Development of obesity and metabolic clinical research programs

在2023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，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。我们感兴趣的是研究（兼性）冷诱导的人体产热能力，定义为增加能量消耗（EE或产热），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（住院患者）在随机环境温度范围为16 - 31 C（61- 88 F）的室内热量计中连续测量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），十三（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。瘦型和肥胖男性的BAT数据于2017年发布;瘦型和肥胖男性的CIT数据于2019年发布。我们进一步将我们的数据与2020年发表的一份与军事行动相关的出版物中的其他冷暴露研究进行了比较。2020年发表了瘦女性队列的BAT数据，并对CIT数据进行了审查并重新提交给PNAS。我们计划修改该协议，以扩大招募范围，包括更多的性别和种族平等。 2.随着对棕色脂肪组织（BAT）的兴趣不断增长，我们正在使用BAT PET/CT图像来训练我们的postbac IRTA。我们继续培训我们的研究员和合作者使用我们开发的流程分析PET/CT图像。NIH临床中心最近获得了他们的第一台研究PET/MR扫描仪。我们正在修改方案，以开发一种新的方法来量化BAT并验证PET/CT技术。 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）刺激人类BAT和能量消耗的剂量反应，导致2018年在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。利用这些经验，我们在Journal of Biological Chemistry（2020）上发表了一篇题为“治疗激活人类能量消耗和产热以管理肥胖的机遇和挑战”的综述，并在2022年的Methods in Molecular Biology上发表了一篇关于米拉贝隆和人类BAT的神话综述。 4.我们在2023财年启动了一项新的自然史方案（000617 NCT 05398783），以检查使用我们的新型3D激光扫描仪（Vitus）测量的全身表面积（BSA）与通过先前建立的预测方程估计的BSA之间的一致性，包括健康儿童和成人、体重变化的参与者以及患有各种疾病的参与者。到目前为止，我们已经累积了49名研究参与者，通过罩间接测热法测量了静息能量消耗（REE），综合身体成分（DXA，BodPod，D2 O/NaBr和BIS），并测量了BSA。 挑战：研究方案管理流程（研究方案导航程序和质量保证程序）发生了很多变化，这导致了更多的监管要求和更慢的研究进展。COVID-19疫情不仅减缓了我们的研究招聘，还导致医院护理和设施维护人员的重大损失。我们的三个全室间接热量计的温度控制对我们的许多热调节协议至关重要。我们依赖了10多年的0.2C设定值公差不再保持，取而代之的是有时达到10 C的大温度波动。在与NIH研究设施办公室多次尝试缓解这一问题失败后，我们决定为三个房间中的两个建立自己的温度控制系统。在2023财年，我们成功地（逐步）转换了它们。我们还遇到了建筑医用空气供应、停电和波动的其他问题，因此我们正在24财年为我们的房间热量计设计一个独立的医用空气系统。

In FY23, 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. 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), thirteen (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 2017; CIT data from lean and obese men was published 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 lean women cohort was published in 2020, and CIT data was reviewed and resubmitted to the PNAS. We plan to amend this protocol to expand the recruitment to include more gender and race equity. 2. With the interests for brown adipose tissue (BAT) continue to grow, we are using the BAT PET/CT images to train our postbac IRTAs. We continue to train our fellows and collaborators to analyze PET/CT images using the process that we developed. The NIH Clinical Center recently acquired their first research PET/MR scanner. We are amending the protocol to develop a new approach to quantify BAT and validate against the 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 a mythological review on mirabegron and human BAT was published in Methods in Molecular Biology in 2022. 4. We started a new natural history protocol (000617 NCT05398783) in FY23 to examine the agreement between measured whole-body surface area (BSA) using our new 3D laser scanner (Vitus) and BSA estimated by previously established prediction equations in both healthy children and adults, participants with changes in weight, and those with various forms of disease. We have accrued 49 study participants so far with measured resting energy expenditure (REE) by hood indirect calorimetry, comprehensive body composition (DXA, BodPod, D2O/NaBr, and BIS), and measured BSA. Challenges: There have been a lot of changes in the protocol management processes (protocol navigation program and quality assurance program), which resulted in more regulatory demands and slower research progresses. The COVID-19 pandemic not only slowed our research recruitments, but also resulted in major losses to support staff to the hospital, both nursing and facility maintenance. The temperature control to our three whole-room indirect calorimeters is critical to many of our thermal regulation protocols. The setpoint tolerance of 0.2C that we relied on for over 10 years was no longer maintained, replaced by large temperature fluctuations reaching 10C at times. After multiple failed attempts to mitigate this problem with the NIH Office of Research Facilities, we made the decision to build our own temperature control system for two of the three rooms. In FY23, we successfully converted them (stepwise). We have also experienced other issues with the building medical air supply and power outages and fluctuations, thus we are designing an independent medical air system for our room calorimeters in FY24.