Obesity
Conditions
Keywords
adipose tissue, brown, obesity, Adrenergic beta-3 Receptor Agonists, thermogenesis, metabolism
Brief summary
This study will test the hypothesis that human brown adipose tissue (BAT) can be activated using a β3-adrenergic receptor (AR) agonist. The efficacy of β3-AR agonist will be compared with cold exposure, which we have already shown can activate human BAT, as well as a placebo control.
Detailed description
This study will include an outpatient screening visit and three separate, independent overnight study visits in the General Clinical Research Center (GCRC) at Beth Israel Deaconess Medical Center (BIDMC). Screening procedures will consist of a medical history, physical examination, blood draw, and ECG. If, from the screening tests, it is determined that the eligibility criteria have been meet, healthy volunteers will participate in three separate inpatient visits at BIDMC. Study procedures will occur in the GCRC and the Nuclear Medicine suite at BIDMC. Volunteers will first complete Day A, in which we will measure BAT volume and activity during cold exposure. Cold exposure will consist of wearing a cooling vest at 55 - 61°F, a temperature shown to be cool enough to activate brown adipose tissue but warm enough not to lead to shivering. Resting metabolic rate (RMR) will be measured by indirect calorimetry before and during cool exposure. If there is detectable brown fat activity on Day A, volunteers will participate in Days B and C. Days B and C will be conducted in random order to reduce any bias from the sequence of treatment and scans, as well as any potential placebo effects. Day B will consist of pharmacological stimulation with β3-AR agonist. On Day C, volunteers will be given a placebo control and will not undergo cooling. A blood draw of 26 cc will always be done prior to FDG injection and FDG PET/CT will always be performed 60 minutes after FDG injection. On Day A, FDG will be injected after 60 minutes of cool exposure and the volunteer will remain in the cooling vest for another 60 minutes after FDG injection. To compare energy expenditure and BAT mass and activity among volunteers, we will normalize the data to fat and muscle mass. Whole-body and regional fat and muscle mass will be measured via a Dual Energy X-ray Absorptiometry (DXA) scan at the end of Day A.
Interventions
DRUGbeta3-adrenergic receptor agonist
single dose. The subjects were randomized to receive placebo on one study day and active beta3-adrenergic receptor agonist on the other study day.
Sponsors
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Aaron Cypess
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy Male * 18-65 years old * BMI between 18-40 * Not participated in clinical trial and received either an investigational or marketed drug within two months prior to the study * Not donated blood in previous two months
Exclusion criteria
* Women * History of local or systemic infection disease with fever or requiring antibiotic within 4 weeks of drug administration * Corrected QT interval above normal * Laboratory test results that is more than 1.5 fold outside normal range and/or is judged to be clinically significant * Current addition to alcohol or substances of abuse * Mental incapacity, unwillingness or language barriers precluding adequate understanding or cooperation * Use of system course of corticosteroids or other medication known to cause insulin resistance in previous 6 weeks * Hyperthyroidism,hypothyroidism, hypertension (even if controlled with medications), heart disease (including CAD and CHF), cardiac arrhythmias, diabetes, unstable vasomotor system, or use of monoamine oxidase (MAO) inhibitors * Diagnosis of bladder outlet obstruction or use of any medication to treat overactive bladder (e.g. Tolterodine, Solifenacin, Propiverine, Oxybutynin, and Fesoterodine)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| BAT Activity as Measured by 18F-FDG PET/CT | 60 min after FDG administration | difference in BAT metabolic activity measured in placebo and active drug arms. The BAT metabolic activity represents the amount of FDG tracer retained within the tissue. Retained FDG is a biomarker for tissue oxygen consumption and hence energy expenditure by the tissue. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Whole-body Energy Expenditure | 30 minutes before drug administration followed by 30 minutes after FDG administration | This is the energy expenditure as calculated using indirect calorimetry. |
Countries
United States
Participant flow
Pre-assignment details
There were 15 participants who were enrolled. Three of them did not have cold-induced detectable brown fat, so they did not continue to the randomization. The remaining 12 participants had cold-induced brown fat, so they were randomized.
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants randomized to placebo or drug first then received the other treatment second. | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 22.2 years STANDARD_DEVIATION 0.6 |
| Region of Enrollment United States | 12 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 12 | 0 / 15 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 15 |
Outcome results
Primary
BAT Activity as Measured by 18F-FDG PET/CT
difference in BAT metabolic activity measured in placebo and active drug arms. The BAT metabolic activity represents the amount of FDG tracer retained within the tissue. Retained FDG is a biomarker for tissue oxygen consumption and hence energy expenditure by the tissue.
Time frame: 60 min after FDG administration
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | BAT Activity as Measured by 18F-FDG PET/CT | 0.92 mL*SUVmean*g/mL |
| beta3-adrenergic Receptor (AR) | BAT Activity as Measured by 18F-FDG PET/CT | 132 mL*SUVmean*g/mL |
Comparison: Since the sample size of twelve subjects limited the ability to demonstrate that measurements were normally distributed, we used the non-parametric Wilcoxon sign-ranks test to assess the primary and secondary endpoints. All p values presented are two tailed. p values \< 0.05 were considered to indicate statistical significance for the primary outcome.p-value: 0.001Wilcoxon sign-ranks test
Other Pre-specified
Whole-body Energy Expenditure
This is the energy expenditure as calculated using indirect calorimetry.
Time frame: 30 minutes before drug administration followed by 30 minutes after FDG administration