Regulation of thermogenesis by the novel brown adipose-specific protein BASIC

新型棕色脂肪特异性蛋白 BASIC 对产热的调节

• 批准号: 10054097
• 负责人: Kevin Qian
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054097
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Adverse effects; Affect; Bioinformatics; Biological Assay; Body Temperature; Brain; Brown Fat; CHS1 gene; CRISPR/Cas technology; Catecholamines; Cells; Chronic; Confocal Microscopy; Coupled; Data; Development; Diabetes Mellitus; Disease; Energy Intake; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Enzymes; Equation; Equilibrium; Expenditure; Extracellular Domain; Failure; Futile Cycling; Gene Expression; Generations; Genes; Genus Hippocampus; Goals; Histology; Homeostasis; Human; Indirect Calorimetry; Introns; Knock-out; Knockout Mice; Light; Lipids; Lipolysis; Literature; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolic syndrome; Mitochondria; Molecular; Molecular Biology; Mus; Names; Obesity; Organ; Organelles; Pathway interactions; Pharmacology; Physiological; Physiological Processes; Plant Roots; Postsynaptic Membrane; Protein Isoforms; Proteins; Proteomics; Regulation; Research; Respiration; Role; Side; Signal Pathway; Signal Transduction; Site; Stimulus; Synapses; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Thermogenesis; Tissues; Translating; Western Blotting; base; comorbidity; energy balance; genome editing; improved; in vivo; insight; interest; knock-down; mouse model; next generation sequencing; novel; obesity treatment; presynaptic; programs; protein aminoacid sequence; rectal; therapeutic target; transcriptome sequencing

PROJECT SUMMARY Failure to maintain systemic energy homeostasis—a balance between energy intake and energy expenditure at the organismal level—is the root cause of obesity and its associated comorbidities. As a result, physiological processes that regulate energy intake and/or expenditure are the subject of intense study and hold great promise as therapeutic targets for obesity. Stimulation of nonshivering thermogenesis (NST)—the generation of heat by futile metabolic cycling in brown (BAT) and beige adipose tissue—has garnered considerable interest as a potential means of increasing energy expenditure in humans to protect against obesity and the metabolic syndrome. However, NST-based therapeutic strategies are limited by the adverse effects of inducing futile cycling in non-BAT tissues. Thus, identifying and characterizing novel BAT-specific proteins could provide opportunities for the development of improved obesity interventions targeting NST. Preliminary studies employing next-generation sequencing, molecular biology, genome editing, and proteomic approaches have led to the discovery of a novel BAT-specific protein of unknown function named BASIC. Basic expression is highly induced by environmental and pharmacological activators of NST in mice, and knockdown of BASIC appears to upregulate the thermogenic gene program in cultured adipocytes, implicating BASIC as a cell- intrinsic negative regulator of adipose thermogenesis. The proposed research plan will first use physiologic and molecular approaches to characterize a newly generated BASIC knockout mouse model and thereby determine the consequence of loss of BASIC function on NST in vivo (Aim 1). Further studies will elucidate BASIC's mechanism of action by defining its subcellular localization and examining its effect on thermogenic signaling pathways in primary brown adipocytes (Aim 2). Completion of the proposed aims will shed light on the function of a hitherto undiscovered BAT-specific protein, which may provide insight into new pathways involved in adipose thermogenesis and reveal a potential target for NST-based therapeutic interventions.

项目概要 未能维持系统能量稳态——能量摄入和能量消耗之间的平衡 在有机体水平上——是肥胖及其相关合并症的根本原因。结果，生理 调节能量摄入和/或消耗的过程是深入研究的主题，并且具有重要意义 有望成为肥胖症的治疗靶点。刺激非颤抖产热（NST）——产生 棕色（BAT）和米色脂肪组织中无用的代谢循环产生的热量——已获得相当多的研究 兴趣作为增加人类能量消耗以防止肥胖和肥胖的潜在手段 代谢综合征。然而，基于 NST 的治疗策略受到诱导的副作用的限制。 非 BAT 组织中的无效循环。因此，鉴定和表征新型 BAT 特异性蛋白可以提供 开发针对 NST 的改进肥胖干预措施的机会。初步研究 采用下一代测序、分子生物学、基因组编辑和蛋白质组学方法 导致发现了一种功能未知的新型 BAT 特异性蛋白，名为 BASIC。基本表达式为 小鼠中 NST 的环境和药理激活剂以及 BASIC 的敲除高度诱导 似乎上调培养脂肪细胞中的生热基因程序，暗示 BASIC 作为一种细胞- 脂肪产热的内在负调节因子。拟议的研究计划将首先利用生理学和 分子方法来表征新生成的 BASIC 敲除小鼠模型，从而 确定 BASIC 功能丧失对体内 NST 的影响（目标 1）。进一步的研究将阐明 BASIC 的作用机制通过定义其亚细胞定位并检查其对产热的影响来确定 原代棕色脂肪细胞中的信号通路（目标 2）。完成拟议目标将揭示 迄今为止尚未发现的 BAT 特异性蛋白的功能，这可能有助于深入了解新的途径 参与脂肪生热作用，并揭示了基于 NST 的治疗干预的潜在目标。