Development of obesity and metabolic clinical research programs

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

In FY21, despite of the significant challenges due to the COVID-19 pandemic and the shutdown of the clinical research programs associated with healthy volunteers during the majority of the year, 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. The BAT data from lean and obese men were published in PNAS in 2017; CIT data from lean and obese men was published in JCEM in 2019. We further compared our data to other cold exposure studies in a publication related to military operations published in 2020. The BAT data from lean women cohort was published in Obesity 2020. 2. With the interests for brown adipose tissue (BAT) continue to grow, we are using the BAT PET/CT images to train our postbac IRTA during the COVID shutdown period. We also trained our collaborators Hollstein et al. in NIDDK Phoenix Branch to analyze their PET/CT images using the analytical process that we developed and resulted in a paper published in Metabolism (2021). In this study, we found that cold-induced BAT (as measured by peak SUV levels) was negatively associated with the reduction in 24-hr EE due to short-term fasting. This suggests that BAT activity could be a trait of the thrifty metabolic phenotype which may impact weight regulation in individuals. 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 2018, 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. Using these experiences, we published a review titled opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity in Journal of Biological Chemistry (2020). And another mythological review on mirabegron and human BAT was accepted in Methods in Molecular Biology in 2021.