMPK信号传导级联反应，从而导致多形态和肥胖。在AIM 1中，我们将表征食物摄入量的变化，体重和下丘脑基因表达的模式在对Synphilin-1过表达的反应中。我们将通过测试对中央和周围肽给药的反应并表征其味道偏好的反应，以增加SP1小鼠的饮食量增加的碱。在AIM 2中，我们将研究内源性下丘脑Synphilin-1对代谢状态改变的作用。在AIM 3中，我们将检验以下假设：Synphilin-1在体外细胞培养系统中改变AMPK信号级联反应及其相关的细胞能量事件。在AIM 4中，我们将测试以下假设：Synphilin-1激活下丘脑中的AMPK信号传导，从而使用过表达和siRNA敲低接近，从而导致体内的心脏和肥胖。这些研究将提供有关Synphilin-1诱导的心形和肥胖的分子机制的洞察力，将扩大我们对Synphilin-1生物学功能的了解，并可能为肥胖发病机理的未来研究提供独特的遗传肥胖模型。公共卫生相关性：我们建议使用行为，药理学和细胞生物学方法研究Synphilin-1蛋白在调节食物摄入和体重中的作用和分子机制。这些研究将大大提高我们对Synphilin-1的生物学功能的理解，并将为肥胖和相关疾病的分子机制提供新的见解。