In FY17, we made steady 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 designed to improve our understanding of dynamic regulation of energy expenditure in response to subtle changes in environmental temperature. In particular, we are interested in studying the capacity of (facultative) cold-induced thermogenesis in humans, 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 cold-induced thermogenesis (CIT) in our and other labs, such clinical research is generating substantial interests in the field of energy metabolism and obesity. We measure 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 measure 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 successfully studied fifteen (15) healthy lean male volunteers as our normative control group, nine (9) healthy obese male volunteers matched for age and race/ethnicity, eight (8) lean female volunteers, six (6) older lean male volunteers, and five (5) young lean African-American male volunteers. Preliminary data analyses showed that the capacity for CIT (before overt shivering) was 17 11% of the basal metabolic rates in healthy lean Caucasian men, but significantly less in obese Caucasian men (6 7%, p=0.03). There was considerable individual variation in the CIT capacity and the lower critical temperature in both groups, suggesting areas for future investigation. Taken together, these results demonstrate that stimulating CIT increases EE impressively in lean but not in obese young subjects, suggesting that if it could be harnessed it could make an impact on obesity prevention. This is also helping us to understand the parameters that define the dynamic human thermobiology to a range of environmental temperatures that have not been available currently. This work (lean and obese data) is being prepared for publication, while the data collection continues for the other cohorts. 2. A new interest in our field is brown adipose tissue (BAT), which is a major mechanism of CIT in small animals, but the evidences in adult humans are lacking. To narrow this knowledge gap, our current work has been focused on how to measure BAT in humans and if the BAT activation can contribute to CIT and other impacts on health. The current methods for measuring BAT in humans are limited. The most common technique (FDG-PET), including the torso-mantle approach that we developed previously, combines BAT activity and volume in a single outcome parameter (e.g., mean standardized uptake value). What we need are independent measurements of BAT volume and BAT activity. We performed BAT FDG-PET/CT scans in 12-DK-0097, and have made improvements to the image analysis methodologies which allow us to define and quantify the BAT volume, activity, and distribution. By using these enhanced techniques, we discovered young healthy obese men had less activated BAT than lean men (mean, 130 vs. 334 mL) but more fat in BAT-containing depots (mean, 1,646 vs. 855 mL). Six anatomic regions had activated BATcervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominalwith 67 20% of all activated BAT concentrated in a continuous fascial layer comprising the first three depots in the upper torso. These nonsubcutaneous fat depots amounted to 1.5% of total body mass (4.3% of total fat mass), and up to 90% of each depot could be activated BAT. The present study suggests that active BAT can be found in specific adipose depots in adult humans, but less than one-half of the fat in these depots is stimulated by acute cold exposure, demonstrating a previously underappreciated thermogenic potential. This work was recently published by the Proceedings of the National Academy of Sciences (USA). 3. For the protocol 13-DK-0200, NCT01950520, we completed the Cohort 3 study (n=13) with Dr. Aaron Cypess on the dose-response of a 3-adrenergic agonists (mirabegron) to stimulate human BAT and energy expenditure. We used cold (positive control) and two single dose of mirabegron (50 vs. 200 mg) in a pharmacokinetic trial design while performing parallel global metabolomic analyses. We found that mirabegron induced a dose-dependent increase in BAT metabolic activity and resting energy expenditure (REE) that reflected the distinct human 3-AR tissue expression and were similar to the response to cold. The changes in REE and glycocholic acid were significantly associated with BAT metabolic activity. Nevertheless, the metabolomic profiles of the two interventions did not overlap. Notably, mirabegron decreased plasma levels of multiple bile acids. The changes in REE and glycocholic acid were significantly associated with BAT metabolic activity. These processes support an emerging model in which activation of human BAT leads to a coordinated response designed to support thermogenesis, but perhaps through/involving different metabolic pathways. This work is being prepared for publication. We also started a new protocol (17-DK-0054, NCT03049462) with Dr. Cypess on chronic stimulation of BAT using the doses of mirabegron that we found to be optimal using this study.
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