Development of obesity and metabolic clinical research programs

在19财年，我们在以下方面取得了进展。 1.我们正在进行的题为热中性区周围一系列环境温度的能量消耗响应的临床方案(12-DK-0097，NCT01568671)旨在提高我们对能量消耗响应环境温度细微变化的动态调节的理解。特别是，我们感兴趣的是研究人类(兼性)冷诱导生热的能力，其定义是能量支出(EE或热产生)对环境温度变化的增加。结合我们和其他实验室正在进行的关于棕色脂肪组织(BAT)及其在冷诱导生热(CIT)中的作用的研究，此类临床研究在能量代谢和肥胖领域引起了极大的兴趣。我们在随机环境温度为16-31摄氏度(61-88华氏度)、连续10-13天(两周住院方案)的情况下，在室内量热计中测量5小时内的静息能量消耗。我们还通过体表肌电(EMG)、加速度、心率、皮肤和核心体温以及血液和尿液标志物的应激反应来仔细测量潜在的颤抖，同时控制体力活动、服装、姿势和饮食摄入量。到目前为止，我们成功地研究了15名健康的瘦男性志愿者作为我们的标准对照组，9(9)名年龄和种族/民族匹配的健康肥胖男性志愿者，16(16)名瘦女性志愿者(12人重复测量卵泡和黄体月经期)，12(12)名年长的瘦男性志愿者(10人有完整的数据)，以及13(13)名年轻的非洲裔美国人志愿者(12人有完整的数据)。到2019年10月，将实现圆满完成所有队列的目标。我们的数据显示，健康的瘦高加索男性的CIT能力(显性颤抖前)是基础代谢率的17.11%，而肥胖的高加索男性的CIT能力显著低于基础代谢率(6.7%，p=0.03)。尽管基础代谢率较低，但瘦女性的临界温度与瘦男性相似，都高于肥胖男性。所有组的CIT容量和较低的临界温度都有相当大的个体差异，这表明未来需要研究的领域。综上所述，这些结果表明，刺激CIT显著增加了瘦年轻男性和女性的EE，这表明如果能够利用它，可能会对肥胖预防产生影响。但肥胖男性的CIT能力较低，这表明使用冷暴露刺激EE作为治疗肥胖症的方法是有限的。该数据发表在2019年《临床内分泌学和代谢杂志》上，来自其他队列的数据目前正在分析中。 2.对棕色脂肪组织(BAT)的兴趣持续增长。我们在12-DK-0097对所有研究对象进行了BAT FDG-PET/CT扫描。我们小组2017年发表的《美国国家科学院院刊》(PNAS)显示，通过对图像分析方法的改进，我们可以更好地量化瘦和肥胖受试者的蝙蝠数量、活动和分布。我们已经培训了几个研究小组，让他们使用我们的方法进行相同的图像分析。为了满足国际研究人员的更多需求，我们在2019年以视频格式发表了《可视化实验杂志》(Journal Of Visualized Experience)，详细介绍了这种BAT量化的方法学途径。目标是提高研究人类蝙蝠的能力，减少研究之间的量化误差。我们也使用这种方法在我们的年轻瘦削女性队列中进行PET/CT扫描，并潜在地发现在女性背颈区存在一个独特的活跃BAT库，与我们之前量化的其他六个较深的BAT库相比，该库是最浅的BAT库：颈部、锁骨上、腋窝、纵隔、脊柱旁和腹部。这篇论文目前正在接受《2019年肥胖》杂志的审查。 3.对于方案13-DK-0200，NCT01950520，我们与Aaron Cypess博士合作，添加了关于3-肾上腺素能激动剂(Mirabegron)刺激人类蝙蝠和能量消耗的剂量-反应的队列3研究(n=13)，导致在2018年发表了一篇《糖尿病》杂志，随后成为一项针对女性的慢性mirabegron研究(4周)。这项研究已经提交给《临床调查杂志》发表，目前正在修订中。我们继续招募Cohort 2的研究参与者(研究FDA批准的4种不同抗肥胖药物单剂的效果。我们目前收集了7名研究参与者(其中6名完成了研究)。我们正在进行中期分析，然后再招募更多的受试者(设计为达到n=16人)。

In FY19, we 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, NCT01568671) was designed to improve our understanding of dynamic regulation of energy expenditure in response to subtle changes in environmental temperature. In particular, we are interested in studying the capacity of (facultative) cold-induced thermogenesis in humans, defined as an increase in energy expenditure (EE or heat production) to a changed environmental temperature. Combined with the ongoing research on brown adipose tissue (BAT) and its role in cold-induced thermogenesis (CIT) in our and other labs, such clinical research is generating substantial interests in the field of energy metabolism and obesity. We measure resting energy expenditure in a 5-hour period in the room calorimeter with randomized environmental temperature ranging between 16 - 31C (61-88F), in 10-13 consecutive days (a 2-week inpatient protocol). We also carefully measure 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 successfully studied fifteen (15) healthy lean male volunteers as our normative control group, nine (9) healthy obese male volunteers matched for age and race/ethnicity, sixteen (16) lean female volunteers (12 had repeated measurements in follicular and luteal menstrual phases), twelve (12) older lean male volunteers (10 with complete data), and thirteen (13) young lean African-American male (12 with complete data) volunteers. The goal of to successfully complete all the cohorts will be achieved by October of 2019. Our data shows that the capacity for CIT (before overt shivering) was 17 11% of the basal metabolic rates in healthy lean Caucasian men, but significantly less in obese Caucasian men (6 7%, p=0.03). Despite of having a lower basal metabolic rate, lean women had similar lower critical temperature as lean men, which were both higher than obese men. There was considerable individual variation in the CIT capacity and the lower critical temperature in all groups, suggesting areas for future investigation. Taken together, these results demonstrate that stimulating CIT increases EE impressively in lean young men and women, suggesting that if it could be harnessed it could make an impact on obesity prevention. But the lower capacity of CIT in obese men does suggest the limitation of using cold exposure to stimulate EE as a treatment of obesity. This data in lean and obese men was published in Journal of Clinical Endocrinology and Metabolism in 2019, the data from other cohorts are currently being analyzed. 2. The interests for brown adipose tissue (BAT) continue to grow. We performed BAT FDG-PET/CT scans for all the study subjects in 12-DK-0097. The publication (PNAS) in 2017 from our group showed that by making improvements to the image analysis methodologies, we could better quantify BAT volume, activity, and distribution in lean and obese subjects. We have trained several research groups to perform the same image analysis using our approaches. To meet more demands from international investigators, we have published manuscript (Journal of Visualized Experiments) by using video format to detail this methodological approach to BAT quantification in 2019. The goal is to improve the ability to study human BAT and reduce the quantification errors between studies. We also used this approach in our PET/CT scans in our lean young women cohort and potentially discovered the existence of a unique depot of active BAT in women dorsocervical region which is the most superficial depot compare to other six deeper BAT depots that we previous quantified: cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal. This paper is now under review by Obesity in 2019. 3. For the protocol 13-DK-0200, NCT01950520, our collaboration with Dr. Aaron Cypess to add the Cohort 3 study (n=13) on the dose-response of a 3-adrenergic agonists (mirabegron) to stimulate human BAT and energy expenditure resulted in a publication in Diabetes in 2018, which then emerged into a chronic mirabegron study (4-weeks) in women. This study has been submitted for publication to Journal of Clinical Investigation, and is now under revision. We continue to recruit study participants for Cohort 2 (studying the effects of a single-dose by 4 different FDA approved anti-obesity drugs. We currently accrued 7 study participants (with 6 completed the study). We are running an interim analysis before recruiting more subjects (designed to reach n=16).