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: 10255246
• 负责人: Kong Chen
• 金额: $ 86.98万
• 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/10255246
• 关键词: Abdomen; Adipose tissue; Adrenergic Agonists; African American; Age; Agonist; Anti-Obesity Agents; Area; Axilla; Basal metabolic rate; Biochemical; Biophysics; Blood; Body Temperature; Brown Fat; COVID-19; COVID-19 pandemic; Caucasians; Cervical; Chronic; Clinical; Clinical Endocrinology; Clinical Protocols; Clinical Research; Clothing; Collaborations; Control Groups; Data; Data Analyses; Diabetes Mellitus; Dietary intake; Distal; Dose; Endocrinology; Energy Intake; Energy Metabolism; Ethnic Origin; FDA approved; Fatty acid glycerol esters; Female; Food; Goals; Heart Rate; Hour; Human; Image Analysis; Inpatients; Interruption; Intervention; Journals; Magnetic Resonance Imaging; Manuscripts; Measurement; Measures; Mediastinal; Metabolic; Methodology; Movement; Obesity; PET/CT scan; Paper; Participant; Pharmaceutical Preparations; Pharmacology; Phase; Physical activity; Property; Protocols documentation; Protons; Publications; Publishing; Race; Radiology Specialty; Randomized; Regulation; Research; Rest; Role; Shivering; Skin; Specificity; Study Subject; Supraclavicular; Sympathetic Nervous System; Techniques; Temperature; Thermogenesis; Thinness; Training; Woman; beta-adrenergic receptor; biological adaptation to stress; clinical investigation; cohort; density; design; environmental change; fight against; fluorodeoxyglucose positron emission tomography; improved; interest; male; men; novel; obesity development; primary outcome; programs; receptor; recruit; response; subcutaneous; total energy expenditure; urinary; volunteer; young woman

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.

在20财年，我们在以下领域取得了进步。 1。我们正在进行的临床协议，标题为对热中性区域周围一系列环境温度（12-DK-0097，NCT01568671）的一系列环境温度的反应，旨在提高我们对环境温度微妙变化的动态能量支出的理解。特别是，我们有兴趣研究（兼性）冷诱导的人类生热的能力，该能力定义为能量消耗（EE或热量产生）到变化的环境温度变化的能力。结合对棕色脂肪组织（BAT）的持续研究及其在我们和其他实验室中冷诱导的生热发生（CIT）中的作用，这种临床研究在能量代谢和肥胖领域产生了巨大的兴趣。我们在5小时内的静息能量在室内量热计中测量静息能量，其随机环境温度在16-31C（61-88F）之间，连续10-13天（为期2周的住院协议）。我们还仔细测量了潜在的发抖，身体运动以及心率，皮肤和核心体温，以及血液和尿路标记物的压力反应，同时控制体育锻炼，衣服和饮食摄入量。迄今为止，我们成功地研究了15（15）个健康的精益男性志愿者，作为我们的规范对照组，九（9）健康的肥胖男性志愿者匹配年龄和种族/种族/种族/种族/种族/种族，16岁（16）个精益女性志愿者（11名瘦的女性志愿者（11个重复测量了卵泡和脂肪阶段和脂肪阶段的二型男性二线（13）年轻人（13）老年人（13）老年人（13）（13）（13）（13）（13）（13）（13）（13）（13）（13）（13）（11）非洲裔美国男性（12个具有完整数据）志愿者。由于COVID-19的延迟，我们的目标是招募和完成2-3岁的研究，这是今年的年龄较大的男性志愿者。精益男性和肥胖男性中的这些数据在2019年发表在临床内分泌学和代谢杂志上，目前正在分析其他同胞的数据。由于我们目前的方案仅包括一支小型且同质的女性志愿者（年轻，精益和高加索人），因此我们计划修改该方案，以包括等同数量的女性志愿者，这些女性志愿者与迄今为止研究的男性志愿者相比，具有不同的肥胖，年龄和种族。 2。棕色脂肪组织（BAT）的兴趣继续增长。我们对12-DK-0097的所有研究对象进行了BAT FDG-PET/CT扫描。我们小组2017年的出版物（PNA）表明，通过改进图像分析方法，我们可以更好地量化瘦肉和肥胖受试者中的蝙蝠体积，活动和分布。我们已经培训了几个研究小组，以使用我们的方法进行相同的图像分析。我们在瘦年的年轻女性队列中使用了这种严格的方法，并确定了在妇女背腹区域中存在一个独特的活跃蝙蝠库，这是最肤浅的仓库，与我们先前量化的其他六个更深的蝙蝠库相比：宫颈，颈椎上，超级，甲状腺肿，腋窝，毛siper虫，甲状腺毛，小菜，帕多纳植物和腹腔，和腹腔。本文由肥胖症于2020年发表。此外，我们与MRI同事合作开发了一种新型的非放射性技术来潜在地识别人类的蝙蝠。我们有一份被放射学接受的论文，我们在我们的研究对象中使用了局部的1H-MRS弛豫计在冷激活的BAT中测量质子密度（T1S和T2S）（由FDG-PET/CT确认），并与远端皮下白色脂肪区相比。 揭示了蝙蝠和白脂肪之间的生物物理和生化差异。我们的数据表明，即使没有冷刺激，也可以通过MRS特征来识别蝙蝠是可行的，这将改善对人类蝙蝠的理解。 3。对于协议13-DK-0200，NCT01950520，我们通过不同的β-肾上腺素能受体改变受体特异性和激动剂/拮抗剂的特性，并测量其在热对方中的效果来调节同步受体的特异性，并通过不同的β-肾上腺素受体来调节交感神经系统（SNS），以调节交感神经系统（SNS）的效果。我们目前正在分析数据并准备手稿。 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在队列中，CYPESS（n = 13）在3-肾上腺素能激动剂（Mirabegron）的剂量反应中刺激了人类的蝙蝠和能量消耗，导致FY19中的糖尿病出版物，然后在该研究中，该研究在妇女中均在妇女中被培养。