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: 9911814
• 负责人: Kevin Qian
• 金额: $ 3.68万
• 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/9911814
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Adverse effects; Affect; Bioinformatics; Biological Assay; Body Temperature; Brain; Brown Fat; CHS protein; 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; Intervention; 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; 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.

项目总结 未能维持全身能量平衡--能量摄入和能量消耗之间的平衡 在生物体水平上-是肥胖及其相关共病的根本原因。因此，生理上的 调节能量摄入和/或消耗的过程是深入研究的主题，并保持了很高的水平 有望成为肥胖的治疗靶点。非颤抖生热(NST)的刺激--生成 在棕色(蝙蝠)和米色脂肪组织中由于无效的代谢循环而产生的热量-已经获得了相当大的研究 兴趣是一种潜在的增加人类能量消耗的手段，以防止肥胖和 代谢综合征。然而，基于NST的治疗策略受到诱导的不良反应的限制 在非蝙蝠组织中骑自行车是徒劳的。因此，鉴定和鉴定新的蝙蝠特异性蛋白可以提供 针对NST制定改进的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 导致了一种新的蝙蝠特异性蛋白质的发现，这种蛋白质的功能未知，取名为BASIC。基本表达式为 NST的环境和药理激活剂对小鼠的高度诱导，以及BASIC 似乎上调了培养的脂肪细胞的生热基因程序，暗示了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使用生理学和 表征新产生的基本基因敲除小鼠模型的分子方法 在体内确定NST基本功能丧失的后果(目标1)。进一步的研究将阐明 BASIC的作用机制：确定其亚细胞定位并检测其对生热的影响 原代棕色脂肪细胞的信号通路(目标2)。拟议目标的完成将揭示 一种迄今未被发现的蝙蝠特有蛋白的功能，这可能为深入了解新的途径提供帮助 参与脂肪的热生成，并揭示了基于NST的治疗干预的潜在靶点。