Novel Thermogenic Factors to Combat Obesity and Metabolic Disease

对抗肥胖和代谢疾病的新型生热因子

• 批准号: 10190927
• 负责人: Joeva J. Barrow
• 金额: $ 18.84万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190927
• 关键词: Ablation; Adipocytes; Adipose tissue; Adrenergic Agents; Agonist; Biochemical; Biology; Biotechnology; Brown Fat; CRISPR/Cas technology; Cardiovascular Diseases; Cell physiology; Chemicals; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Data; Defect; Dependence; Development; Diabetes Mellitus; Energy Metabolism; Epidemic; Exhibits; Fatty acid glycerol esters; Future; Gene Proteins; Genes; Genetic Transcription; Genus Hippocampus; Goals; Health Expenditures; Heart; Human; Impairment; Incidence; Individual; Knockout Mice; Link; Malignant Neoplasms; Mediating; Metabolic Diseases; Mitochondria; Molecular; Mus; Muscle; Obesity; Obesity associated disease; Overweight; Oxidative Phosphorylation; Pathway interactions; Pattern; Performance; Phosphoric Monoester Hydrolases; Play; Process; Protein Dynamics; Proteins; Protons; Regulation; Reporting; Risk Factors; Role; S-nitro-N-acetylpenicillamine; Signal Transduction; Small Interfering RNA; Stimulus; System; Testing; Therapeutic; Thermogenesis; Time; Tissues; Transcript; Translations; Work; World Health Organization; Yin-Yang; combat; cost; gain of function; insight; interest; knock-down; lentiviral-mediated; loss of function; metabolomics; molecular targeted therapies; mouse model; novel; novel therapeutics; obesity management; obesity treatment; overexpression; programs; protein function; protein profiling; respiratory; response; statistics; targeted treatment; transcription factor; transcriptomics; uncoupling protein 1

PROJECT SUMMARY Obesity is a significant risk factor for the development of chronic disorders such as diabetes and cardiovascular disease. Current treatments are ineffectual given the worldwide increase in obesity rates to now epidemic proportions. The World Health Organization (WHO) reports that 1.9 billion (1 in 3) individuals globally are overweight and the rising cost to manage obesity-related diseases represented $147 billion dollars of the annual U.S. healthcare expenditure in 2008. The need for additional treatment options is critical. The goal of this proposal is to develop molecular treatments for obesity and associated metabolic disease. We take advantage of the thermogenic brown and beige fat biology that, when targeted, can increase energy expenditure and confer protection against obesity through the action of uncoupling protein 1 (UCP1). The mechanisms of this process, however, are not completely understood. Unveiling novel pathways and regulatory factors that can activate this process will maximize treatment options for individuals suffering from obesity and associated metabolic disease. Our previous work in murine models demonstrated that the transcription factor Yin Yang 1 (YY1) is critical for brown fat function. Adipose-specific ablation of YY1 (YY1bKO) results in significant thermogenic defects in the brown fat tissue, but the mechanism is unknown. In order to gain insight into the mechanism of action, we performed unbiased transcriptomic profiling in YY1bKO brown fat in search for novel thermogenic regulators and identified the gene nipsnap1 (4-nitrophenyl phosphatase domain and non-neuronal SNAP-25 like protein homolog1). Nipsnap1 is evolutionarily conserved across species, yet a clear functional annotation remains to be assigned. Our preliminary data show that Nipsnap1 exhibits a strong thermogenic profile and dramatically alters UCP1 protein levels. The goal of this proposal therefore is to identify the molecular function of Nipsnap1 in thermogenic adipose tissue in order to test the hypothesis that Nipsnap1 plays a significant role in thermogenesis. The studies proposed will use biochemical approaches in primary brown and beige adipocytes to detail the transcription and translation dynamics of Nipsnap1 in response to various thermogenic stimuli (Aim1). We will then continue with the functional characterization of Nipsnap1 through gain- and CRISPR-loss- of-function studies in addition to testing the coupled and uncoupled mitochondrial respiratory capacity of the system. Thermogenic adipose metabolomic profiling using high performance LC-MS/MS will also be assessed (Aim 2). Our studies will be the first to characterize the molecular function as well as the metabolomic-linked network of Nipsnap1 in thermogenic adipose tissue. The findings from this proposal will determine if Nipsnap1 can be leveraged towards a treatment for obesity and associated metabolic disorders.

项目概要 肥胖是糖尿病和心血管等慢性疾病发展的重要危险因素 疾病。鉴于全球肥胖率不断上升，目前的治疗方法无效 比例。世界卫生组织 (WHO) 报告称，全球有 19 亿人（三分之一）患有此病 超重和控制肥胖相关疾病的成本上升占每年 1,470 亿美元 2008 年美国医疗保健支出。对额外治疗方案的需求至关重要。此举的目标 提案是开发针对肥胖和相关代谢疾病的分子治疗方法。我们利用优势 产热棕色和米色脂肪生物学的研究成果，当有针对性时，可以增加能量消耗并赋予 通过解偶联蛋白 1 (UCP1) 的作用预防肥胖。这个过程的机制， 然而，还没有完全理解。揭示可以激活这种现象的新途径和调节因素 该过程将为患有肥胖症和相关代谢疾病的个体提供最大程度的治疗选择。 我们之前在小鼠模型中的工作表明转录因子 Yin Yang 1 (YY1) 至关重要 对于棕色脂肪的功能。 YY1 (YY1bKO) 的脂肪特异性消融导致显着的生热缺陷 棕色脂肪组织，但机制尚不清楚。为了深入了解作用机制，我们 在 YY1bKO 棕色脂肪中进行无偏转录组分析，以寻找新的产热调节剂和 鉴定出基因 nipsnap1（4-硝基苯基磷酸酶结构域和非神经元 SNAP-25 样蛋白 同系物1）。 Nipsnap1 在物种间进化上是保守的，但仍需要明确的功能注释 分配的。我们的初步数据表明 Nipsnap1 表现出强烈的生热特征并显着改变 UCP1 蛋白水平。因此，该提案的目标是确定 Nipsnap1 在 生热脂肪组织，以检验 Nipsnap1 在生热脂肪组织中发挥重要作用的假设 生热作用。拟议的研究将在原代棕色和米色脂肪细胞中使用生化方法 详细描述 Nipsnap1 响应各种生热刺激的转录和翻译动态 （目标1）。然后我们将通过增益和 CRISPR 损失继续对 Nipsnap1 进行功能表征 除了测试线粒体的耦合和非耦合呼吸能力之外，还进行功能丧失研究 系统。还将评估使用高性能 LC-MS/MS 进行的生热脂肪代谢组学分析 （目标 2）。我们的研究将是第一个表征分子功能以及代谢组学相关的研究 产热脂肪组织中的 Nipsnap1 网络。该提案的结果将决定 Nipsnap1 是否 可用于治疗肥胖和相关代谢紊乱。