Study of Human Non-Shivering Thermogenesis and Basal Metabolic Rate

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.

- INCLUSION CRITERIA:

- 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.