Mitochondrial PE in Brown Adipose Thermogenesis

棕色脂肪产热中的线粒体 PE

基本信息

批准号：
10313609
负责人：
Alek Peterlin
金额：
$ 3.6万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10313609
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

项目摘要

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.

项目摘要肥胖是糖尿病，心血管疾病，中风和癌症的合并症。肥胖是由长时间消耗超过能量消耗的卡路里，这通常也会导致胰岛素阻力和最终II型糖尿病。利用棕色脂肪生热作用提供了有希望的潜力鉴于其能够增加热量支出的能力，肥胖和高血糖的长期治疗。解偶联蛋白1（UCP1），一种位于内部线粒体膜（IMM）的蛋白质，负责棕色脂肪组织（BAT）中的热发生。线粒体能量与IMM密切相关磷脂组成。除了影响Cristae的结构和功能外，这些磷脂还调节由于磷脂结合和相互作用位点，线粒体内膜内膜蛋白的活性。我的初步发现表明磷脂酰乙醇胺（PE）在BAT中起重要的适应性作用线粒体。在逐渐寒冷的环境中，线粒体PE的增加显示出增加与热能能力增加的内容（通过UCP1依赖性呼吸测量）。缺乏蝙蝠线粒体PE缺乏的小鼠对这些小鼠的分离线粒体的耐受性较低表现出降低的呼吸率。基于这些观察结果，我建议线粒体PE是对于最佳的UCP1功能以及冷和饮食诱导的热发生所需的必要。为此，我打算通过研究线粒体PE的增加或减少来询问这种关系如果该磷脂直接通过UCP1起作用。我的大量专家导师团队将支持我通过审查我的发现，确定逻辑中的潜在漏洞，并协助我未来对蝙蝠线粒体生物能学的探究途径。另外，犹他大学的协作和互动学习环境将有助于我利用我的培训鼠标模型生成质量数据，进行线粒体生物能测定，解释数据和使用我的外展技能促进生物医学研究的多样性。该提议解决了一个切实需求在代谢研究中，我们希望这些发现将为未来提供重要的垫脚石研究人员可以更好地理解和利用蝙蝠的热发生治疗。