Breaking-up sitting to offset sedentary behaviors-induced metabolic alterations

描述(由申请人提供)：本提案概述了一项职业发展计划，以帮助Audrey Bergouignan博士完成她的博士后培训，并建立一个专注于久坐行为的生理病理学的独立研究计划。她的培训将在一个多学科的科学家小组中进行，这些科学家在肥胖、新陈代谢、全身和线粒体生理学、生物化学和生物统计学方面具有研究专长。她的导师Daniel Bessesen博士对学员有着丰富的经验，她的顾问团队中的Reusch博士、Murphy博士、Melanson博士和潘博士将补充这一经验。总体而言，这个团队将提供一个出色的培训环境，使她能够填补工具箱中的关键空白，她需要使用从全身到组织、细胞、蛋白质和基因水平的综合方法来研究久坐行为和不良代谢健康结果之间因果关系的潜在机制。这一奖项还将巩固她在生物统计学方面的知识和进行临床研究研究的能力。在该奖项的培训阶段，她将加强她的学术活动，建立重要的合作关系，并获得关键数据，以确保她成功过渡到独立。理性：从人群研究中有新的证据表明，久坐的时间与包括肥胖、2型糖尿病和心血管疾病在内的各种原因的死亡率有关。重要的是，这些联系与锻炼时间无关。然而，经常中断久坐时间与代谢健康结果有关，即使是在经常锻炼的人中也是如此。我们的假设是，长时间久坐可以改善新陈代谢健康。我们的目标是使用综合的方法来理解频繁中断久坐与改善代谢健康结果之间的联系的生物学机制。设计：一项24小时的研究将首先确定超重成年人长时间坐着休息对全身底物使用以及餐后血糖和胰岛素浓度的影响，这是代谢健康的两个核心组成部分。第一项研究将为申请者提供培训经验和初步数据，以执行R00阶段建议的更明确的研究。比较4周微突发性运动训练与传统能量等量运动训练对血浆心脏代谢指标、代谢健康指标的影响。与胰岛素敏感性相关的潜在机制，即全身底物的使用、膳食脂肪的氧化和骨骼肌脂类组分的运输以及线粒体功能将被进一步描述。相关性：我们相信，拟议的研究将为打破长时间久坐和短时间活动的健康益处提供初步的证据基础。在对抗久坐行为的不利影响方面，这一创新策略可能比更传统的方法更有效。

DESCRIPTION (provided by applicant): This proposal outlines a career development plan to help Dr. Audrey Bergouignan complete her postdoctoral training and establish an independent research program focused on the physiopathology of sedentary behaviors. Her training will be conducted in a multidisciplinary group of scientists with research expertise in obesity, metabolism, whole-body and mitochondrial physiology, biochemistry and biostatistics. Her mentor, Dr. Daniel Bessesen, has an extensive experience with trainees that will be complemented by those in her advisory team, Drs. Reusch, Murphy, Melanson and Pan. Collectively, this team will provide an outstanding training environment that will allow her to fil critical gaps in her toolbox needed to use an integrative approach from whole-body to tissue, cell, protein and gene levels to study mechanisms underlying the causal relationship between sedentary behaviors and adverse metabolic health outcomes. This award will also solidify her knowledge in biostatistics and ability to conduct clinical research studies. During the training phase of this award, she will strengthen her scholarly activities, establish important collaborations, and acquire critical data that will ensure her successful transition to independence. Rational: There is emerging evidence from population studies that time spent in sedentary behaviors is associated with all-cause mortality including obesity, type 2 diabetes, and cardiovascular diseases. Importantly, these associations are independent of time spent in exercise. Frequent interruptions to sedentary time are however beneficially associated with metabolic health outcomes, even in individuals who exercise regularly. Our hypothesis is that breaking-up prolonged sitting improves metabolic health. Our goal is to use integrative approach to understand the biological mechanisms that underlie associations of frequent interruptions of prolonged sitting with improved metabolic health outcomes. Design: A 24-hr study will first determine in overweight adults the effects of breaking-up prolonged sitting on whole-body substrate use and postprandial glucose and insulin concentrations, two core components of metabolic health. The first study will provide the applicant with training experiences and preliminary data to perform the more definitive study proposed in the R00 phase. The effects of 4 weeks of microbursts of activity will be compared with traditional caloric equivalent exercise training on plasma cardiometabolic markers, index of metabolic health. The underlying mechanisms, i.e. whole body substrate use, dietary fat oxidation and trafficking in skeletal muscle lipid fractions and mitochondrial function will be further delineated in association with insulin sensitivity. Relevance: We believe that the proposed studies will provide an initial evidence base for the health benefits of breaking up prolonged sitting with short bursts of activity. This innovative strategy may be more effective at combating the adverse effects of sedentary behaviors than more traditional approaches.