The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists

Study Overview
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Brief Summary
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Background: Brown adipose tissue (BAT) is a type of fat in the body. It may prevent weight gain, improve insulin sensitivity, and reduce fatty liver. Researchers want to see if BAT helps the body burn energy. Objective: To learn more about how BAT works to burn energy. Eligibility: People ages 18-40 with a body mass index between 18 and 40 Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests Dietitian interview Participants will have an overnight baseline visit. This includes: Repeats of screening tests Exercise test Scans. For one scan, a radioactive substance is injected into the arm. FSIVGIT: An IV is inserted into veins in the right and left arms. Glucose and insulin are injected in one arm. Blood glucose and insulin levels are measured from the other. Metabolic suite: Participants stay 18 19 hours in a room that measures their metabolic rate. Monitors on the body measure heart rate, movement, and temperature. Optional fat biopsy: A small piece of tissue is removed with a needle. Participants will take 2-4 pills daily for 4 weeks. All women will take the drug mirabegron. Men will be randomly get either the drug or a placebo. All participants will have a visit after 2 weeks of the pills. They will repeat the screening tests. Participants will have an overnight visit 2 weeks later. They will repeat the baseline tests. Participants will keep food and medication diaries. Participants will have a follow-up visit 2 weeks after stopping the pills. This includes heart tests. ...

Detailed Description
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Background issues and controversies More than ever before, there is a rise in the rates of obesity and diabetes. As opposed to white fat which stores excess calories, brown fat - also known as brown adipose tissue or BAT - consumes this energy to generate heat. In settings of increased food consumption and cold-exposure, studies show that human BAT becomes more active, potentially combatting weight gain. Other emerging evidence indicates that human BAT may be an endocrine organ, releasing hormones into the blood and regulating other organs like skeletal muscle, liver, and the insulin-releasing pancreatic Beta-cell. However, alongside these promising studies are those people who believe that there is not enough BAT in humans to be functionally relevant, and it contributes little to heat generation or overall health. Purpose/Rationale of the proposed study One of the principal reasons for skepticism about the ability to utilize human BAT is that there is not very much compared to smaller animals in which BAT activation has shown such promise. Therefore, a critical step is to develop medicines that can grow BAT in people and evaluate what kind of health benefits can be achieved. Specific objectives This study will administer the clinically-available beta3-AR agonist, mirabegron (Myrbetriq(R), Astellas Pharma). We will determine whether we can increase BAT volume and activity in people after they have taken this medication daily for four weeks. Our current goal is to see if chronic administration of mirabegron leads to an increase in BAT volume and metabolic activity and if it produces health benefits. Key elements of what is involved At the beginning of the study, the participants will undergo a series of tests to determine their baseline amounts of BAT, blood sugar status, and levels of specified hormones. The testing will take place over the course of two to three days while an inpatient on the Metabolic Patient Care Unit at the NIH Clinical Center. Depending on the Cohort, participants will then take the medication alone for four weeks or both the medication and placebo for four weeks each, during which time they will continue their standard daily routines. At two weeks after starting placebo or mirabegron, participants will return for one day for the assessment of any interim changes and to validate safety. At the end of each set of four weeks there will be a second set of inpatient testing over two to three days. Participants will be brought back two weeks after finishing the study for a follow-up safety visit, at which time they will receive an ECG and heart rate monitoring. Primary outcomes The primary outcome is either the change in BAT metabolic activity as measured by 18FFDG PET/CT or glucose infusion rate as measured by a hyperinsulinemic euglycemic clamp. Secondary endpoints will examine multiple other factors, including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function.

Official Title
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The Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta3-Adrenergic Receptor Agonists

Conditions
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Polycystic Ovary Syndrome

Intervention / Treatment
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* Drug: Mirabegron
* Other: B Complex Plus Vitamin C Tablets


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Cohorts 1 and 2: Men and Women ages 18-40 years; All ethnicities BMI 18.0-40.0 kg/m2 Cohort 3: Women ages 18-40 years; All ethnicities BMI 25.0-50.0 kg/m2 Use of birth control such as intrauterine devices (hormonal or copper), hormonal implants, or oral contraceptives and with stable use for at least 3 months excluding exclusive use of barrier methods Insulin Resistance defined by either: HOMA-IR (a) >5.9 or (b) 2.8 < HOMA-IR < 5.9 with HDL< 51 mg/dL or Fasting Insulin >10.6 microU/mL EXCLUSION CRITERIA: Self-reported weight loss or weight gain >5% in the preceding 6 months Abnormal bladder function, diagnosis of bladder outlet obstruction, urinary incontinence, urgency, and urinary frequency or use of antimuscarinic medication to treat overactive bladder (OAB) Type 1 or Type 2 Diabetes mellitus (fasting serum glucose >125 mg/dL), an HbA1c test >6.5%, or medications used to treat diabetes mellitus Elevated blood pressure that is >135/85 mmHg or currently taking antihypertensive therapy Hypo- or hyper-thyroid disease (TSH >5.0, <0.4 miU/L) that is controlled for less than one year Hypersensitivity and associated allergic reactions to mirabegron or similar drug substances or components of this medication Anemia, defined by Hemoglobin <= 13.8 g/dL (males) or 11.3 g/dL (females) Cardiovascular disease, cardiac arrhythmias, orthostasis, unstable vasomotor system, or renal impairment A clinically-significant abnormal ECG, QTc interval above normal, or the current use of any QT-prolonging drug Use of any known adrenergic agonists, CYP3A or CYP2D6 substrates, cardiac beta-blockers, calcium channel blockers, systemic corticosteroids, monoamine oxidase (Nirengi et al.) inhibitors Concomitant use of spironolactone is permissible in participants in Cohort 3. Investigators will monitor for side effects of study drug and spironolactone use during study participation. Use of medications related to glucose metabolism or known to cause insulin resistance (in preceding 6 months) Psychological conditions including (but not limited to) claustrophobia, untreated clinical depression, bipolar disorders, or forms of mental incapacity that would be incompatible with safe and successful participation in this study Concomitant use of bupropion, desvenlafaxine, venlafaxine, and/or escitalopram are permissible due to high incidence of depression and anxiety disorders. Investigators will monitor participants closely for side effects of both the study drug and their antidepressants, when applicable. Addiction to alcohol or substances of abuse within the last 5 years; self-reported current use of drugs Self-reported current alcohol consumption of more than 2 servings of alcohol per day Self-reported current use of nicotine and/or tobacco products Pregnancy, childbirth within the last year, or breastfeeding in the past 12 months (for women only) Current use of medications/dietary supplements/alternative therapies known to alter energy metabolism Has participated in a clinical trial where there has been treatment with an investigational or marketed drug within 2 months prior to the start of the study Have had previous radiation exposure (X-rays, PET scans, etc.) within the last year or anticipate radiation exposure in the upcoming year - clinical and/or research - that would exceed research limits Donated blood within last 2 months Recent history (4 weeks) of any local or systemic infectious disease with fever or requiring antibiotics Raynaud s disease or intolerance of cold that would prevent the individual from spending 6 hours in a chilled room with a cooling vest Has elevated liver enzymes and is believed to have liver disease other than fatty liver disease Sickle cell anemia or other blood disorder such as hypercoagulable clotting disorders, Tissue conditions such as local infection or wound healing problems, Individuals who spend >70% of daily hours outdoors since the exposure to varied environmental temperatures will potentially impact the ability to influence and measure BAT activity. All subjects will be fully informed of the aims, nature, and risks of the study prior to giving written informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Females taking 100 mg of mirabegron | Drug: Mirabegron<br>* Women will take 100mg daily for 4 weeks. Men will take 200mg daily for 4 weeks. The medication is available in 50 mg tablets.<br>|
| Active Comparator: Cohort 2A<br>Males taking 200 mg mirabegron | Drug: Mirabegron<br>* Women will take 100mg daily for 4 weeks. Men will take 200mg daily for 4 weeks. The medication is available in 50 mg tablets.<br>|
| Placebo Comparator: Cohort 2B<br>Males taking placebo drug | Other: B Complex Plus Vitamin C Tablets<br>* Males will be randomized to take placebo versus active drug (mirabegron). Those taking placebo will take 4 tablets each day to mirror to active group (taking 4 tablets of 50 mg each).<br>|
| Active Comparator: Cohort 3A<br>Females taking 100 mg of mirabegron | Drug: Mirabegron<br>* Women will take 100mg daily for 4 weeks. Men will take 200mg daily for 4 weeks. The medication is available in 50 mg tablets.<br>|
| Placebo Comparator: Cohort 3B<br>Females taking placebo drug | Other: B Complex Plus Vitamin C Tablets<br>* Males will be randomized to take placebo versus active drug (mirabegron). Those taking placebo will take 4 tablets each day to mirror to active group (taking 4 tablets of 50 mg each).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohorts 1 and 2: Change in BAT metabolic activity | Change in brown adipose tissue (BAT) metabolic activity as measured by 18FFDG PET/CT | 4 weeks | 
| Cohort 3: Change in insulin sensitivity | Change in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify changes in metabolic health arising from BAT activation and/or prolonged treatment with mirabegron | Change in metabolic health parameters including body weight, fat mass, glucose tolerance, changes in levels of hormones, and improved liver function | 4 weeks | 
| Cohort 3: Changes in BAT metabolic activity | Change in brown adipose tissue (BAT) metabolic activity as measured by 18FFDG PET/CT | 4 weeks | 
| Cohorts 1 and 2: Changes in insulin sensitivity | Changes in glucose infusion rate, as measured by the hyperinsulinemic euglycemic clamp | 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brown Adipose Tissue, Energy Expenditure, Energy Metabolism, Obesity