Study of Human Non-Shivering Thermogenesis and Basal Metabolic Rate
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT01950520|
Recruitment Status : Recruiting
First Posted : September 25, 2013
Last Update Posted : April 6, 2021
- 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.
- 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.
- Healthy, lean adult males ages 18 to 35.
- Participants will be screened with medical history, physical exam, blood test, and EKG.
For sub-studies 1 and 2:
- Participants will receive one X-ray scan.
- Each day, all participants will:
<TAB>- Have height and weight measured, and have urine collected.
- 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.
<TAB>- Walk for 30 minutes.
-For sub-study 3:
- Participants will receive one DXA scan and up to 4 PET/CT scans and 4 MRIs
- Each stay, all participants will:
<TAB>- Have height and weight measured, and have urine collected.
- 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.
- Participants will be compensated for their time and participation at the end of the study
|Condition or disease||Intervention/treatment||Phase|
|Healthy Volunteers||Drug: Propranolol 160 mg Drug: Pindolol 20 mg Drug: Dantrolene 100 mg Drug: Magnesium Sulfate Drug: Caffeine 200 mg Drug: Qsymia (topiramate 92 mg CR,phentermine 15 mgPO) Drug: Topiramate 200 mg Drug: Phentermine 37.5 mg Behavioral: Naltrexone 100 mg Drug: Mirabegron 50 mg Drug: Mirabgron 200 mg Other: Placebo||Phase 4|
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 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), b-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 C vs. at thermoneutrality of 27 C) and using b-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 aitu-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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||134 participants|
|Intervention Model:||Single Group Assignment|
|Official Title:||The Mechanism of Human Non-Shivering Thermogenesis and Basal Metabolic Rate|
|Actual Study Start Date :||February 15, 2014|
|Estimated Primary Completion Date :||February 2, 2023|
|Estimated Study Completion Date :||October 19, 2029|
Placebo Comparator: Cohort 1, The Mechanism of Human Nonshivering Thermogenesis
Cohort 1 is a singleblind, fixed order (for drug treatment), partially randomized (for temperature), crossover study. Cohort 1 uses a pharmacologicapproach to investigate the mechanism of NST in young healthy lean males.
Drug: Propranolol 160 mg
Drug: Pindolol 20 mg
Drug: Dantrolene 100 mg
Drug: Magnesium Sulfate
Placebo Comparator: Cohort 2, Pharmacologic Perturbations of Resting Energy Expend
Cohort 2 is a randomized, doubleblind, placebocontrolled, 6-period cross-over study, with data analysisperformed in a blinded manner. Focus is on measuring of FDAapproved drugs (such as anti-obesitydrugs) potential effect on basal metabolic rate(BMR) under thermoneutral conditions.
Drug: Caffeine 200 mg
Drug: Qsymia (topiramate 92 mg CR,phentermine 15 mgPO)
Drug: Topiramate 200 mg
Drug: Phentermine 37.5 mg
Behavioral: Naltrexone 100 mg
Placebo Comparator: Cohort 3, (SqrRoot) 3- Adrenergic Receptor Agonist (mirabegron) Studies
Cohort 3 is a randomized, singleblind, placebocontrolled study, with the quantifier of BAT activity blinded to the four different interventions.Volunteers will undergo up to four experiments tostudy the effects of mirabegron on BMR and BAT activity.
Drug: Mirabegron 50 mg
Cohort 3, IND # 116246
Drug: Mirabgron 200 mg
Cohort 3, IND # 116246
- Cohort 1 interventions Cohort 1 interventions (propranolol 160 mg, pindolol 20 mg, dantrolene 100 mg, and magnesium sulfate (50mg/kg bolus followed by maintenance infusion at 2 g /h), resting energy expenditure, shivering threshold temps, the... [ Time Frame: 17 day inpatient stay ]Effect of interventions on resting energy expenditure at temperature just above placebo shivering threshold.
- Cohort 2 interventions (caffeine (300 mg PO), Qsymia (topiramate 92 mg CR, phentermine 15 mg PO), phentermine (37.5 mg PO),topiramate (200 mg PO), naltrexone (100 mg PO), resting energy expenditure, BMR (basal metabolic rate), thermoneutralit... [ Time Frame: Six one-day overnight inpatient stays over a six to twelve week period. ]Evaluate effect of interventions on BMR (=REE27 (Infinite)C).
- Cohort 3 interventions: mirabegron at 0mg, 50mg, and 200mg, resting energy expenditure, BMR (basal metabolic rate), BATMetabolic activity measured by 18FDG PET/CT, thermoneutrality, coolenvironmental temperature [ Time Frame: 4 study visits: one-day overnight inpatient stays, completed within a 12-week time window ]Effects of interventions on BAT metabolic activity and BMR.
- Shivering thresholds [ Time Frame: 12 months ]We hypothesize that, by careful measurements of NST (at an individually-titrated cool environmental temperature, between 18-21 C vs. at thermoneutrality of 27 C) and using b-adrenergic drugs that differ in receptor specificity and agonist/antagonist properties, we will gain better understanding of the regulation of human NST.
- To compare the effects of mirabegron at 0mg, 50mg, and 200mg on BAT metabolic activity. [ Time Frame: 12 months ]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 as well as further evaluation of the pharmacological activation of human BAT.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01950520
|Contact: Margaret S McGehee, C.R.N.P.||(301) firstname.lastname@example.org|
|Contact: Kong Y Chen, Ph.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Kong Y Chen, Ph.D.||National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)|