Development of obesity and metabolic clinical research programs

就第一个目标而言，我们在以下三个领域取得了进展。 1. 间接热量计是测量能量消耗的黄金标准。然而，使用代谢推车的标准测量仅限于短时间测量，例如30分钟的基础或运动条件。全室热量计（呼吸室）扩大了我们在接近自由生活条件下研究人类的能力，并允许我们分离出能量消耗的不同成分（例如，睡眠与休息、活动与餐后）。腔室的主要限制是较大的尺寸（20-30 m3）降低了其灵敏度和响应时间，并允许环境人为因素。 自2008年开始，我们一直在系统地评估我们的全室间接量热室系统，并在2011财年进行了一系列修改。我们测量了进气供应、流出流特性、温度、湿度和过滤对氧气和二氧化碳测量的具体影响。 最终，我们利用这些知识来优化腔室性能（准确度、精度和响应时间）。这些数据将在第二届测量能量代谢的最新进展和争议国际会议（11月2日至4日，马斯特里赫特，荷兰）上公布。 2. 对于精确的自由生活身体活动测量，便携式加速度计是黄金标准的客观技术。这是一个快速发展的领域，无论是在传感器设计还是在数据分析方面。我们从标准台式轨道振荡器开发了一种通用校准器，并评估了两种新一代体力活动监测仪（Actigraph GT 3X+和GENEActive G3）的技术和现场适用性，用于国家健康和营养检查调查（NHANES 2011-12）研究。我们设计了用于研究NHANES现场应用的这些监测器的特性的具体指标，同时从我们以前的传感器设计（Chen等人，2011年）、模型开发（货车Hees等人，2011年）和2003-2006年NHANES现场数据分析（Bankoski等人，2011年）工作中汲取经验和专业知识。我们与NCI和NHANES合作者密切合作，选择了满足NHANES主要需求的监测仪，并在2年的数据收集过程中一直致力于持续评估监测仪（现场1800台）和质量控制。 3. 我们继续与冰岛和NIA研究人员合作，研究我们为年龄、基因/环境易感性-雷克雅未克研究（AGES-Reykjavik Study，2009年3月至2010年7月）收集的自由生活体力活动和睡眠评估数据。我们已经清理了活动和睡眠数据，提取了与代谢健康和功能相关的参数，例如体力活动总量和中度至剧烈活动时间。我们正在分析这些参数与来自大型数据库的组合措施，如心血管健康，骨骼和肌肉，代谢和认知功能。两个手稿正在准备中。 对于第二个目标，我们尽一切努力招募研究志愿者，用于题为“人类饮食诱导的肥胖抵抗表型”（09-DK-0238）的临床方案，目的是确定对高热量饮食抵抗（体重增加低于预测的25%）的健康瘦型受试者，持续4周（体重平衡饮食+1000 kcal/天）。在2011财年，我们通过电话筛选了32名潜在志愿者（通过NIH患者招募办公室、传单、口口相传或直接联系）。我们同意4名受试者进行门诊筛选，并招募了2名研究志愿者。不幸的是，两例受试者在研究第一周后决定自愿退出，一例是由于饮食不依从问题，另一例是由于家人死亡。 影响入组的主要因素是对研究时长的承诺（5周住院研究+1个月导入期）。在与我们的分支负责人Marc Reitman博士讨论后，我们决定暂时停止进一步招募新的研究志愿者并重新评估方案。 我们开发了一种新的临床方案，标题为能量消耗对热中性区周围环境温度范围的反应，热中性区是产热（能量消耗）最小且不随环境温度变化的温度区域。 令人惊讶的是，人们对身体如何调节热量产生（以及能量消耗）以应对环境温度的微妙变化以及这些过程中的人口变化知之甚少。控制产热的机制有助于调节体重，这似乎是合理的。 因此，了解这些控制机制应该提供深入了解的病理生理学基础的肥胖症的流行。 本研究的主要目标是制定指标，研究静息能量消耗对温度变化的反应，包括冷和热，并建立正常瘦和肥胖，年轻人和老年人，女性和男性的这种反应的范围。虽然这个话题几十年来引起了许多人的兴趣，但我们并不知道多个温度点和不同受试者群体的热量和能量平衡的详细数据。我们计划在2012财年启动该方案。

For the first aim, we have made progress in the following three areas. 1. Indirect calorimeters are gold-standard measurements of energy expenditure. However, standard measurements using metabolic carts limit to only short time measurements such as 30-minute basal or exercise conditions. Whole-room calorimeters (respiration chambers) expand our ability to study humans in near free-living conditions and allow us to separate out different components of energy expenditure (e.g., sleeping vs. resting, activity vs. postprandial). The major limitation of the chambers is the larger size (20-30 m3) reduces its sensitivity and response time, and allows environmental artifacts. We have been systematically evaluating our whole-room indirect calorimetry chamber systems since their inception (2008) and through a series of modifications we performed in FY 2011. We measured specific impacts from inlet air supply, outgoing flow characteristics, temperature, humidity, and filtering on the measurements of oxygen and carbon dioxide. Ultimately, we are using this knowledge to optimize the chamber performances (accuracy, precision, and response time). The data will be presented at the 2nd international conference on Recent Advances and Controversies in Measuring Energy Metabolism (Nov 2-4, Maastricht, The Netherlands). 2. For accurate free-living physical activity measurements, portable accelerometers are the gold-standard objective technique. This is a fast-developing field, both in sensor designs and in data analyses. We developed a universal calibrator from a standard bench-top orbital shaker, and evaluated the technical and field applicability of two new generation physical activity monitors (Actigraph GT3X+ and GENEActive G3) for the National Health and Nutrition Examination Survey (NHANES 2011-12) study. We designed specific metrics for studying the properties of these monitors for the NHANES field applications, while drawing experiences and expertise from our previous work with sensor designs (Chen et al. 2011), model development (Van Hees et al. 2011), and analysis of the NHANES field data from 2003-2006 (Bankoski et al. 2011). Working closely with our NCI and NHANES collaborators, we selected the monitor that met the major needs of NHANES, and has been working on continue evaluation the monitor (1800 units in the field) and quality control during the 2-year data collection process. 3. We continue to work with our Iceland and NIA investigators on the free-living physical activity and sleep assessment data we collected for the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study from March 2009 to July 2010. We have cleaned the activity and sleep data, extracted parameters relevant to metabolic health and function, such as total amount of physical activity and moderate to vigorous activity times. We are analyzing these parameters with combined measures from the large database such as cardiovascular health, bone and muscle, metabolism, and cognitive function. Two manuscripts are in preparations. For the second aim, we made every effort in recruiting study volunteers for the clinical protocol titled Diet-Induced-Obesity Resistant Phenotypes in Humans (09-DK-0238), with the goal of identifying healthy lean subjects who are resistant (gain less than 25% of weight as predicted) to hypercaloric diets for 4 weeks (+1000 kcal/day over weight balanced diets). During FY11, we have phone-screened 32 potential volunteers (referred either by NIH Patient Recruitment office, flyers, word of mouth, or by direct contact). We consented 4 subjects for outpatient screening, and two study volunteers have enrolled. Unfortunately, both subject decided to withdraw voluntarily after the first week of study, one due to dietary noncompliance issue, and the other had a family death. The major factor impacted accrual has been the commitment to the study length (5 weeks of inpatient study + one month run-in period). After discussions with our Branch Chief Dr. Marc Reitman, we decided to temporarily halt further recruitment of new study volunteers and reevaluate the protocol. We have developed a new clinical protocol titled Energy expenditure responses to a range of environmental temperatures around the thermal neutral zone, which is the temperature region where heat production (energy expenditure)is a minimum and does not vary with environmental temperature. Surprisingly, little is understood about how the body regulates heat production (and thus energy expenditure) in response to subtle changes in environmental temperature and about the population variation in these processes. It is plausible that the mechanisms governing heat production contribute to regulation of body weight. Thus understanding these control mechanisms should provide insight into the pathophysiology underlying the current epidemic of obesity. The primary goals of this study are to develop metrics to study resting energy expenditure responses to change in temperature, both cold and hot, and establish the ranges of such responses in normal lean and obese, young and old, women and men. While this topic has interested many over decades, we were unaware of detailed data in heat and energy balances over multiple temperature points and in different subject populations. We plan to start the protocol in FY12.