Development of obesity and metabolic clinical research programs

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications & trials

Abstract

In FY23, 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. 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), thirteen (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 2017; CIT data from lean and obese men was published 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 2020, and CIT data was reviewed and resubmitted to the PNAS. We plan to amend this protocol to expand the recruitment to include more gender and race equity. 2. With the interests for brown adipose tissue (BAT) continue to grow, we are using the BAT PET/CT images to train our postbac IRTAs. We continue to train our fellows and collaborators to analyze PET/CT images using the process that we developed. The NIH Clinical Center recently acquired their first research PET/MR scanner. We are amending the protocol to develop a new approach to quantify BAT and validate against the 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 a mythological review on mirabegron and human BAT was published in Methods in Molecular Biology in 2022. 4. We started a new natural history protocol (000617 NCT05398783) in FY23 to examine the agreement between measured whole-body surface area (BSA) using our new 3D laser scanner (Vitus) and BSA estimated by previously established prediction equations in both healthy children and adults, participants with changes in weight, and those with various forms of disease. We have accrued 49 study participants so far with measured resting energy expenditure (REE) by hood indirect calorimetry, comprehensive body composition (DXA, BodPod, D2O/NaBr, and BIS), and measured BSA. Challenges: There have been a lot of changes in the protocol management processes (protocol navigation program and quality assurance program), which resulted in more regulatory demands and slower research progresses. The COVID-19 pandemic not only slowed our research recruitments, but also resulted in major losses to support staff to the hospital, both nursing and facility maintenance. The temperature control to our three whole-room indirect calorimeters is critical to many of our thermal regulation protocols. The setpoint tolerance of 0.2C that we relied on for over 10 years was no longer maintained, replaced by large temperature fluctuations reaching 10C at times. After multiple failed attempts to mitigate this problem with the NIH Office of Research Facilities, we made the decision to build our own temperature control system for two of the three rooms. In FY23, we successfully converted them (stepwise). We have also experienced other issues with the building medical air supply and power outages and fluctuations, thus we are designing an independent medical air system for our room calorimeters in FY24.