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: 10529339
• 负责人: Kevin Qian
• 金额: $ 5.27万
• 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/10529339
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; 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; Extracellular Domain; Failure; Futile Cycling; Gene Expression; Generations; Genes; Genetic Transcription; Genus Hippocampus; Goals; Histology; Homeostasis; Human; Indirect Calorimetry; Introns; Knock-out; Knockout Mice; Lipids; Lipolysis; Literature; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolic syndrome; Mitochondria; Molecular; Molecular Biology; Mus; Names; Obesity; Organ; Organelles; Pathway interactions; Physiological; Physiological Processes; Postsynaptic Membrane; Protein Isoforms; Proteins; Proteomics; Rectum; Regulation; Research; Respiration; Role; Side; Signal Pathway; Signal Transduction; Site; Spirometry; Stimulus; Synapses; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Thermogenesis; Tissues; Translating; Western Blotting; comorbidity; energy balance; genome editing; improved; in vivo; insight; interest; knock-down; mouse model; next generation sequencing; novel; obesity treatment; pharmacologic; 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.

项目摘要 无法维持全身能量稳态 - 能量摄入与能量消耗之间的平衡 在有机水平上，是肥胖及其相关合并症的根本原因。结果，生理学 调节能量摄入和/或支出的过程是激烈研究的主题 承诺作为对象的治疗目标。刺激非刺激性热发生（NST） - 生成 棕色（蝙蝠）和米色脂肪组织中徒劳的代谢循环的热量 兴趣是增加人类能源消耗以防止肥胖和 代谢综合征。但是，基于N的基于N的治疗策略受到诱导的不利影响的限制 在非蝙蝠组织中徒劳的循环。那，识别和表征新颖的蝙蝠特异性蛋白可以提供 发展针对NST的改善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具有 导致发现了一种新型的蝙蝠特异性蛋白质，该蛋白质未知功能名为Basic。基本表达是 由小鼠NST的环境和药物激活剂高度诱导，基本的敲低 似乎在培养的脂肪细胞中上调了热基因程序，隐含的基础是细胞 脂肪热发生的固有负调节剂。拟议的研究计划将首先使用生理学和 分子方法来表征新生成的基本基础敲除鼠标模型，从而 确定NST在体内基本功能丧失的后果（AIM 1）。进一步的研究将阐明 基本的作用机理通过定义其亚细胞定位并检查其对热基因的影响 原代棕色脂肪细胞中的信号通路（AIM 2）。提议的目标的完成将揭示 隐藏未发现的蝙蝠特异性蛋白质的功能，这可能会洞悉新途径 参与脂肪的热发生，并揭示了基于NST的治疗干预措施的潜在靶标。

项目成果

CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization.

• DOI: 10.1038/s41586-022-05507-1
• 发表时间: 2023-01
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Qian, Kevin;Tol, Marcus J.;Wu, Jin;Uchiyama, Lauren F.;Xiao, Xu;Cui, Liujuan;Bedard, Alexander H.;Weston, Thomas A.;Rajendran, Pradeep S.;Vergnes, Laurent;Shimanaka, Yuta;Yin, Yesheng;Jami-Alahmadi, Yasaman;Cohn, Whitaker;Bajar, Bryce T.;Lin, Chia-Ho;Jin, Benita;DeNardo, Laura A.;Black, Douglas L.;Whitelegge, Julian P.;Wohlschlegel, James A.;Reue, Karen;Shivkumar, Kalyanam;Chen, Feng-Jung;Young, Stephen G.;Li, Peng;Tontonoz, Peter
• 通讯作者: Tontonoz, Peter