Physiological Responses and Adaptation of Brown Adipose Tissue to Chronic Treatment With Beta 3-Adrenergic Receptor Agonists

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
insulinreleasing 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 beta 3-AR agonist, mirabegron (Myrbetriq
, 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 days while an inpatient on the Metabolic
Patient Care Unit at the NIH Clinical Center. Participants will then take the medication or
placebo for four weeks during which time they will continue their standard daily routines. At
two weeks, participants will return for one day for the assessment of any interim changes and
to validate safety. At the end of the four weeks there will be a second set of inpatient
testing over two 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 the change in BAT metabolic activity as measured by 18F-FDG PET/CT.
Secondary endpoints will examine multiple other factors, including body weight, fat mass,
glucose tolerance, changes in levels of hormones, and improved liver function.

- INCLUSION CRITERIA:

Men and Women ages 18-40 years

- All ethnicities

- BMI 18.0-40.0 kg/m2

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 >140 mg/dL), an HbA1c test
>7.0%, 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 (history or TSH >5.0, <0.4 miU/L); L-T4 replacement,

- Hypersensitivity and associated allergic reactions to mirabegron or similar drug
substances or components of this medication

- Anemia or other iron deficiency (Ferritin <15 mcg/L for women and <30 mcg/L for men)

- 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 (MAO)
inhibitors

- 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, clinical
depression, bipolar disorders, or forms of mental incapacity that would be
incompatible with safe and successful participation in this study

- Addiction to alcohol or substances of abuse within the last 5 years; current use of
drugs or alcohol (CAGE greater than or equal to 2)

- Irregular menstrual cycle or menstrual cycle lasting fewer than 25 days or longer than
31 days, 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, or received 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

- Has elevated liver enzymes and is believed to have liver disease other than fatty
liver disease,

- 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.