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.

项目摘要 肥胖是心血管疾病的主要危险因素。各种简历危险因素，例如胰岛素抵抗， 血脂异常和炎症与线粒体功能障碍有关。减肥是主要的 建议减少肥胖患者的心脏代谢风险，但保护与 体重减轻的大小，随着时间的流逝，体重维持过程会随着时间的流逝而随着逆转或恶化的风险而逐渐消失。 那些恢复体重的人。该建议旨在调查线粒体适应，以减轻体重 可能会降低其预防简历疾病的能力。我们将通过研究高原的适应来做到这一点 阶段，尽管努力继续减肥，但进一步的体重减轻变得最小，并且 体重恢复通常会随之而来。高原阶段目前已经研究了，并将重量的出现联系起来 损失高原降低了针对心脏代谢风险的保护。 在AIM 1中，我将确定免疫细胞体重减轻平台上线粒体的功能差异 与肥胖症患者分离。在AIM 2中，我将开发高原的范例 - 饮食引起肥胖的小鼠的状态，以测试肝脏线粒体呼吸能力是否降低 肌肉和免疫细胞是适应能量消耗的基本机制（代谢 适应）在高原上促进体重恢复。对于AIM 3，我将在鼠标模型中确定 加速性动脉粥样硬化是否会出现高原状态的饮食诱导的CMR，是否形成更严重的CMR， 动脉粥样硬化和免疫细胞氧化还原应激。 该提案将在一个机构中进行，并具有强大的新陈代谢，肥胖和 心血管疾病。我将获得最先进的技术和分析工具培训 所有目标的完成，包括来自NIH资助的肥胖研究的临床样本，间接量热法 啮齿动物和小鼠动脉粥样硬化风险的评估。该建议将生成数据为 我的独立研究生涯的重点是影响心脏代谢风险的线粒体机制 肥胖。