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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.

项目总结