Development of obesity and metabolic clinical research programs

在2013财年，我们在以下领域取得了进展。 1. 我们正在进行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（12-DK-0097），旨在提高我们对人类能量消耗动态调节的理解，以响应环境温度的细微变化。特别是，我们有兴趣研究兼性产热的能力，定义为EE（或产热）的增加，以改变环境温度。结合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，这样的临床研究正在能量代谢和肥胖领域产生巨大的兴趣。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。到目前为止，我们已经研究了十五（15）个健康的瘦志愿者作为我们的规范对照组。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。 2. 我们还完成了四个健康的年轻肥胖男性为我们的第二队列。其基本原理是研究肥胖对人类非颤抖性产热的影响。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。 3. 此外，我们对过去的研究（通过与Francesco Celi博士的合作）进行了随访，我们量化了24至19 ℃之间的冷诱导产热。为了研究BAT在EE个体变异性中的作用，在EE过夜测量后，我们通过18F-氟脱氧葡萄糖（FDG）正电子发射断层扫描（PET）在31名男性和女性受试者中测量BAT激活。而不是依赖于视觉BAT检测，我们开发了一种定量成像躯干地幔方法，适用于BAT区域，并证明了在BAT地幔体积内FDG摄取的净增加与个体兼性产热之间的显著相关性，即使在70%的视觉BAT阴性的受试者中也是如此。因此，这种定量方法证明了即使在轻微的冷扰动下，在兼性产热和BAT活化中的测量灵敏度的改善，以及探索BAT与骨密度和其他激素如成纤维细胞生长因子21（FGF 21）之间的复杂关系。随着我们在12-DK-0097方案中继续收集PET/CT数据，我们将采用这种方法来量化BAT体积和总体活性，因为我们研究了其在非颤抖性产热（NST）中的作用。 4. 我们发现，与文献中发现的轻度感冒（3-11%）相比，健康年轻瘦男性的NST能力出乎意料地大（17%）。其机制尚不清楚，但临床发现表明NST可以作为对抗肥胖的干预措施进行探索。 我们制定了一项新的临床方案，使用药理学方法剖析NST的机制（13-DK-0200，IRB于2013年8月30日批准）。由于BAT（可能还有肌肉）NST的主要生理刺激是通过交感神经系统，我们假设，通过仔细测量NST并使用受体特异性和激动剂/拮抗剂性质不同的β-肾上腺素能药物，我们将更好地了解人类NST和静息EE的调节。第二阶段的研究重点是测量抗-肥胖药物对基础代谢率的潜在影响。其理由是，先前关于药物对人体EE影响的研究并不总是严格执行热中性的使用，因此可能增加了变异性和低估了影响，导致结果不确定。新方案将于2014财年开始实施。

In FY13, we have made progresses in the following areas. 1. Our ongoing clinical protocol titled Energy expenditure responses to a range of environmental temperatures around the thermal neutral zone (12-DK-0097) was developed to improve our understanding of human dynamic regulation of energy expenditure in response to subtle changes in environmental temperature. In particular, we are interested in studying the capacity of facultative thermogenesis, defined as an increase in EE (or heat production) to a changed environmental temperature. Combined with the ongoing research on brown adipose tissue and its role in non-shivering thermogensis in our and other labs, such clinical research is generating substantial interests in the field of energy metabolism and obesity. 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. To date, we have studied fifteen (15) healthy lean volunteers as our normative control group. 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. 2. We have also completed four healthy young obese males for our second cohort. The rationale is to study the influence of obesity in human non-shivering thermogenesis. 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. 3. In addition, we followed up on the past studies (through collaborations with Dr. Francesco Celi) which we quantified cold-induced thermogenesis between 24 and 19 C. To investigate the role of BAT in the individual variability in EE, after overnight measurements of EE, we measured BAT activation via 18F-fluro-deoxyglucose (FDG) positron emission tomography (PET) scans in 31 male and female subjects. Rather than relying on the visual BAT detection, we developed a quantitative imaging torso mantle approach to apply over the BAT area and demonstrated a significant correlation between the net increase in FDG uptake within this BAT mantle volume and individual facultative thermogenesis, even in the 70% of the subjects who were visually BAT negative. This quantification method thus demonstrates an improvement in measurement sensitivity in both facultative thermogenesis and BAT activation with even mild cold perturbation, as well as exploring the complex relationship between BAT and bone density and other hormones such as fibroblast growth factor 21 (FGF21). As we continue to gather PET/CT data in the 12-DK-0097 protocol, we will incorporate this approach to quantify BAT volume and overall activity, as we investigate its role in the non-shivering thermogenesis (NST). 4. We have found that the capacity of NST in healthy young lean males is unexpectedly large (17%) as compared to prior reports of mild cold (3-11%) that was found in the literature. The mechanisms underlying this are unclear but the clinical finding suggests NST could be explored as an intervention to combat obesity. We developed a new clinical protocol to use a pharmacologic approach to dissect the mechanism of NST (13-DK-0200, IRB approved 08/30/2013). Since the principal physiologic stimulus to BAT (and possibly muscle) NST is via sympathetic nervous system, we hypothesize that, by careful measurements of NST and using -adrenergic drugs that differ in receptor specificity and agonist/antagonist properties, we will gain better understanding of the regulation of human NST and resting EE. The second phase of the study focuses on measuring anti-obesity drugs potential effect on basal metabolic rate. The rationale is that previous studies of drug effect on EE in humans have not always rigorously enforced the use of thermoneutrality, thus may have increased variability and underestimated effects, contributing to inconclusive findings. This new protocol will begin in FY14.