Development of obesity and metabolic clinical research programs

于2020财政年度，我们在以下方面取得进展。 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。我们还仔细测量潜在的颤抖，身体运动，心率，皮肤和核心体温，以及血液和尿液标记物的压力反应，同时控制身体活动，服装和饮食摄入。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（11人在卵泡期和黄体期重复测量），12（13）名老年瘦男性志愿者（11个具有完整数据），和十三（13）名年轻瘦的非洲裔美国男性（12个具有完整数据）志愿者。由于COVID-19延迟，我们计划于来年招募并完成2-3名年长瘦男性志愿者的研究。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。由于我们目前的方案只包括一个小型和同质的女性志愿者队列（年轻，瘦，和高加索人），我们计划修改方案，以包括相同数量的不同肥胖，年龄和种族的女性志愿者，以与迄今为止研究的男性志愿者进行比较。 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。我们在我们的瘦型年轻女性队列的PET/CT扫描中使用了这种严格的方法，并确定了女性颈背部区域存在一个独特的活性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，该储存库是最浅的储存库：颈部，锁骨上，腋窝，纵隔，脊柱旁和腹部。这篇论文于2020年由Obesity发表。此外，我们与MRI同事合作开发了一种新的非放射性技术，以潜在地识别人类BAT。我们有一篇被放射学接受的论文，我们使用局部1H-MRS弛豫法测量了我们研究受试者冷激活BAT（经FDG-PET/CT证实）中的质子密度（T1和T2），并与远端皮下白色脂肪区域进行了比较。 揭示了BAT和白色脂肪之间的生物物理和生物化学差异。我们的数据表明，通过MRS特征识别BAT是可行的，甚至可能没有冷刺激，这将提高对人类BAT的理解。 3.对于方案13-DK-0200，NCT 01950520，我们完成了队列1研究（n=16），该研究使用药理学方法通过不同的β-肾上腺素能受体调节交感神经系统（SNS），改变受体特异性和激动剂/拮抗剂特性，并测量其在热中性与冷刺激状态下对静息EE的影响。我们目前正在分析数据并准备手稿。我们继续招募队列2的研究参与者（研究4种不同FDA批准的抗肥胖药物的单剂量效应）。在COVID-19大流行暂停我们的研究之前，我们迄今为止招募了9名研究参与者（8名完成，1名研究中断）。中期分析显示，我们将在16名受试者中达到主要结局（一种药物的BMR增加5%）。此外，我们与Aaron Cypess博士在队列3研究（n=13）中合作，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，结果在2019财年的糖尿病杂志上发表了一篇文章，然后在女性中进行了一项慢性mirabegron研究（4周）。这项研究也导致了2020年在临床研究杂志上发表。

In FY20, 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, body movements, and heart rate, skin and core body temperatures, and stress responses by blood and urinary markers, while controlling for physical activity, clothing, 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 (11 had repeated measurements in follicular and luteal menstrual phases), twelve (13) older lean male volunteers (11 with complete data), and thirteen (13) young lean African-American male (12 with complete data) volunteers. Due to the COVID-19 delays, we aim to recruit and complete the studies in 2-3 more older lean male volunteers this coming year. 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. Since our current protocol only includes one small and homogeneous cohort of female volunteers (young, lean, and Caucasian), we plan to amend the protocol to include equal numbers of female volunteers of different adiposity, age, and race to be compared with the male volunteers studied so far. 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. We used this rigorous approach in our PET/CT scans in our lean young women cohort and identified 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 was published by Obesity in 2020. In addition, we collaborated with our MRI colleagues in developing a novel non-radioactive technique to potentially identify human BAT. We have a paper accepted by Radiology, which we used localized 1H-MRS relaxometry to measure proton densities (T1s and T2s) in cold-activated BAT (confirmed by FDG-PET/CT) in our study subjects and compared to distal subcutaneous white adipose regions. reveals biophysical and biochemical differences between BAT and white fat. Our data suggest that it is feasible to identify BAT by MRS signatures, perhaps even without cold stimulation, which will improve the understanding of BAT in humans. 3. For the protocol 13-DK-0200, NCT01950520, we completed Cohort 1 studies (n=16) of using a pharmacologic approach to regulating sympathetic nervous system (SNS) by different beta-adrenergic receptors varying receptor specificity and agonist/antagonist properties and measure their effects on resting EE in thermoneutral vs. cold-stimulated states. We are currently analyzing the data and preparing manuscripts. We continue to recruit study participants for Cohort 2 (studying the single-dose effects of 4 different FDA approved anti-obesity drugs. Before the COVID-19 pandemic that paused our studies, we accrued 9 study participants so far (8 completed, one study was interrupted). An interim analysis showed that we would reach our primary outcome (5% increase of BMR in one drug) with 16 subjects. In addition, our collaboration with Dr. Aaron Cypess in 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 FY19, which then emerged into a chronic mirabegron study (4-weeks) in women. This study has also resulted in a publication in the Journal of Clinical Investigation in 2020.