Study of Human Non-Shivering Thermogenesis and Basal Metabolic Rate

Phase 2

Completed

Conditions: Healthy Volunteers

Interventions: Drug: Mirabegron 50mg
Drug: Propranolol
Drug: Caffeine
Drug: Mirabegron 200mg
Drug: Pindolol
Drug: Qsymia
Drug: Dantrolene
Drug: Placebo for Mirabegron
Drug: Topiramate
Drug: Magnesium Sulfate
Behavioral: Phentermine
Drug: Placebo Cohort 1
Drug: Naltrexone
Drug: Placebo Cohort 2

Registration Number: NCT01950520

Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Brief Summary: 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:

* 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:

* 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.

* 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:

* 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

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 47

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Cohort 3	Mirabegron 200mg	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)
Cohort 3	Mirabegron 50mg	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)
Cohort 1	Propranolol	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)
Cohort 1	Pindolol	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)
Cohort 1	Dantrolene	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)
Cohort 1	Magnesium Sulfate	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)
Cohort 3	Placebo for Mirabegron	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)
Cohort 1	Placebo 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)
Cohort 2	Caffeine	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)
Cohort 2	Qsymia	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)
Cohort 2	Topiramate	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)
Cohort 2	Phentermine	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)
Cohort 2	Naltrexone	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)
Cohort 2	Placebo 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)

Primary Outcome Measures

Name	Time	Method
Resting Energy Expenditure at Low Temperature	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	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)	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.