The role of mitochondrial energetics in adaptive thermogenesis with overfeeding

描述(由申请人提供)：项目摘要 NIDDK K01奖项的目标是允许候选人通过学术课程、实践培训、有重点的会议和拟议研究项目的实施相结合的方式，在能量代谢和线粒体生物能量学领域发展成为一名独立的翻译研究员。具体来说，候选人将完成几门关于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K01提案的研究目标。在这项提案中，候选人将利用一项受资助的研究(“脂肪细胞大小、过度喂养和异位脂肪”；资金：R01-DK060412-06A1；PI：Ravussin，E)来研究40名年轻、健康的男性和女性在8周140%过度喂养后的适应性产热作用。适应性产热被定义为基础能量消耗的增加，而过度摄食超过了基于身体质量和成分变化的预期。以前的过量喂养研究已经证明了不同程度的适应性产热，从零适应到显著的(过剩能量的50%)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荷相同的情况下，受试者之间的体重增加也存在显著差异。令人惊讶的是，很少有研究调查适应性产热与过度进食导致的体重增加之间的变异性。我们将在K01提案中调查这种关系。此外，我们将利用体内光谱和体外呼吸的新组合，通过测量过量进食前后线粒体生物能量学(功能)来研究适应性产热的机制。具体地说，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文献中的一个关键空白，解决了过度摄食的适应性产热是由于骨骼肌线粒体解偶联增加，还是细胞能量需求增加，或者两者兼而有之的问题。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靶点。 公共卫生相关性：项目叙述 肥胖症在美国和世界范围内都在上升。体重增加导致肥胖是正能量平衡的次要原因，即卡路里的摄入量超过卡路里的消耗。随着时间的推移，能量消耗的微小差异可能会对体重调节产生重大影响。伴随着过量卡路里的适应性产热(过度进食)，或者是与身体尺寸的增加不成比例地增加休息时的能量消耗的能力，可能是一种重要的机制，通过这种机制来分散多余的能量来调节体重。然而，适应性产热对过度进食时体重增加的贡献尚不清楚。此外，适应性产热的机制，包括骨骼肌生物能量学，目前尚不清楚。

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.