In FY15, we have made progresses in the following areas. 1. Our ongoing clinical protocol titled Energy expenditure responses to a range of environmental temperatures around the thermal neutral zone (12-DK-0097, NCT01568671) was developed to improve our understanding of human dynamic regulation of energy expenditure in response to subtle changes in environmental temperature. In particular, we are interested in studying the capacity of facultative thermogenesis, defined as an increase in energy expenditure (EE or heat production) to a changed environmental temperature. Combined with the ongoing research on brown adipose tissue (BAT) and its role in non-shivering thermogensis in our and other labs, such clinical research is generating substantial interests in the field of energy metabolism and obesity. We measured resting energy expenditure in a 5-hour period in the room calorimeter with randomized environmental temperature ranging between 16C and 31C, in 10-13 consecutive days (a 2-week inpatient protocol). We also carefully measured potential shivering by surface electromyography (EMG), acceleration, and heart rate, skin and core body temperatures, and stress responses by blood and urinary markers, while controlling for physical activity, clothing, posture, and dietary intake. To date, we have successfully studied fifteen (15) healthy lean male volunteers as our normative control group and eight (8) healthy obese male volunteers matched for age and race/ethnicity. Two healthy lean female volunteers have also been studied under a shortened (7-day) protocol. Preliminary data analyses showed that we could reproduce the resting EE in the thermal neutral zone (TNZ) within 2.5% coefficient of variation, detect shivering onset with EMG and heart rate, and the slope and the maximum capacity of non-shivering thermogenesis (in lean more so than in the obese), all of which are helping us to understand the parameters that define the dynamic human thermobiology to a range of environmental temperatures that have not been available. We are closely collaborating with Dr. Aaron Cypess, a new clinical investigator with the expertise in BAT research who joined our Branch in FY15, and utilize the PET/CT images taken in these subjects to improve our techniques to quantify human BAT. These efforts will guide us in understanding the role BAT plays in regulating cold-induced thermogenesis. Dr. Cypess and I are also involved in an international consensus group of human BAT researchers to develop the first brown adipose acquisition and reporting criteria in imaging studies (BAARCIST). The goal is to establish minimal requirements for conducting FDG PET/CT experiments on human BAT, data analysis and publication of results. Since there are no validated best practices at this time, our final recommendations will enhance comparability across experiments in this ever-developing research area. 2. We accrued ten (10) new study volunteers for the protocol 13-DK-0200, NCT01950520, in which we use a pharmacologic approach to dissect the mechanism of non-shivering thermogenesis (NST). Since the principal physiologic stimulus to BAT (and possibly muscle) NST is via sympathetic nervous system, we hypothesize that, by careful measurements of NST and using -adrenergic drugs that differ in receptor specificity and agonist/antagonist properties, we will gain better understanding of the regulation of human NST and resting EE. The second phase of the study focuses on measuring anti-obesity drugs potential effect on basal metabolic rate. The rationale is that previous studies of drug effect on EE in humans have not always rigorously enforced the use of thermoneutrality, thus may have increased variability and underestimated effects, contributing to inconclusive findings. We have studied six (16) healthy subjects to date to successfully complete the first phase (Cohort 1), and are in the data analysis phase of the research. Interestingly, Dr. Cypess recently conducted a proof-of-concept study in 2012-2014 on the efficacy of β3-adrenergic agonists to stimulate human BAT and energy expenditure. He used mirabegron (Astellas Pharma US, Inc.), which is approved by the FDA to treat overactive bladder. As the primary endpoint, the efficacy of mirabegron was compared with placebo, and as a secondary endpoint, with cold exposure, which has already been shown can activate human BAT. Interim data show that when compared with placebo, a one-time, oral dose of mirabegron (200 mg) profoundly stimulated BAT thermogenesis, white adipose tissue lipolysis, and whole-body energy expenditure by 203 kcal/day, or +13%. To our knowledge, this study represents the first evaluation of the pharmacological activation of human BAT. Using the paradigm under our current protocol, with the advanced technology available at our lab, we added an arm to this study to explore the effects of mirabegron on BAT activity in more depth. The proposed Amendment would allow for recruitment of up to 84 lean, healthy males, 18-35 years, identified at Cohort 3. We will evaluate the effects of mirabegron on BAT activity at various dosages 0 mg, 50 mg (the FDA-approved dose with limited cardiovascular stimulation), and 200 mg compared to cold exposure. We will also compare the effects of mirabegron on basal metabolic rate (BMR). Our first study volunteer has just started the study in September 2015. 3. We are continuing in the investigations of body composition and activity monitoring technologies and applications. We demonstrated that abdominal/visceral fat estimated using dual-energy x-ray absorptiometry scans can independently predict some cardiometabolic risk factors cross-sectionally, and validated a new type of thigh-worn accelerometer which could be used to estimate sitting and movement in human subject that could improve our free-living physical activity type detection. 4. In 2012-13, Irisin and FGF21 became interesting targets of research as potential modulators for BAT and perhaps beige fat. Collaborating with Dr. Celi and a reserach fellow Dr. Paul Lee, we conducted a series of studies under the protocols 07-DK-0202 and 13-DK-0013 (ClinicalTrials.gov:NCT 00521729 and 01730105, respectively). we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. In ten (10) subjects, we found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. Irisin (FNDC5) and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shiveringrelated muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.
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