Development of obesity and metabolic clinical research programs

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications & trials

Abstract

During the majority of FY22, we still face the significant challenges related to the COVID-19 pandemic and the intermittent shutdowns, staff and supply shortages of the clinical research programs associated with healthy volunteers; however, 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 energy expenditure continuously in a 5-hour period (0800-1300 fasted) in the room calorimeter with randomized environmental temperature ranging between 16 - 31C (61-88F) in 10-13 consecutive days (inpatient). We also carefully measure skeletal muscle shivering, body movements, 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 12 lean women was published in Obesity 2020, and the EE and other physiological data is currently being analyzed for a paper submission. We are also amending this protocol to expand the recruitment to include more gender and race equity in our study population. 2. With the interests for brown adipose tissue (BAT) continue to grow, we are using the BAT PET/CT images in the 12-DK-0097 to train our postbac IRTAs during the COVID shutdown period. We also continue to train other BAT clinical researchers to analyze PET/CT images using the process that we developed. In FY22, the NIH Clinical Center acquired their first research PET/MR scanner. We have established a close collaboration with the CC PET Dept and are amending the protocol to develop a new approach to quantify BAT and validate it against our current PET/CT technique. 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 published in Methods in Molecular Biology in FY22. 4. We acquired a 3D laser-guided body surface scanner to our lab during FY21. The goal of using this non-invasive scanner is to accurately measure body surface area (BSA) in human subjects rather than relying on simple prediction models using weight, height, and sex parameters which were developed over 60-70 years ago. We are planning a new natural history protocol (IRB approved 000617 NCT05398783 and waiting for regulatory clearance before we start recruiting subjects) to examine the agreement between measured BSA and BSA estimated by previously established prediction equations in both healthy children and adults, those with recent changes in weight, and those with various forms of disease. If successful, we plan to add this as another non-invasive measurement to our body composition lab. We also plan to compare laser measured BSA with body composition and energy expenditure parameters to investigate the underlying mechanism(s) that BSA may contribute to human energy expenditure and balance.