The role of mitochondrial metabolism in weight loss

线粒体代谢在减肥中的作用

• 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
• 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

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，但保护程度与 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、肥胖和健康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。