Development of obesity and metabolic clinical research programs

肥胖和代谢临床研究项目的开发

• 批准号: 10697802
• 负责人: Kong Chen
• 金额: $ 91.21万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697802
• 关键词: 3-Dimensional; Adrenergic Agonists; Adult; African American; Agonist; Agreement; Anti-Obesity Agents; Area; Basal metabolic rate; Biochemistry; Blood; Body Composition; Body Surface; Body Surface Area; Body Temperature; Body measure procedure; Brown Fat; COVID-19 pandemic; Child; Chronic; Clinical; Clinical Protocols; Clinical Research; Clothing; Collaborations; Control Groups; Data; Data Analyses; Diabetes Mellitus; Dietary intake; Disease; Dose; Energy Intake; Energy Metabolism; Equation; Ethnic Origin; FDA approved; Face; Fasting; Fatty acid glycerol esters; Female; Food; Gender; Goals; Heart Rate; Height; Hour; Human; Inpatients; Institutional Review Boards; Interruption; Intervention; Journals; Lasers; Manuscripts; Measurement; Measures; Metabolic; Methods; Molecular Biology; Movement; Mythology; Natural History; Obesity; PET/CT scan; Paper; Participant; Pharmaceutical Preparations; Pharmacology; Phase; Physical activity; Physiological; Positron-Emission Tomography; Process; Property; Protocols documentation; Publications; Publishing; Race; Randomized; Regulation; Research; Research Personnel; Rest; Role; Shivering; Skeletal Muscle; Skin; Specificity; Sympathetic Nervous System; Techniques; Temperature; Therapeutic; Thermogenesis; Thinness; Training; United States National Institutes of Health; Weight; Woman; X-Ray Computed Tomography; antagonist; beta-adrenergic receptor; biological adaptation to stress; clinical center; clinical investigation; cohort; coronavirus disease; design; energy balance; environmental change; experience; fight against; healthy volunteer; human subject; improved; interest; male; men; military operation; novel strategies; obesity development; obesity management; predictive modeling; primary outcome; programs; receptor; recruit; response; sex; study population; total energy expenditure; urinary; volunteer

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.

于2022财政年度大部分时间，我们仍面临与COVID-19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间歇性停工、员工及供应短缺;然而，我们在以下方面取得进展。 1.我们正在进行的题为“能量消耗对热中性区周围一系列环境温度的响应”的临床方案（12-DK-0097，NCT 01568671）旨在提高我们对响应环境温度微妙变化的能量消耗动态调节的理解。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（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），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。2017年，瘦男性和肥胖男性的BAT数据发表在PNAS上; 2019年，瘦男性和肥胖男性的CIT数据发表在JCEM上。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。来自12名瘦女性的BAT数据发表在Obesity 2020上，目前正在分析EE和其他生理数据以提交论文。我们还修订了该方案，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.随着对棕色脂肪组织（BAT）的兴趣持续增长，我们正在使用12-DK-0097中的BAT PET/CT图像在COVID关闭期间训练我们的postbac IRTA。我们还继续培训其他BAT临床研究人员使用我们开发的流程分析PET/CT图像。在2022财年，NIH临床中心获得了他们的第一台研究PET/MR扫描仪。我们已经与CC PET部门建立了密切的合作，并正在修改方案，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，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。另一篇关于米拉贝隆和人类BAT的神话评论发表在2022财年的《分子生物学方法》上。 4.我们的实验室于2021财年购置了一台3D激光引导体表扫描仪。使用这种非侵入式扫描仪的目标是准确测量人体的体表面积（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史方案（IRB批准000617 NCT 05398783，并在我们开始招募受试者之前等待监管机构的批准），以检查健康儿童和成人、近期体重变化的受试者以及患有各种疾病的受试者中测量的BSA与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，我们计划将其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BSA与身体成分和能量消耗参数进行比较，以研究BSA可能有助于人体能量消耗和平衡的潜在机制。