In FY18, 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 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, eight (12) lean female volunteers, six (9) older lean male volunteers, and five (9) young lean African-American male volunteers. The goal is to successfully complete all the cohorts with 12-15 subjects in each. 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). 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 but not in obese young subjects, suggesting that if it could be harnessed it could make an impact on obesity prevention. But the temperature window of tolerable CIT for the obese is narrower, suggesting the challenge of using cold as obesity treatment. This work (lean and obese data) is being prepared for publication, while the data collection continues for the other cohorts. 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 an accepted manuscript (Journal of Visualized Experiments) by using video format to detail this methodological approach to BAT quantification. The goal is to improve the ability to study human BAT and reduce the quantification errors between studies. 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 now published in Diabetes. We are now working with Dr. Cypess on chronic stimulation of BAT using the doses of mirabegron.
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