Development of obesity and metabolic clinical research programs

为了实现第一个目标，我们在以下领域取得了进展。 1. 间接热量计被认为是能量消耗组成部分（睡眠，休息，餐后，运动和恢复）的黄金标准测量。在过去的4年里，我们与Brychta博士（生物医学工程博士）一起系统地改进了我们的3室全室间接量热室系统，使我们不仅实现了精度，响应性和准确性，而且还实现了可靠性，一致性和效率。具体来说，我们已经大大降低了环境对系统性能的影响（例如建筑物湿度和电力波动）。 我们在腔室设计和操作方面的专业知识得到了美国和国际研究人员的认可。我与美国和欧洲的其他三位专家共同组织了第二届能量代谢测量最新进展和争议国际会议（11月2日至4日，荷兰马斯特里赫特），Brychta博士和我分别做了口头报告和全体会议。 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。在这个快速发展的领域（Chen et al. 2012）的基础上，我们将继续与NIH和全球的几个团队合作。在2011财年，我们评估了新开发的加速度计的技术性能和可靠性，该加速度计将用于国家健康和营养调查（NHANES 2011-12）研究。在2012财年，与之前的NHANES加速度计研究（2005-06）相比，现场应用（迄今为止已收集了超过7000人-周）显示出受试者的依从性明显更高，身体活动数据更详细。我们已经完成了对多次使用后的加速度计的后续全面技术评估，以确认灵敏度和监测器间变异性没有偏离新监测器。这是一个重要的发现，以确保连续性和可比性的NHANES研究和其他纵向研究，使用这些监测器重复多年。这项研究的发现已经在《美国流行病学杂志》上发表。其他合作也导致了四个出版的手稿。 关于第二个目标，我们在以下领域取得了进展： 1. 在2012财年，我们的新临床方案，标题为能量消耗对热中性区周围一系列环境温度的反应（12-DK-0097），获得了科学评审员和NIDDK IRB的批准（2012年4月）。其基本原理是提高我们对人类能量消耗动态调节的理解，以应对环境温度的微妙变化。特别是，我们和其他实验室正在进行的关于棕色脂肪组织及其在非颤抖性产热中的作用的研究，在能量代谢和肥胖领域产生了巨大的兴趣。到目前为止，我们已经研究了七（7）名健康的瘦志愿者（21.6 - 4.6岁，BMI 23.3 - 1.6 kg/m2，DXA脂肪% 18.7 - 2.8%）。我们在连续10-13天（2周住院协议）的随机环境温度范围为16 ℃至31 ℃的室内热量计中测量了5小时内的静息能量消耗。我们还通过表面肌电图（EMG）、加速度和心率、皮肤和核心体温以及血液和尿液标记物的应激反应仔细测量了潜在的颤抖，同时控制了身体活动、服装、姿势和饮食摄入。初步结果表明，我们已经开发出一种灵敏的和可重复的测量协议，以量化冷诱导产热及其相关的生理反应。此外，我们现在可以自信地量化热中性区（TNZ）中的静息EE，用EMG检测颤抖发作，非颤抖产热的斜率和最大容量，所有这些都有助于我们了解EE与环境温度曲线的正常形状和个体变异性。初步研究结果显示，这些个体的最大非颤抖性发热和颤抖阈值个体间变异性比我们最初假设的要高。 2. 我们现在正朝着我们的第二个（也是主要的）研究目标前进，研究肥胖对人类非颤抖性产热的影响。我们现在正在积极招募下一批BMI在30-40 kg/m2之间且其他方面健康的患者。通过使用相同的协议，我们将比较的参数，定义的TNZ的形状，颤抖阈值，和斜率和最大能力的非颤抖产热肥胖和瘦的年轻男性之间。

For the first aim, we have made progress in the following areas. 1. Indirect calorimeters are recognized as the gold-standard measurement of the components of energy expenditure (sleeping, resting, postprandial, exercise, and recovery). Together with Dr. Brychta (PhD in Biomedical Engineering), we have systematically modified our 3-room whole-room indirect calorimetry chamber system in the past 4 years, such that we achieve not only precision, responsiveness, and accuracy, but also reliability, consistency, and efficiency. Specifically, we have dramatically reduced the environmental influences on the performance of the system (such as building humidity and electrical power fluctuations). Our expertise in chamber design and operations has been recognized by US and International researchers. With three other experts in US and Europe, I co-organized the 2nd international conference on Recent Advances and Controversies in Measuring Energy Metabolism (Nov 2-4, Maastricht, The Netherlands), where Dr. Brychta and I gave an oral presentation and a plenary talk, respectively. 2. For accurate free-living physical activity measurements, portable accelerometers are the gold-standard objective technique. Building on the foundation of our previous work in this fast-developing area (Chen et al. 2012), we are continuing our collaborations with several groups here at the NIH and globally. In FY 2011, we have evaluated the technical performance and reliability of a newly developed accelerometer to be implemented in the National Health and Nutrition Examination Survey (NHANES 2011-12) study. In FY 2012, the field application (more than 7000 person-weeks have been collected to date) has shown significantly more compliance from test subjects and more detailed physical activity data as compared to the previous NHANES accelerometer study (2005-06). We have completed a follow-up thorough technical evaluation of the accelerometers after multiple use to confirm that the sensitivity and the inter-monitor variability has not deviated from new monitors. This is an important finding to ensure the continuity and comparability of the NHANES study and for other longitudinal studies that use these monitors repeatedly over years. The finding of this study has been submitted in a manuscript for American Journal of Epidemiology. Other collaborations have also resulted in four published manuscripts. For the second aim, we made progress in the following areas: 1. In FY 2012, our new clinical protocol titled Energy expenditure responses to a range of environmental temperatures around the thermal neutral zone (12-DK-0097) was approved by scientific reviewers and NIDDK IRB (in April 2012). The rationale is to improve our understanding of human dynamic regulation of energy expenditure in response to subtle changes in environmental temperature. In particular, the ongoing research on brown adipose tissue and its role in non-shivering thermogensis in our and other labs have generated substantial interests in the field of energy metabolism and obesity. To date, we have studied seven (7) healthy lean volunteers (21.64.6 yrs, BMI 23.31.6 kg/m2, and %fat by DXA 18.72.8%). We measured resting energy expenditure in a 5-hour period in the room calorimeter with randomized environmental temperature ranging between 16C and 31C, in 10-13 consecutive days (a 2-week inpatient protocol). We also carefully measured potential shivering by surface electromyography (EMG), acceleration, and heart rate, skin and core body temperatures, and stress responses by blood and urinary markers, while controlling for physical activity, clothing, posture, and dietary intake. Preliminary results have shown that we have developed a sensitive and reproducible measurement protocol to quantify cold-induced thermogenesis and its associated physiological responses. Moreover, we can now confidently quantify the resting EE in the thermal neutral zone (TNZ), detect shivering onset with EMG, the slope and the maximum capacity of non-shivering thermogenesis, all of which are helping us to understand the normal shape and individual variability of EE vs. environmental temperature curve in this elemental human physiology. The preliminary findings have revealed a higher maximum non-shivering theremogenesis and a wider shivering threshold inter-individual variability in these individuals than we originally hypothesized. 2. We are now moving towards our second (and primary) study aim to study the influence of obesity in human non-shivering thermogenesis. We are now actively recruiting our next cohort of patients who are between the BMI of 30-40 kg/m2 and otherwise healthy. By using the same protocol, we will compare the parameters that define the shape of the TNZ, shivering threshold, and the slope and the maximum capacity of non-shivering thermogenesis between obese and lean young males.