Development of obesity and metabolic clinical research programs

在22财年的大部分时间里，我们仍然面临着与新冠肺炎疫情相关的重大挑战，以及与健康志愿者相关的临床研究项目的间歇性关闭、工作人员和供应短缺；然而，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)的情况下，在连续10-13天的住院期间，在室内量热计中连续测量5小时内(0800-1300禁食)的能量消耗。我们还仔细测量骨骼肌颤抖、身体运动、心率、皮肤和核心体温，以及通过血液和尿液标志物做出的压力反应，同时控制体力活动、服装和饮食摄入量。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(11人重复测量卵泡和黄体月经期)，12(13)名年长的瘦男性志愿者(11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)。来自瘦身和肥胖男性的BAT数据于2017年发表在PNAS上；CIT来自瘦身和肥胖男性的数据于2019年发表在JCEM上。我们在2020年发表的一份与军事行动有关的出版物中，进一步将我们的数据与其他寒冷暴露研究进行了比较。来自12名苗条女性的蝙蝠数据发表在《肥胖2020》杂志上，目前正在分析EE和其他生理数据，准备提交论文。我们还在修改这项议定书，以扩大招募范围，在我们的研究人群中纳入更多的性别和种族平等。 2.随着人们对棕色脂肪组织(BAT)的兴趣继续增长，我们正在使用12-DK-0097中的BAT PET/CT图像来训练我们在COVID关闭期间的BAC后IRTA。我们还继续培训其他BAT临床研究人员使用我们开发的过程来分析PET/CT图像。在22财年，美国国立卫生研究院临床中心购买了他们的第一台研究型PET/MR扫描仪。我们已经与CC PET部门建立了密切的合作关系，并正在修改协议，以开发一种新的方法来量化BAT，并根据我们目前的PET/CT技术对其进行验证。 3.对于方案13-DK-0200，NCT01950520，我们完成了第一组研究(n=16)，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，并测量它们对热刺激状态和冷刺激状态下静息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FDA批准的4种不同减肥药物的单剂量效应)。在新冠肺炎大流行暂停我们的研究之前，到目前为止，我们积累了9名研究参与者(8名完成，1项研究中断)。一项中期分析显示，我们将在16名受试者中达到初步结果(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，研究了一种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，导致在2018年发表了一篇关于糖尿病的文章，随后出现在一项针对女性的慢性mirabegron研究(4周)。这项研究还导致了2020年《临床调查杂志》的一篇文章。利用这些经验，我们在《生物化学杂志》(2020)上发表了一篇综述，题为《人类能量消耗和生热治疗的激活以管理肥胖的机遇和挑战》。关于米拉贝格龙和人类蝙蝠的另一篇神话评论发表在22财年的《分子生物学方法》上。 4.我们在21财年为我们的实验室购买了一台3D激光引导的体表扫描仪。使用这种非侵入性扫描仪的目的是准确测量受试者的身体表面积(BSA)，而不是依赖于60-70年前开发的使用体重、身高和性别参数的简单预测模型。我们正在计划一项新的自然历史方案(IRB批准了000617 NCT05398783，在我们开始招募受试者之前等待监管部门的批准)，以检查在健康儿童和成人、最近体重变化的人和有各种疾病的人中测量的BSA和通过先前建立的预测方程估计的BSA之间的一致性。如果成功，我们计划将这项技术作为另一种非侵入性测量添加到我们的身体成分实验室。我们还计划将激光测量的牛血清白蛋白与人体成分和能量消耗参数进行比较，以探讨牛血清白蛋白可能有助于人体能量消耗和平衡的潜在机制(S)。

During the majority of FY22, we still face the significant challenges related to the COVID-19 pandemic and the intermittent shutdowns, staff and supply shortages of the clinical research programs associated with healthy volunteers; however, 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 energy expenditure continuously in a 5-hour period (0800-1300 fasted) in the room calorimeter with randomized environmental temperature ranging between 16 - 31C (61-88F) in 10-13 consecutive days (inpatient). We also carefully measure skeletal muscle shivering, body movements, 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. The BAT data from lean and obese men were published in PNAS in 2017; CIT data from lean and obese men was published in JCEM in 2019. We further compared our data to other cold exposure studies in a publication related to military operations published in 2020. The BAT data from 12 lean women was published in Obesity 2020, and the EE and other physiological data is currently being analyzed for a paper submission. We are also amending this protocol to expand the recruitment to include more gender and race equity in our study population. 2. With the interests for brown adipose tissue (BAT) continue to grow, we are using the BAT PET/CT images in the 12-DK-0097 to train our postbac IRTAs during the COVID shutdown period. We also continue to train other BAT clinical researchers to analyze PET/CT images using the process that we developed. In FY22, the NIH Clinical Center acquired their first research PET/MR scanner. We have established a close collaboration with the CC PET Dept and are amending the protocol to develop a new approach to quantify BAT and validate it against our current PET/CT technique. 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 2018, 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. Using these experiences, we published a review titled opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity in Journal of Biological Chemistry (2020). And another mythological review on mirabegron and human BAT was published in Methods in Molecular Biology in FY22. 4. We acquired a 3D laser-guided body surface scanner to our lab during FY21. The goal of using this non-invasive scanner is to accurately measure body surface area (BSA) in human subjects rather than relying on simple prediction models using weight, height, and sex parameters which were developed over 60-70 years ago. We are planning a new natural history protocol (IRB approved 000617 NCT05398783 and waiting for regulatory clearance before we start recruiting subjects) to examine the agreement between measured BSA and BSA estimated by previously established prediction equations in both healthy children and adults, those with recent changes in weight, and those with various forms of disease. If successful, we plan to add this as another non-invasive measurement to our body composition lab. We also plan to compare laser measured BSA with body composition and energy expenditure parameters to investigate the underlying mechanism(s) that BSA may contribute to human energy expenditure and balance.