The Mechanism of Human Non-Shivering Thermogenesis and Basal Metabolic Rate
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 47
- 试验地点
- 1
- 主要终点
- Resting Energy Expenditure at Low Temperature
研究概览
简要总结
Background:
- Changes in how a person's body burns energy or calories can affect their weight over time. The lowest level of energy the body needs to function is called basal metabolic rate. In the cold, we burn extra energy, even before we start to shiver. This is called non-shivering thermogenesis and it occurs in different types of tissue such as muscle and fat. Researchers want to learn more about this type of energy burning and how it is regulated. They hope this will help treat obesity in the future.
Objectives:
- Sub-study 1: to better understand how non-shivering thermogenesis works.
- Sub-study 2: to measure the effects of anti-obesity drugs on basal metabolic rate.
- Sub-study 3: to better understand the effects of mirabegron, a beta-3 adrenergic receptor agonist, on brown fat activity.
Eligibility:
- Healthy, lean adult males ages 18 to 35.
Design:
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Participants will be screened with medical history, physical exam, blood test, and EKG.
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For sub-studies 1 and 2:
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Participants will receive one X-ray scan.
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Each day, all participants will:
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Have height and weight measured, and have urine collected.
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Spend 4 hours in a temperature-controlled room with furniture, toilet area, phone, and computer. They will wear small non-invasive devices to monitor activity, heart rate, temperature, and shivering.
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Walk for 30 minutes.
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For sub-study 3:
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Participants will receive one DXA scan and up to 4 PET/CT scans and 4 MRIs
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Each stay, all participants will:
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Have height and weight measured, and have urine collected.
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Spend 6 hours in a temperature-controlled room with furniture, toilet area, phone, and computer. They will wear small non-invasive devices to monitor activity, heart rate, temperature, and shivering.
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Participants will be compensated for their time and participation at the end of the study
详细描述
The balance between energy expenditure (EE) and energy intake ultimately determines body weight. Resting EE is the major component (60-75%) of total EE in an adult human being. Resting EE dynamically adapts to environmental changes such as ambient temperature. In our on-going study of environmental temperature changes within and around the thermoneutral zone, we observed that healthy young men can increase EE by 17 % of the basal metabolic rate through the process of non-shivering thermogenesis (NST). This capacity for NST is unexpectedly large as compared to prior reports of mild cold-induced thermogenesis (3 to 11%) and suggests that increasing NST could be explored as an intervention to combat obesity.
The aim of this study is to better understand the physiology of NST and to develop improved assays for evaluating the effect of drugs that alter EE. For example, only recently has it been realized that brown adipose tissue (BAT) is functional in adult humans and that white adipose tissue can be converted to brown-adipose-like tissue to increase heat production during cold exposures. Moreover, skeletal muscle likely also plays a role in cold-induced thermogenesis even before overt shivering occurs. It is plausible that the mechanisms governing heat production for NST contribute to regulation of body weight and thus may be contributing to the current obesity epidemic: even small changes in EE, if not compensated by changes in food intake, can have long-term effects on body weight.
This protocol has two phases. The first uses a pharmacologic approach to investigate the mechanism of NST in young healthy lean males. Since the principal physiologic stimulus to BAT (and possibly muscle for NST) is via the sympathetic nervous system (SNS), beta-adrenergic receptors may hold key roles in regulating human EE. We hypothesize that, by careful measurements of NST (at an individually-titrated cool environmental temperature, between 18 21 degrees C vs. at thermoneutrality of 27 degrees C) and using beta-adrenergic drugs that differ in receptor specificity and agonist/antagonist properties, we will gain better understanding of the regulation of human NST.
The second phase of the study focuses on measuring of FDA-approved drugs (such as anti-obesity drugs) potential effect on basal metabolic rate (BMR) under thermoneutral conditions. The rationale is that previous studies of drug effect on EE in humans have not always rigorously enforced the use of thermoneutral conditions, thus may have increased variability and underestimated the effect, contributing to inconclusive findings.
It is envisioned that this study will further our knowledge of the mechanisms that regulate the acute adaptive changes in resting energy expenditure and the effects of drug therapy targeting obesity in humans.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 35 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Cohort 1
Chamber temperature will be block randomized with low temperature and 27°C (Cohort 1 only)
Within each block, the following five interventions will be repeated:
Propranolol: Propanolol 160mg, oral, by mouth (Cohort 1 only)
Pindolol: Pindolol 20mg, oral, by mouth (Cohort 1 only)
Dantrolene: Dantrolene 100mg, oral, by mouth (Cohort 1 only)
Magnesium Sulfate: Magnesium Sulfate, infusion, 50 mg/kg bolus followed by maintenance infusion at 2g/h (Cohort 1 only)
Placebo Cohort 1: Placebo, oral, by mouth (Cohort 1 only)
干预措施: Propranolol (Drug)
Cohort 1
Chamber temperature will be block randomized with low temperature and 27°C (Cohort 1 only)
Within each block, the following five interventions will be repeated:
Propranolol: Propanolol 160mg, oral, by mouth (Cohort 1 only)
Pindolol: Pindolol 20mg, oral, by mouth (Cohort 1 only)
Dantrolene: Dantrolene 100mg, oral, by mouth (Cohort 1 only)
Magnesium Sulfate: Magnesium Sulfate, infusion, 50 mg/kg bolus followed by maintenance infusion at 2g/h (Cohort 1 only)
Placebo Cohort 1: Placebo, oral, by mouth (Cohort 1 only)
干预措施: Pindolol (Drug)
Cohort 1
Chamber temperature will be block randomized with low temperature and 27°C (Cohort 1 only)
Within each block, the following five interventions will be repeated:
Propranolol: Propanolol 160mg, oral, by mouth (Cohort 1 only)
Pindolol: Pindolol 20mg, oral, by mouth (Cohort 1 only)
Dantrolene: Dantrolene 100mg, oral, by mouth (Cohort 1 only)
Magnesium Sulfate: Magnesium Sulfate, infusion, 50 mg/kg bolus followed by maintenance infusion at 2g/h (Cohort 1 only)
Placebo Cohort 1: Placebo, oral, by mouth (Cohort 1 only)
干预措施: Dantrolene (Drug)
Cohort 1
Chamber temperature will be block randomized with low temperature and 27°C (Cohort 1 only)
Within each block, the following five interventions will be repeated:
Propranolol: Propanolol 160mg, oral, by mouth (Cohort 1 only)
Pindolol: Pindolol 20mg, oral, by mouth (Cohort 1 only)
Dantrolene: Dantrolene 100mg, oral, by mouth (Cohort 1 only)
Magnesium Sulfate: Magnesium Sulfate, infusion, 50 mg/kg bolus followed by maintenance infusion at 2g/h (Cohort 1 only)
Placebo Cohort 1: Placebo, oral, by mouth (Cohort 1 only)
干预措施: Magnesium Sulfate (Drug)
Cohort 1
Chamber temperature will be block randomized with low temperature and 27°C (Cohort 1 only)
Within each block, the following five interventions will be repeated:
Propranolol: Propanolol 160mg, oral, by mouth (Cohort 1 only)
Pindolol: Pindolol 20mg, oral, by mouth (Cohort 1 only)
Dantrolene: Dantrolene 100mg, oral, by mouth (Cohort 1 only)
Magnesium Sulfate: Magnesium Sulfate, infusion, 50 mg/kg bolus followed by maintenance infusion at 2g/h (Cohort 1 only)
Placebo Cohort 1: Placebo, oral, by mouth (Cohort 1 only)
干预措施: Placebo Cohort 1 (Drug)
Cohort 2
Interventions, in random order, will be administered during one of the six one-day stays
Caffeine: Caffeine 200mg, oral, by mouth (Cohort 2 only)
Qsymia: Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only)
Topiramate: Topiramate 200mg, oral, by mouth (Cohort 2 only)
Phentermine: Phentermine 37.5mg, oral, by mouth (Cohort 2 only)
Naltrexone: Naltrexone 100mg, oral, by mouth (Cohort 2 only)
Placebo Cohort 2: Placebo, oral, by mouth (Cohort 2 only)
干预措施: Caffeine (Drug)
Cohort 2
Interventions, in random order, will be administered during one of the six one-day stays
Caffeine: Caffeine 200mg, oral, by mouth (Cohort 2 only)
Qsymia: Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only)
Topiramate: Topiramate 200mg, oral, by mouth (Cohort 2 only)
Phentermine: Phentermine 37.5mg, oral, by mouth (Cohort 2 only)
Naltrexone: Naltrexone 100mg, oral, by mouth (Cohort 2 only)
Placebo Cohort 2: Placebo, oral, by mouth (Cohort 2 only)
干预措施: Qsymia (Drug)
Cohort 2
Interventions, in random order, will be administered during one of the six one-day stays
Caffeine: Caffeine 200mg, oral, by mouth (Cohort 2 only)
Qsymia: Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only)
Topiramate: Topiramate 200mg, oral, by mouth (Cohort 2 only)
Phentermine: Phentermine 37.5mg, oral, by mouth (Cohort 2 only)
Naltrexone: Naltrexone 100mg, oral, by mouth (Cohort 2 only)
Placebo Cohort 2: Placebo, oral, by mouth (Cohort 2 only)
干预措施: Topiramate (Drug)
Cohort 2
Interventions, in random order, will be administered during one of the six one-day stays
Caffeine: Caffeine 200mg, oral, by mouth (Cohort 2 only)
Qsymia: Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only)
Topiramate: Topiramate 200mg, oral, by mouth (Cohort 2 only)
Phentermine: Phentermine 37.5mg, oral, by mouth (Cohort 2 only)
Naltrexone: Naltrexone 100mg, oral, by mouth (Cohort 2 only)
Placebo Cohort 2: Placebo, oral, by mouth (Cohort 2 only)
干预措施: Phentermine (Behavioral)
Cohort 2
Interventions, in random order, will be administered during one of the six one-day stays
Caffeine: Caffeine 200mg, oral, by mouth (Cohort 2 only)
Qsymia: Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only)
Topiramate: Topiramate 200mg, oral, by mouth (Cohort 2 only)
Phentermine: Phentermine 37.5mg, oral, by mouth (Cohort 2 only)
Naltrexone: Naltrexone 100mg, oral, by mouth (Cohort 2 only)
Placebo Cohort 2: Placebo, oral, by mouth (Cohort 2 only)
干预措施: Naltrexone (Drug)
Cohort 2
Interventions, in random order, will be administered during one of the six one-day stays
Caffeine: Caffeine 200mg, oral, by mouth (Cohort 2 only)
Qsymia: Qsymia (topiramate 92mg CR, phentermine 15mg PO), oral, by mouth (Cohort 2 only)
Topiramate: Topiramate 200mg, oral, by mouth (Cohort 2 only)
Phentermine: Phentermine 37.5mg, oral, by mouth (Cohort 2 only)
Naltrexone: Naltrexone 100mg, oral, by mouth (Cohort 2 only)
Placebo Cohort 2: Placebo, oral, by mouth (Cohort 2 only)
干预措施: Placebo Cohort 2 (Drug)
Cohort 3
Interventions, in random order, will be administered during one of the four overnight inpatient stays
Mirabegron 50mg: Mirabegron 50mg, oral, by mouth (Cohort 3 only)
Mirabegron 200mg: Mirabegron 200mg, oral, by mouth (Cohort 3 only)
Placebo for Mirabegron: Placebo for Mirabegron, oral, by mouth (Cohort 3 only)
干预措施: Mirabegron 50mg (Drug)
Cohort 3
Interventions, in random order, will be administered during one of the four overnight inpatient stays
Mirabegron 50mg: Mirabegron 50mg, oral, by mouth (Cohort 3 only)
Mirabegron 200mg: Mirabegron 200mg, oral, by mouth (Cohort 3 only)
Placebo for Mirabegron: Placebo for Mirabegron, oral, by mouth (Cohort 3 only)
干预措施: Mirabegron 200mg (Drug)
Cohort 3
Interventions, in random order, will be administered during one of the four overnight inpatient stays
Mirabegron 50mg: Mirabegron 50mg, oral, by mouth (Cohort 3 only)
Mirabegron 200mg: Mirabegron 200mg, oral, by mouth (Cohort 3 only)
Placebo for Mirabegron: Placebo for Mirabegron, oral, by mouth (Cohort 3 only)
干预措施: Placebo for Mirabegron (Drug)
结局指标
主要结局
Resting Energy Expenditure at Low Temperature
时间窗: Cohort 3: Four one-day overnight inpatient stays over a 12-week period.
Resting energy expenditure (REE) at a temperature just above the subject's placebo shivering threshold.
Basal Metabolic Rate
时间窗: Cohort 1: Days 1-17
Basal metabolic rate (BMR) is the resting energy expenditure (REE) at thermoneutrality (27c).
Brown Adipose Tissue Activity (Cohort 3 Only)
时间窗: Cohort 3: Four one-day overnight inpatient stays over a 12-week period.
Brown adipose tissue (BAT) activity is a quantification of tissue volume and metabolic activity per unit volume.
次要结局
未报告次要终点