Development of obesity and metabolic clinical research programs

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In FY20, 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, body movements, and heart rate, skin and core body temperatures, and stress responses by blood and urinary markers, while controlling for physical activity, clothing, 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 (11 had repeated measurements in follicular and luteal menstrual phases), twelve (13) older lean male volunteers (11 with complete data), and thirteen (13) young lean African-American male (12 with complete data) volunteers. Due to the COVID-19 delays, we aim to recruit and complete the studies in 2-3 more older lean male volunteers this coming year. 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. Since our current protocol only includes one small and homogeneous cohort of female volunteers (young, lean, and Caucasian), we plan to amend the protocol to include equal numbers of female volunteers of different adiposity, age, and race to be compared with the male volunteers studied so far. 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. We used this rigorous approach in our PET/CT scans in our lean young women cohort and identified 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 was published by Obesity in 2020. In addition, we collaborated with our MRI colleagues in developing a novel non-radioactive technique to potentially identify human BAT. We have a paper accepted by Radiology, which we used localized 1H-MRS relaxometry to measure proton densities (T1s and T2s) in cold-activated BAT (confirmed by FDG-PET/CT) in our study subjects and compared to distal subcutaneous white adipose regions. reveals biophysical and biochemical differences between BAT and white fat. Our data suggest that it is feasible to identify BAT by MRS signatures, perhaps even without cold stimulation, which will improve the understanding of BAT in humans. 3. For the protocol 13-DK-0200, NCT01950520, we completed Cohort 1 studies (n=16) of using a pharmacologic approach to regulating sympathetic nervous system (SNS) by different beta-adrenergic receptors varying receptor specificity and agonist/antagonist properties and measure their effects on resting EE in thermoneutral vs. cold-stimulated states. We are currently analyzing the data and preparing manuscripts. We continue to recruit study participants for Cohort 2 (studying the single-dose effects of 4 different FDA approved anti-obesity drugs. Before the COVID-19 pandemic that paused our studies, we accrued 9 study participants so far (8 completed, one study was interrupted). An interim analysis showed that we would reach our primary outcome (5% increase of BMR in one drug) with 16 subjects. In addition, our collaboration with Dr. Aaron Cypess in 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 FY19, which then emerged into a chronic mirabegron study (4-weeks) in women. This study has also resulted in a publication in the Journal of Clinical Investigation in 2020.