The role of mitochondrial metabolism in weight loss

线粒体代谢在减肥中的作用

基本信息

批准号：
10673135
负责人：
Ana Patricia Valencia
金额：
$ 12.74万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673135
关键词：
Acceleration Address Adherence Animals Area Arterial Fatty Streak Atherogenic Diet Atherosclerosis Basic Science Behavioral Bioenergetics Biological Biology Body Composition Body Weight decreased CCL2 gene Carbohydrates Cardiovascular Diseases Cell Separation Cells Clinical Clinical Research Data Diet Dyslipidemias Energy Metabolism Exposure to Fatty Acids Fatty acid glycerol esters Foundations Funding Future Genetic Goals Hepatocyte Human Immune In Vitro Indirect Calorimetry Individual Inflammation Institution Insulin Resistance Interleukin-10 Interleukin-6 Knowledge Learning Life Style Link Lipids Liver Magnetic Resonance Measures Mediating Mentorship Metabolic Metabolism Mitochondria Monocytosis Mononuclear Mus Muscle Muscle Cells Muscle Mitochondria Neutrophilia Obesity Oxidants Oxidation-Reduction Participant Peripheral Persons Phase Predisposition Production Recommendation Relapse Research Research Activity Resistance Respiration Risk Risk Factors Rodent Rodent Model Role Sampling Serum Skeletal Muscle Stress System T-Lymphocyte TNF gene Techniques Testing Therapeutic Thinness Time Tissues Training Translational Research United States National Institutes of Health Weight Weight maintenance regimen analytical tool cardiometabolic risk cardiovascular disorder risk cardiovascular risk factor career career development cell type diet-induced obesity experience experimental study healthy weight human model insight insulin sensitivity lonely individuals metabolic phenotype mitochondrial dysfunction mitochondrial metabolism monocyte mouse model novel nutrition oxidation prevent programs protein expression respiratory response weight maintenance

项目摘要

PROJECT SUMMARY Obesity is a major risk factor for cardiovascular (CV) disease. Various CV risk factors like insulin resistance, dyslipidemia, and inflammation are associated with mitochondrial dysfunction. Weight loss is the main recommendation to reduce cardiometabolic risk for people with obesity, but the protection is proportional to the magnitude of weight lost, and fades over time during weight maintenance with the reversal or worsened risk in those who regain weight. This proposal aims to investigate mitochondrial adaptations with weight loss that might lessen its capacity to protect against CV disease. We will do this by studying adaptation in the plateau phase, a time period when further weight loss becomes minimal despite efforts to continue losing weight, and weight regain often follows. The plateau phase is currently understudied and links the occurrence of a weight loss plateau with diminished protection against cardiometabolic risk. In AIM 1, I will determine functional differences in mitochondria at the weight loss plateau in immune cells isolated from people with obesity undergoing weight loss. In AIM 2, I will develop paradigms of the plateau- state in mice with diet-induced obesity to test whether reduced mitochondrial respiratory capacity in liver muscle and immune cells is an underlying mechanism for adaptation in energy expenditure (metabolic adaptation) at the plateau that promote weight regain. For AIM 3, I will determine in a mouse model of accelerated atherosclerosis whether mice the plateau state develop more severe diet-induced CMR, atherosclerosis, and immune cell redox stress. This proposal will be carried out in an institution with strong research programs in metabolism, obesity, and cardiovascular disease. I will receive state-of-the-art training in techniques and analytical tools necessary for completion of all aims, including clinical samples from NIH-funded obesity studies, indirect calorimetry in rodents, and assessment of atherogenic risk in mice. This proposal will generate data laying the foundation for my independent research career focused on mitochondrial mechanisms that influence cardiometabolic risk in obesity.

项目概要肥胖是心血管（CV）疾病的主要危险因素。各种心血管危险因素，如胰岛素抵抗、血脂异常和炎症与线粒体功能障碍有关。减肥是主要建议降低肥胖者的心脏代谢风险，但保护作用与体重减轻的幅度，并在体重维持过程中随着时间的推移而减弱，并伴有逆转或恶化的风险那些体重反弹的人。该提案旨在研究线粒体对减肥的适应可能会降低其预防心血管疾病的能力。我们将通过研究高原适应来做到这一点阶段，尽管努力继续减肥，但进一步减重变得最小的时间段，以及体重通常会反弹。平台期目前尚未得到充分研究，它与体重的发生有关损失平台期，对心脏代谢风险的保护作用减弱。在 AIM 1 中，我将确定免疫细胞中减肥平台期线粒体的功能差异与正在进行减肥的肥胖者隔离。在 AIM 2 中，我将开发高原范例饮食诱导肥胖小鼠的状态，以测试肝脏线粒体呼吸能力是否降低肌肉和免疫细胞是能量消耗适应的潜在机制（代谢适应）在促进体重恢复的平台期。对于 AIM 3，我将确定鼠标模型加速动脉粥样硬化，平台状态的小鼠是否会出现更严重的饮食诱导的 CMR，动脉粥样硬化和免疫细胞氧化还原应激。该提案将在一个在新陈代谢、肥胖和肥胖等方面拥有强大研究项目的机构中进行。心血管疾病。我将接受必要的技术和分析工具方面的最先进的培训完成所有目标，包括 NIH 资助的肥胖研究的临床样本、间接量热法啮齿类动物，以及小鼠动脉粥样硬化风险的评估。该提案将生成数据，为以下方面奠定基础：我的独立研究生涯专注于影响心脏代谢风险的线粒体机制肥胖。