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性疾病，由摄入超过持续需要的卡路里引起。肥胖率的增加导致肥胖相关疾病的发病率迅速上升，如2型糖尿病和心血管疾病。肥胖症的发病机制仍不完全清楚。在目前的应用中，我们建议研究SynPhilin-1在食物摄取和体重控制中的一个新角色。SynPhilin-1是一种细胞质蛋白，与α-突触核蛋白和parkin相互作用，在帕金森病的发病机制中与蛋白质聚集有关。通过检测Synphlin-1转基因小鼠(SP1)的表型，我们有证据表明SynPhilin-1过度表达显著增加体重，并通过增加食物摄入量来实现这一点。我们发现突触素-1在参与能量平衡的下丘脑核团神经元中高表达，提示突触素-1可能通过调节下丘脑信号而影响能量平衡。我们的初步数据表明，SynPhilin-1可能通过增加下丘脑神经元中促食欲素基因NPY和AgRP的表达来影响摄食量和体重。最近的研究表明，AMP激活的激酶(AMPK)是一种中枢神经能量感受器，在维持能量平衡方面发挥着重要作用。我们的初步数据表明，在培养的N1E-115细胞中，人SynPhilin-1的表达增加了AMPK的磷酸化，并进一步表明，免疫共沉淀表明SynPhilin-1与AMPK相互作用。因此，在这项提议中，我们将检验这一假设，即SynPhilin-1调节下丘脑摄食相关基因的表达和AMPK信号级联导致吞噬和肥胖。在目标1中，我们将表征食物摄入量、体重和下丘脑基因表达模式的变化，以响应SynPhilin-1的过度表达。我们将通过测试SP1小鼠对中枢和外周多肽注射的反应并表征它们的口味偏好，来具体评估SP1小鼠吞噬功能亢进的食量增加的基础。在目标2中，我们将研究内源性下丘脑突触素-1在代谢状态改变中的作用。在目标3中，我们将在体外细胞培养系统中验证SynPhilin-1改变AMPK信号级联及其相关细胞能量事件的假设。在目标4中，我们将使用过表达和siRNA敲除方法在体内验证SynPhilin-1激活下丘脑AMPK信号导致体内过度吞噬和肥胖的假设。这些研究将有助于深入了解SynPhilin-1诱导的吞噬功能亢进和肥胖的分子机制，扩大我们对SynPhilin-1生物学功能的认识，并可能为未来肥胖发病机制的研究提供一个独特的遗传肥胖模型。公共卫生相关性：我们建议使用行为学、药理学和细胞生物学的方法来研究SynPhilin-1蛋白在调节食物摄入量和体重方面的作用和分子机制。这些研究将大大增加我们对SynPhilin-1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。