The role of mitochondrial metabolism in weight loss

项目总结 肥胖是心血管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。减肥是主要的 建议减少肥胖者的心脏代谢风险，但保护与 体重下降的幅度，并在体重维持期间随着时间的推移而逐渐消失， 那些恢复体重的人。这项建议旨在研究线粒体与体重减轻之间的适应 可能会削弱其抵御心血管疾病的能力。我们将通过研究高原的适应来做到这一点 阶段，即尽管努力继续减肥，但进一步减肥变得微乎其微的时期，以及 体重恢复通常是随之而来的。目前对平台期的研究不足，它与体重的发生有关 损失停滞，对心脏代谢风险的保护减弱。 在目标1中，我将确定免疫细胞中体重减轻平台期线粒体的功能差异 从正在减肥的肥胖者中分离出来的。在目标2中，我将开发高原的范例- 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(代谢)适应的潜在机制 适应)在促进体重恢复的高原。对于AIM 3，我将在鼠标模型中确定 加速动脉粥样硬化无论是高原状态的小鼠发展为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。 这项提议将在一个拥有强大的新陈代谢、肥胖症和 心血管疾病。我将接受最先进的技术和分析工具方面的培训 完成所有目标，包括来自美国国立卫生研究院资助的肥胖研究的临床样本，间接热量测量 啮齿动物和小鼠动脉粥样硬化风险的评估。该提案将生成数据，为 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。

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.