Study of Human Non-Shivering Thermogenesis and Basal Metabolic Rate

  • STATUS
    Recruiting
  • End date
    Oct 19, 2029
  • participants needed
    134
  • sponsor
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Updated on 30 November 2020
Investigator
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Primary Contact
National Institutes of Health Clinical Center, 9000 Rockville Pike (9.7 mi away) Contact
blood test

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:

<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

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 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.

Details
Treatment Placebo, Magnesium Sulfate, Mirabegron 50 MG, Caffeine 200 mg, Propranolol 160 mg, Pindolol 20 mg, Dantrolene 100 mg, Qsymia (topiramate 92 mg CR,phentermine 15 mgPO), Topiramate 200 mg, Phentermine 37.5 mg, Naltrexone 100 mg, Mirabgron 200 mg
Clinical Study IdentifierNCT01950520
SponsorNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Last Modified on30 November 2020

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Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 18 yrs and 35 yrs?
Are you male?
Do you have any of these conditions: Healthy Volunteers or Healthy Volunteer?
Do you have any of these conditions: or Diet and Nutrition or Chronic Diarrhea or Peripheral Arterial Occlusive Disease or Primary Immunodeficiency or Pediatric Health or Healthy Volunte...?
Do you have any of these conditions: or Pediatric Health or Near-Sighted Corrective Surgery or Skin Wounds or Chronic Diarrhea or Chronic Shoulder Pain or Razor Bumps (Pseudofolliculitis...?
Do you have any of these conditions: or Chronic Shoulder Pain or Diet and Nutrition or Adverse Effects, Drugs or Injection Port or Breast Cancer - HER2 Positive or Anal Dysplasia or Pedi...?
Generally healthy
Males between the age 18-35 years
Written informed consent

Exclusion Criteria

BMI less than 18.5 or greater than 25.0 kg/M(2)
History of cardiovascular disease such as congestive heart failure, heart block, clinically abnormal EKG as determined by investigators
History of liver disease or ALT serum level greater than two times the laboratory upper limit of normal
History of kidney diseases or renal insufficiency or estimated creatinine clearance less than or equal to 50 mL/min (MDRD equation)
History of cancer or bariatric surgery
History of diabetes mellitus or fasting serum glucose > 126 mg/dL
History of hypo- or hyper-thyroid or abnormal TSH, except minor deviations deemed to be of no clinical significance by the investigator
History of asthma, chronic obstructive pulmonary disease and glaucoma
Psychological conditions, such as (but not limited to) claustrophobia, clinical depression, bipolar disorders, that would be incompatible with safe and successful participation in this study
Weight change >5 percent in the past 6 months or a trained athlete
Blood pressure greater than 140/90 mmHg or current antihypertensive therapy
Iron deficiency (Hemoglobin <13.7 g/dL and Hematocrit <40.1%)
History of illicit drug, opioids, or alcohol abuse within the last 5 years; current use of drugs (by history) or alcohol (CAGE greater than or equal to 2) (95)
Current use of medications/dietary supplements/alternative therapies known to alter energy metabolism
Current medications that may have interactions with study drugs as determined by the investigators
History of adverse or allergic reactions to the study drugs
Daily caffeine intake >500 mg (about 4 cups) and have withdrawal symptoms
Current smoker or user of tobacco products
Cannot commit to the schedule of visits to the Clinical Research Center (CRC) as required by the study timeline
Have had previous radiation exposure within the last year (X-rays, PET scans, etc.) that would exceed research limits (please let us know if you have received radiation for research purposes)
Have inflexible dietary restrictions
Any other reason that the investigator thinks would make interpretation of the study results difficult
For subjects having an MRD (cOHORT 3), history of pacemaker, metallic heart valves, aneurysm clip, pedicle screws, metallic foreign body in eye, or other metallic implant
For subjects receiving mirabegron (Cohort 3), a diagnosis of bladder outlet obstruction or the use of antimuscarinic medications for the treatement of overactive bladder
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