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: 10924930
• 负责人: Kong Chen
• 金额: $ 170.4万
• 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/10924930
• 关键词: 3-Dimensional; Adrenergic Agonists; Adult; African American; Age; Agonist; Agreement; Air; Amendment; Anti-Obesity Agents; Area; Basal metabolic rate; Biochemistry; Blood; Body Composition; 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; Decision Making; Diabetes Mellitus; Dietary intake; Discipline of Nursing; Disease; Dose; Dual-Energy X-Ray Absorptiometry; Energy Intake; Energy Metabolism; Equation; Ethnic Origin; FDA approved; Fasting; Fatty acid glycerol esters; Female; Food; Goals; Heart Rate; Hospitals; Hour; Human; Indirect Calorimetry; Inpatients; Interruption; Intervention; Journals; Lasers; Maintenance; Manuscripts; Measurement; Measures; Medical; Metabolic; Methods; Molecular Biology; Movement; Mythology; Natural History; Obesity; PET/CT scan; Participant; Pharmaceutical Preparations; Phase; Physical activity; Positron-Emission Tomography; Postbaccalaureate; Process; Property; Protocols documentation; Publications; Publishing; Race; Racial Equity; Randomized; Regulation; Research; Rest; Role; Shivering; Skeletal Muscle; Skin; Specificity; Sympathetic Nervous System; 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; design; environmental change; experience; fighting; gender equity; improved; interest; male; men; military operation; novel strategies; obesity development; obesity management; pharmacologic; primary outcome; programs; quality assurance; receptor; recruit; research facility; response; total energy expenditure; urinary; volunteer

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.

在23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。我们有兴趣研究（兼性）冷诱导的人类热生成的能力，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。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。我们在室内量热计的5小时（0800-1300禁食）中连续测量能量支出，随机环境温度在连续10-13天（住院）内随机环境温度在16-31C（61-88F）之间。我们还仔细测量骨骼肌发抖，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）个精益的女性志愿者（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的年轻人（13）年轻人（13）老年人（13）（13）年轻人（13）（13）（13）（13）（11）非洲裔美国男性（12个具有完整数据）志愿者。精益男性和肥胖男子的蝙蝠数据于2017年出版；来自精益和肥胖男性的CIT数据于2019年发表。我们在与2020年发表的军事行动有关的出版物中进一步将数据与其他冷曝光研究进行了比较。2020年出版了来自Lean妇女队列的BAT数据，并审查了CIT数据并将其重新提交给PNA。我们计划修改该协议，以扩大招聘，以包括更多的性别和种族公平。 2。随着棕色脂肪组织（BAT）的兴趣不断增长，我们正在使用BAT PET/CT图像来训练我们的邮政在BAC IRTAS上进行训练。我们继续培训我们的研究员和合作者，使用我们开发的过程分析PET/CT图像。 NIH临床中心最近获得了他们的第一个研究宠物/MR Scanner。我们正在修改制定一种新方法来量化蝙蝠并验证PET/CT技术的方案。 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3的研究中，CYPESS（n = 13）对3-肾上腺素能激动剂（Mirabegron）的剂量反应刺激人类的蝙蝠和能量消耗，导致2018年糖尿病的出版物，然后在该研究中涉及妇女的2020年临床研究。一项评论题为《人类能量消耗和热生成的治疗激活的机会和挑战》，以管理生物化学杂志（2020）中的肥胖症，以及2022年在Molecular Biology中发表了有关Mirabegron和Human BAT的神话般的评论。 4。我们在FY23中启动了一种新的自然历史协议（000617 NCT05398783），以检查测量的全身表面积（BSA）之间使用我们的新3D激光扫描仪（VITUS）和由先前确定的预测方程式估算的健康儿童和成人的预测方程估计的健康儿童和成人，体重和各种疾病的参与者估计的一致性。到目前为止，我们已经通过Hood间接量热法，全面的身体组成（DXA，BODPOD，D2O/NABR和BIS）以及测量的BSA来获得49名研究参与者。 挑战：协议管理流程（协议导航计划和质量保证计划）发生了很多变化，这导致了更多的监管要求，并且研究进展速度较慢。 COVID-19的大流行不仅减慢了我们的研究招聘，而且还造成了重大损失，以支持医院的护理和设施维护。我们三个全室间接热量表的温度控制对于我们的许多热调节方案至关重要。我们依赖10年以上的0.2C的设定值不再维持，取而代之的是，有时会达到10C的大温度波动。在多次尝试通过研究设施的NIH办公室来减轻此问题的失败尝试后，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23财年，我们成功地将它们转换为（逐步）。我们还遇到了建筑物医疗供应和停电和波动的其他问题，因此我们正在为24财年的房间量热量计设计一个独立的医疗空气系统。

项目成果

Fibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans?

• DOI: 10.1007/s00198-013-2464-9
• 发表时间: 2013-12
• 期刊: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
• 作者: Lee P;Linderman J;Smith S;Brychta RJ;Perron R;Idelson C;Werner CD;Chen KY;Celi FS
• 通讯作者: Celi FS

[Physical activity and sleep in Icelandic adolescents].

• DOI: 10.17992/lbl.2018.02.173
• 发表时间: 2018-03
• 期刊: Laeknabladid
• 影响因子: 0.4
• 作者: Rognvaldsdottir V;Valdimarsdottir BM;Brychta RJ;Hrafnkelsdottir SM;Arngrimsson SA;Johannsson E;Chen KY;Gudmundsdottir SL
• 通讯作者: Gudmundsdottir SL

Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans.

• DOI: 10.1016/j.cmet.2016.07.014
• 发表时间: 2016-08-09
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Chen KY;Cypess AM;Laughlin MR;Haft CR;Hu HH;Bredella MA;Enerbäck S;Kinahan PE;Lichtenbelt Wv;Lin FI;Sunderland JJ;Virtanen KA;Wahl RL
• 通讯作者: Wahl RL

Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity.

• DOI: 10.1016/j.cmet.2015.07.021
• 发表时间: 2015-09-01
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Hall KD;Bemis T;Brychta R;Chen KY;Courville A;Crayner EJ;Goodwin S;Guo J;Howard L;Knuth ND;Miller BV 3rd;Prado CM;Siervo M;Skarulis MC;Walter M;Walter PJ;Yannai L
• 通讯作者: Yannai L

Cold-activated brown adipose tissue is an independent predictor of higher bone mineral density in women.

• DOI: 10.1007/s00198-012-2110-y
• 发表时间: 2013-04
• 期刊: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
• 作者: Lee P;Brychta RJ;Collins MT;Linderman J;Smith S;Herscovitch P;Millo C;Chen KY;Celi FS
• 通讯作者: Celi FS