In FY19, we 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 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 16 - 31C (61-88F), 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, sixteen (16) lean female volunteers (12 had repeated measurements in follicular and luteal menstrual phases), twelve (12) older lean male volunteers (10 with complete data), and thirteen (13) young lean African-American male (12 with complete data) volunteers. The goal of to successfully complete all the cohorts will be achieved by October of 2019. Our data shows 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). Despite of having a lower basal metabolic rate, lean women had similar lower critical temperature as lean men, which were both higher than obese men. There was considerable individual variation in the CIT capacity and the lower critical temperature in all groups, suggesting areas for future investigation. Taken together, these results demonstrate that stimulating CIT increases EE impressively in lean young men and women, suggesting that if it could be harnessed it could make an impact on obesity prevention. But the lower capacity of CIT in obese men does suggest the limitation of using cold exposure to stimulate EE as a treatment of obesity. This data in lean and obese men was published in Journal of Clinical Endocrinology and Metabolism in 2019, the data from other cohorts are currently being analyzed. 2. The interests for brown adipose tissue (BAT) continue to grow. We performed BAT FDG-PET/CT scans for all the study subjects in 12-DK-0097. The publication (PNAS) in 2017 from our group showed that by making improvements to the image analysis methodologies, we could better quantify BAT volume, activity, and distribution in lean and obese subjects. We have trained several research groups to perform the same image analysis using our approaches. To meet more demands from international investigators, we have published manuscript (Journal of Visualized Experiments) by using video format to detail this methodological approach to BAT quantification in 2019. The goal is to improve the ability to study human BAT and reduce the quantification errors between studies. We also used this approach in our PET/CT scans in our lean young women cohort and potentially discovered the existence of a unique depot of active BAT in women dorsocervical region which is the most superficial depot compare to other six deeper BAT depots that we previous quantified: cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominal. This paper is now under review by Obesity in 2019. 3. For the protocol 13-DK-0200, NCT01950520, our collaboration with Dr. Aaron Cypess to add the Cohort 3 study (n=13) on the dose-response of a 3-adrenergic agonists (mirabegron) to stimulate human BAT and energy expenditure resulted in a publication in Diabetes in 2018, which then emerged into a chronic mirabegron study (4-weeks) in women. This study has been submitted for publication to Journal of Clinical Investigation, and is now under revision. We continue to recruit study participants for Cohort 2 (studying the effects of a single-dose by 4 different FDA approved anti-obesity drugs. We currently accrued 7 study participants (with 6 completed the study). We are running an interim analysis before recruiting more subjects (designed to reach n=16).

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