Mitochondrial PE in Brown Adipose Thermogenesis

棕色脂肪产热中的线粒体 PE

• 批准号: 10472501
• 负责人: Alek Peterlin
• 金额: $ 3.67万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472501
• 关键词: Address; Adipose tissue; Adrenergic beta-Agonists; Adult; Affect; Binding; Bioenergetics; Biological Assay; Biomedical Research; Brown Fat; Calories; Carboxy-Lyases; Cardiovascular Diseases; Cone; Consumption; Crista ampullaris; Data; Dependence; Diabetes Mellitus; Diet; Electron Transport; Energy Metabolism; Environment; Ethanolamines; Exhibits; Expenditure; Future; Glucose; High Fat Diet; House mice; Hyperglycemia; In Vitro; Inner mitochondrial membrane; Insulin Resistance; Integral Membrane Protein; Intervention; Knock-out; Lead; Lipids; Logic; Malignant Neoplasms; Measures; Membrane; Membrane Lipids; Mentors; Metabolic; Mitochondria; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Oxidative Phosphorylation; Phosphatidylethanolamine; Phosphatidylserines; Phospholipids; Play; Proteins; Proton-Motive Force; Public Health; Research; Research Personnel; Research Training; Resolution; Respiration; Role; Route; Shapes; Site; Stroke; Structure; System; Tamoxifen; Testing; Therapeutic; Thermogenesis; Training; United States; Universities; Utah; base; comorbidity; diet-induced obesity; educational atmosphere; experience; experimental study; hands-on learning; interest; knock-down; lipidome; mouse model; obesity treatment; outreach; overexpression; overweight adults; reconstitution; respiratory; skills; success; uncoupling protein 1

PROJECT SUMMARY Obesity is a comorbidity for diabetes, cardiovascular disease, stroke, and cancer. Obesity is caused by consuming calories in excess of energy expenditure for prolonged periods, which also often leads to insulin resistance and eventually type II diabetes. Exploiting brown adipose thermogenesis offers promising potential for the long-term treatment of obesity and hyperglycemia given its ability to increase caloric expenditure. Uncoupling protein 1 (UCP1), a protein located in the inner mitochondrial membrane (IMM), is responsible for thermogenesis in brown adipose tissue (BAT). Mitochondrial energetics are intimately tied to the IMM phospholipid composition. In addition to affecting cristae structure and function, these phospholipids regulate inner mitochondrial transmembrane protein activities due to phospholipid binding and interaction sites. My preliminary findings suggest that phosphatidylethanolamine (PE) plays an important adaptive role in BAT mitochondria. Mice housed in progressively colder environments displayed an increase in mitochondrial PE content concomitant with increased thermogenic capacity (as measured by UCP1-dependent respiration). Mice deficient in BAT mitochondrial PE are less cold tolerant with the isolated mitochondria from these mice exhibiting reduced respiratory rates. Based on these observations, I propose that mitochondrial PE is necessary for optimal UCP1 function and for cold- and diet-induced thermogenesis. To that end, I plan to interrogate this relationship by studying how increases or decreases in mitochondrial PE affect thermogenesis and if this phospholipid acts directly through UCP1. My extensive team of expert mentors will support my wholistic research training experience by reviewing my findings, identifying potential loopholes in my logic, and assisting with my future route of inquiry into BAT mitochondrial bioenergetics. Additionally, the collaborative and interactive learning environment at the University of Utah will facilitate my training in utilizing mouse models to generate quality data, conducting mitochondrial bioenergetic assays, interpreting data, and promoting diversity in biomedical research using my outreach skills. This proposal addresses a critical need in metabolic research and our hope is that these findings will provide an important steppingstone for future researchers to better understand and exploit BAT thermogenesis therapeutically.

项目概要 肥胖是糖尿病、心血管疾病、中风和癌症的共病。肥胖是由以下原因引起的 长时间消耗热量超过能量消耗，这也常常导致胰岛素分泌 耐药性并最终导致 II 型糖尿病。利用棕色脂肪生热作用具有广阔的前景 鉴于其增加热量消耗的能力，可用于长期治疗肥胖和高血糖。 解偶联蛋白 1 (UCP1) 是一种位于线粒体内膜 (IMM) 的蛋白质，负责 棕色脂肪组织（BAT）的产热作用。线粒体能量学与 IMM 密切相关 磷脂成分。除了影响嵴结构和功能外，这些磷脂还调节 由于磷脂结合和相互作用位点而产生的线粒体内跨膜蛋白活性。我的 初步研究结果表明磷脂酰乙醇胺 (PE) 在 BAT 中发挥重要的适应性作用 线粒体。生活在逐渐寒冷的环境中的小鼠线粒体 PE 有所增加 含量伴随着生热能力的增加（通过 UCP1 依赖性呼吸测量）。 缺乏 BAT 线粒体 PE 的小鼠对从这些小鼠中分离出的线粒体的耐冷能力较差 表现出呼吸频率降低。基于这些观察，我认为线粒体 PE 是 对于最佳 UCP1 功能以及寒冷和饮食诱导的产热作用是必需的。为此，我计划 通过研究线粒体 PE 的增加或减少如何影响产热来探究这种关系 如果这种磷脂直接通过 UCP1 起作用。我庞大的专家导师团队将支持我 通过回顾我的发现，识别我的逻辑中的潜在漏洞，获得全面的研究培训经验， 并协助我未来研究 BAT 线粒体生物能学。此外， 犹他大学的协作和互动学习环境将促进我在利用 小鼠模型，用于生成高质量数据、进行线粒体生物能测定、解释数据和 利用我的外展技能促进生物医学研究的多样性。该提案解决了一个关键需求 在代谢研究中，我们希望这些发现将为未来提供重要的垫脚石 研究人员更好地理解和利用 BAT 生热作用进行治疗。