The role of mitochondrial energetics in adaptive thermogenesis with overfeeding

线粒体能量学在过度喂养的适应性产热中的作用

• 批准号: 8076395
• 负责人: Darcy LaRae Johannsen
• 金额: $ 11.59万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8076395
• 关键词: ATP Synthesis Pathway; Address; Adipocytes; Automobile Driving; Basal metabolic rate; Bioenergetics; Bioethics; Body Composition; Body Size; Body Weight; Calories; Cell Size; Coupling; Energy Metabolism; Environment; Expenditure; Fatty acid glycerol esters; Female; Funding; Homeostasis; Human; Human Volunteers; Hyperphagia; Image; In Vitro; Individual; Intake; Ions; Knowledge; Laboratories; Lead; Literature; Maintenance; Measures; Mentored Research Scientist Development Award; Mentors; Metabolism; Methods; Mitochondria; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity; Optics; Outcome Study; Oxygen Consumption; Participant; Physiology; Play; Process; Production; Regulation; Research; Research Personnel; Research Project Grants; Research Proposals; Resistance; Respiration; Rest; Role; Site; Skeletal Muscle; Spectrum Analysis; Substrate Cycling; Supervision; Techniques; Technology; Testing; Thermogenesis; Time; Training; United States; Visit; Weight; Weight Gain; Work; base; career; energy balance; in vivo; interest; male; new technology; novel; protein degradation; public health relevance; response; skills; statistics; symposium; volunteer

DESCRIPTION (provided by applicant): Project Summary The objective of this NIDDK K01 award is to allow the Candidate to develop a career as an independent, translational investigator in the field of energy metabolism and mitochondrial bioenergetics, through a combination of academic coursework, hands-on training, focused conferences, and implementation of the proposed research project. Specifically, the Candidate will complete several courses on cellular and mitochondrial physiology, bio-imaging (spectroscopy), statistics and bioethics, and will visit the laboratories of two co-mentors in order to apply the academic knowledge to research situations. Under the supervision of the on-site primary and co-mentors, the Candidate will utilize these skills and knowledge to carry out the research objectives of the K01 proposal. In this proposal, the Candidate will utilize a funded study ("Fat Cell Size, Overfeeding & Ectopic Fat"; Funding: R01-DK060412-06A1; PI: Ravussin, E) to investigate adaptive thermogenesis in response to 8 weeks of 140% overfeeding in 40 young, healthy males and females. Adaptive thermogenesis is defined as the increase in basal energy expenditure with overfeeding beyond that which is expected based on changes in body mass and composition. Previous overfeeding studies have demonstrated different levels of adaptive thermogenesis, from zero adaptation to significant (>50% of excess energy) adaptation (presented as average adaptation across participants). Additionally, these studies show significant variability in weight gain among subjects, even when the excess calorie burden is equal. Surprisingly few studies have investigated the variability in adaptive thermogenesis in relation to weight gain with overfeeding. We will investigate this relationship in the K01 proposal. Furthermore, we will investigate mechanisms underlying adaptive thermogenesis by measuring mitochondrial bioenergetics (function) before and after overeating, using a novel combination of in vivo spectroscopy and in vitro respiration. Specifically, we will measure changes in mitochondrial uncoupling and resting ATP synthesis (cellular energy demand). Results from this study will fill a critical void in the literature by addressing the question whether adaptive thermogenesis with overfeeding is due to increased skeletal muscle mitochondrial uncoupling, increased cellular energy demand or both. Further studies will investigate the mechanisms responsible for uncoupling and/or increased energy demand, which in the long term, may be important pharmacological targets for energy balance and body weight regulation. PUBLIC HEALTH RELEVANCE: Project Narrative Obesity is on the rise in the United States and worldwide. Weight gain leading to obesity occurs secondarily to positive energy balance, i.e. calorie intake exceeds calorie expenditure. Small differences in energy expenditure may have significant effects on body weight regulation over time. Adaptive thermogenesis with excess calories (overfeeding), or the ability to increase energy expenditure at rest out of proportion to the increase in body size, may be an important mechanism by which excess energy is dissipated to regulate body weight. However, the contribution of adaptive thermogenesis to weight gain with overfeeding is unclear. Additionally, the mechanisms underlying adaptive thermogenesis, including skeletal muscle bioenergetics, are presently unknown.

描述（由申请人提供）：项目摘要 该NIDDK K 01奖项的目的是让候选人通过学术课程，实践培训，重点会议和拟议研究项目的实施相结合，在能量代谢和线粒体生物能量学领域发展成为独立的翻译研究者。具体而言，候选人将完成细胞和线粒体生理学，生物成像（光谱学），统计学和生物伦理学的几门课程，并将访问两位共同导师的实验室，以便将学术知识应用于研究情况。在现场主要导师和共同导师的监督下，候选人将利用这些技能和知识来实现K 01提案的研究目标。在本提案中，候选人将利用一项资助研究（“脂肪细胞大小，过度喂养和异位脂肪”;资助：R 01-DK 060412 - 06 A1; PI：Ravussin，E）来研究40名年轻健康男性和女性在8周140%过度喂养后的适应性产热。适应性产热被定义为基础能量消耗的增加与过度喂养超过预期的基础上，在身体质量和组成的变化。以前的过度喂养研究已经证明了不同水平的适应性产热，从零适应到显著（>50%的过剩能量）适应（以参与者的平均适应表示）。此外，这些研究表明，即使在过量卡路里负担相同的情况下，受试者之间的体重增加也存在显著差异。令人惊讶的是，很少有研究调查了适应性产热与过度喂养体重增加有关的变化。我们将在K 01提案中研究这种关系。此外，我们将研究适应性产热的机制，通过测量线粒体生物能量（功能）暴饮暴食前后，使用体内光谱学和体外呼吸的新组合。具体来说，我们将测量线粒体解偶联和静息ATP合成（细胞能量需求）的变化。这项研究的结果将填补一个关键的空白，在文献中解决的问题是否适应性产热与过度喂养是由于增加骨骼肌线粒体解偶联，增加细胞的能量需求或两者兼而有之。进一步的研究将探讨解偶联和/或增加能量需求的机制，从长远来看，这可能是能量平衡和体重调节的重要药理学靶点。 公共卫生相关性：项目叙述 肥胖症在美国和全世界都在上升。导致肥胖的体重增加发生在正能量平衡之后，即卡路里摄入超过卡路里消耗。随着时间的推移，能量消耗的微小差异可能对体重调节产生显著影响。过量热量的适应性产热（过度喂养），或在休息时增加能量消耗的能力与身体大小的增加不成比例，可能是一个重要的机制，多余的能量被耗散，以调节体重。然而，适应性产热对过度饲养增重的贡献尚不清楚。此外，适应性产热的潜在机制，包括骨骼肌生物能量学，目前尚不清楚。