Mechanisms of fat regulation by conserved anti-obesity genes

保守抗肥胖基因的脂肪调节机制

• 批准号: 9235043
• 负责人: Tania Reis
• 金额: $ 36.04万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235043
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Alleles; Alpha Cell; American; Behavioral; Binding; Biochemistry; Biological Models; Body Weight; Body fat; Candidate Disease Gene; Catabolism; Cells; Cues; Cultured Cells; Data; Data Analyses; Defect; Deposition; Development; Disease; Drosophila genus; Drug Targeting; Family; Family member; Fat Body; Fatty acid glycerol esters; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genetic study; Goals; Health; Human; Individual; Inherited; Larva; Lipids; Liver; Mammalian Cell; Mammals; Measures; Metabolic; Metabolic Diseases; Metabolism; Mission; Modeling; Molecular; Molecular Biology; Mus; Nature; Obesity; Orthologous Gene; Outcome Study; Output; Pathway interactions; Play; Predisposition; Protein Family; Proteins; RNA Binding; RNA Recognition Motif; RNA-Binding Proteins; Recruitment Activity; Regulation; Regulator Genes; Regulatory Pathway; Research; Role; Signal Transduction; Specificity; Susceptibility Gene; System; Techniques; Testing; Tissues; Transcription Repressor/Corepressor; Transcriptional Regulation; Translating; United States National Institutes of Health; Variant; drug development; energy balance; experimental study; fly; gene function; genome-wide analysis; innovation; insight; metabolic phenotype; mutant; novel; obesity treatment; overexpression; paralogous gene; prevent; success; tool; uptake

Obesity affects a majority of American adults, with diverse and significant detrimental effects on human health. Despite a major role for genetic background in obesity, only a small number of the human genes that predispose individuals to obesity have been identified. Understanding the pathways that control storage of body fat will be crucial for pinpointing genes likely to cause susceptibility to this disease. The long-term goal is to identify genes whose activities can be modified to prevent or treat human obesity. The goals of this application are to elucidate the mechanism by which the related RNA-binding proteins Spen and Nito regulate adiposity, and to identify other candidates for cell-autonomous regulation of adiposity. A fruit fly model has been developed to dissect the tissue specificity of gene function in the regulation of body fat levels, as well as new tools to parse out the contributions of behavioral alterations and to directly measure rates of fat incorporation into stores. A complementary approach using cultured cells will directly translate findings in the fly model to functions in mammalian fat storage. The central hypothesis is that genes acting autonomously in the fruit fly fat-storage tissue (the fat body, FB) to control levels of body fat will play conserved roles in mammalian fat storage. This idea is supported by the applicant's previous success in identifying such genes, and by preliminary data analyzing specific candidate genes, like Spen. The rationale for this project is that regulatory pathways in fat storage tissues must respond to organismal cues to control levels of stored fat, and that identifying key genes acting in these pathways may translate directly to insights into genetic predispositions to human obesity. This model will be tested by pursuing three specific aims: (1) Test the hypothesis that Spen and Nito function in an opposing manner to regulate body fat. (2) Test the hypothesis that Spen/Nito regulate energy balance by binding specific RNAs to alter gene expression; and (3) Identify candidate genes for novel, conserved autonomous regulators of fat storage. In Aim 1, we will determine the mechanistic basis of defects leading to altered fat in fly larvae lacking Spen and/or Nito, two RNA-binding proteins in the same family known to modulate transcriptional output of other pathways but never before implicated in the control of adiposity. In Aim 2, we test a model that Spen and Nito bind specific RNAs to target specific metabolic target genes for transcriptional control. In the Aim 3, the mouse orthologs of fly genes that directly regulate fat storage in the FB (including Shep, Rala and NFAT) will be analyzed functionally in cultured mouse adipocytes to identify those that also control mammalian fat storage in an autonomous manner. This innovative combination of approaches will uncover new roles for genes whose functions in fat regulation are currently unknown. The significance of this proposal lies in its potential to elucidate a new pathway controlling fat storage via RNA-binding proteins, and to characterize other candidate obesity genes, providing significant insights into the multigenic nature of this disease, and identifying new targets for future treatments.

肥胖会影响大多数美国成年人，对人类健康产生多种多样的有害影响。 尽管遗传背景在肥胖中起着重要作用，但只有少数人类基因 已经确定了肥胖的易感性。了解控制存储的途径 体内脂肪对于确定可能引起这种疾病敏感的基因至关重要。长期目标是 确定可以修改活动以预防或治疗人类肥胖的基因。目标的目标 应用是为了阐明相关的RNA结合蛋白SPEN和NITO调节的机制 肥胖，并确定其他候选肥胖调节的候选者。果蝇模型有 已开发为在体内脂肪水平的调节中剖析基因功能的组织特异性，以及 解析行为改变并直接衡量脂肪速率的新工具 并入商店。使用培养细胞的互补方法将直接转化 飞行模型以在哺乳动物脂肪存储中起作用。中心假设是在 从 哺乳动物脂肪储存。申请人以前在识别此类基因方面的成功支持了这个想法， 通过初步数据分析特定候选基因，例如SPEN。这个项目的理由是 脂肪存储组织中的调节途径必须对有机线索做出反应，以控制储存的脂肪水平，并且 识别在这些途径中作用的关键基因可能直接转化为遗传的见解 人类肥胖症的易感性。该模型将通过追求三个具体目标来测试：（1）测试 假设Spen和Nito以相反的方式起作用以调节体内脂肪。 （2）检验以下假设 SPEN/NITO通过结合特定RNA与改变基因表达来调节能量平衡； （3）识别 新型，保守的脂肪存储自主调节剂的候选基因。在AIM 1中，我们将确定 缺陷的机械基础，导致缺乏spen和/或nito的苍蝇幼虫的脂肪改变，两个RNA结合 已知可以调节其他途径的转录输出的同一家族中的蛋白质，但从未 与肥胖的控制有关。在AIM 2中，我们测试了一个跨越和NITO结合特定RNA与目标的模型 转录控制的特定代谢靶基因。在目标3中，蝇基因的小鼠直系同源物 直接调节FB中的脂肪存储（包括SHEP，RALA和NFAT），将在培养中进行功能分析 小鼠脂肪细胞以自主方式识别那些也控制哺乳动物脂肪储存的人。这 方法的创新组合将发现脂肪调节功能的基因的新作用 目前未知。该提案的重要性在于它有潜力阐明一种新的途径 通过RNA结合蛋白储存脂肪，并表征其他候选肥胖基因，可提供显着 深入了解该疾病的多基因性质，并确定未来治疗的新目标。