Effects of b3-Adrenergic Receptor Agonists on Brown Adipose Tissue

Study Overview
=================
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.

Official Title
-----------------
Effects of b3-Adrenergic Receptor Agonists on Brown Adipose Tissue

Conditions
-----------------
Obesity

Intervention / Treatment
-----------------
* Drug: beta3-adrenergic receptor agonist


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: beta3-adrenergic receptor agonist<br>single dose. Each subject was randomized to receive placebo at one visit and then the beta3-adrenergic receptor agonist on another study day. | Drug: beta3-adrenergic receptor agonist<br>* single dose. The subjects were randomized to receive placebo on one study day and active beta3-adrenergic receptor agonist on the other study day.<br>* Other names: mirabegron, which is Myrbetriq (TM) by Astellas Pharma;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 60 min after FDG administration | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adipose tissue, brown, obesity, Adrenergic beta-3 Receptor Agonists, thermogenesis, metabolism