Development of obesity and metabolic clinical research programs

在2019财年，我们在以下方面取得了进展。 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，NCT 01568671），旨在提高我们对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）冷诱导的人体产热的能力，定义为能量消耗（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（BAT）及其在冷诱导产热（CIT）中的作用的研究，这种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 - 31 C（61- 88 F）的室内热量计中测量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压力反应来仔细测量潜在的颤抖，同时控制身体活动，服装，姿势和饮食摄入量。到目前为止，我们成功地研究了十五（15）名健康瘦男性志愿者作为我们的标准对照组，九（9）名健康肥胖男性志愿者年龄和种族/民族匹配，十六（16）名瘦女性志愿者（12名在卵泡期和黄体期重复测量），12名老年瘦男性志愿者（10个具有完整数据），和十三（13）名年轻的瘦非洲裔美国男性（12个具有完整数据）志愿者。成功完成所有队列的目标将在2019年10月实现。我们的数据表明，CIT（前明显颤抖）的能力是17 - 11%的基础代谢率在健康的瘦白人男性，但显着低于肥胖的白人男性（6 - 7%，p=0.03）。尽管有较低的基础代谢率，瘦女性有类似的较低的临界温度瘦男性，都高于肥胖男性。有相当大的个体差异的CIT能力和较低的临界温度在所有组中，建议未来的调查领域。综上所述，这些结果表明，刺激CIT可以显著增加瘦年轻男性和女性的EE，这表明如果可以利用它，它可以对肥胖预防产生影响。但肥胖男性CIT能力较低确实表明使用冷暴露刺激EE作为肥胖治疗的局限性。瘦型和肥胖男性的这一数据于2019年发表在《临床内分泌学与代谢杂志》上，目前正在分析其他队列的数据。 2.对棕色脂肪组织（BAT）的兴趣继续增长。我们对12-DK-0097中的所有研究受试者进行了BAT FDG-PET/CT扫描。我们小组在2017年的出版物（PNAS）表明，通过改进图像分析方法，我们可以更好地量化瘦和肥胖受试者的BAT体积，活动和分布。我们已经训练了几个研究小组使用我们的方法执行相同的图像分析。为了满足国际研究人员的更多需求，我们在2019年通过视频格式发表了手稿（Journal of Visualized Experiments），详细介绍了BAT量化的方法学方法。目的是提高研究人类BAT的能力，减少研究之间的量化误差。我们还在我们的瘦型年轻女性队列的PET/CT扫描中使用了这种方法，并可能发现在女性颈背部区域存在独特的活性BAT储存库，与我们之前量化的其他六个更深的BAT储存库相比，这是最浅表的储存库：颈部，锁骨上，腋窝，纵隔，脊柱旁和腹部。这篇论文目前正在由Obesity在2019年进行审查。 3.对于方案13-DK-0200，NCT 01950520，我们与Aaron Cypess博士合作增加了队列3研究（n=13），研究3-肾上腺素能受体激动剂（mirabegron）刺激人体BAT和能量消耗的剂量反应，结果于2018年在Diabetes杂志上发表，随后成为女性慢性mirabegron研究（4周）。该研究已提交临床研究杂志发表，目前正在修订中。我们继续招募队列2的研究参与者（研究4种不同FDA批准的抗肥胖药物单次给药的效果）。我们目前招募了7名研究参与者（其中6名完成了研究）。在招募更多受试者（设计达到n=16）之前，我们正在进行中期分析。

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).