In FY13, we have 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) was developed to improve our understanding of human dynamic regulation of energy expenditure in response to subtle changes in environmental temperature. In particular, we are interested in studying the capacity of facultative thermogenesis, defined as an increase in EE (or heat production) to a changed environmental temperature. Combined with the ongoing research on brown adipose tissue and its role in non-shivering thermogensis in our and other labs, such clinical research is generating substantial interests in the field of energy metabolism and obesity. We measured resting energy expenditure in a 5-hour period in the room calorimeter with randomized environmental temperature ranging between 16C and 31C, in 10-13 consecutive days (a 2-week inpatient protocol). We also carefully measured 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 have studied fifteen (15) healthy lean volunteers as our normative control group. Preliminary results have shown that we have developed a sensitive and reproducible measurement protocol to quantify cold-induced thermogenesis and its associated physiological responses. Moreover, we can now confidently quantify the resting EE in the thermal neutral zone (TNZ), detect shivering onset with EMG, the slope and the maximum capacity of non-shivering thermogenesis, all of which are helping us to understand the normal shape and individual variability of EE vs. environmental temperature curve in this elemental human physiology. 2. We have also completed four healthy young obese males for our second cohort. The rationale is to study the influence of obesity in human non-shivering thermogenesis. By using the same protocol, we will compare the parameters that define the shape of the TNZ, shivering threshold, and the slope and the maximum capacity of non-shivering thermogenesis between obese and lean young males. 3. In addition, we followed up on the past studies (through collaborations with Dr. Francesco Celi) which we quantified cold-induced thermogenesis between 24 and 19 C. To investigate the role of BAT in the individual variability in EE, after overnight measurements of EE, we measured BAT activation via 18F-fluro-deoxyglucose (FDG) positron emission tomography (PET) scans in 31 male and female subjects. Rather than relying on the visual BAT detection, we developed a quantitative imaging torso mantle approach to apply over the BAT area and demonstrated a significant correlation between the net increase in FDG uptake within this BAT mantle volume and individual facultative thermogenesis, even in the 70% of the subjects who were visually BAT negative. This quantification method thus demonstrates an improvement in measurement sensitivity in both facultative thermogenesis and BAT activation with even mild cold perturbation, as well as exploring the complex relationship between BAT and bone density and other hormones such as fibroblast growth factor 21 (FGF21). As we continue to gather PET/CT data in the 12-DK-0097 protocol, we will incorporate this approach to quantify BAT volume and overall activity, as we investigate its role in the non-shivering thermogenesis (NST). 4. We have found that the capacity of NST in healthy young lean males is unexpectedly large (17%) as compared to prior reports of mild cold (3-11%) that was found in the literature. The mechanisms underlying this are unclear but the clinical finding suggests NST could be explored as an intervention to combat obesity. We developed a new clinical protocol to use a pharmacologic approach to dissect the mechanism of NST (13-DK-0200, IRB approved 08/30/2013). Since the principal physiologic stimulus to BAT (and possibly muscle) NST is via sympathetic nervous system, we hypothesize that, by careful measurements of NST and using -adrenergic drugs that differ in receptor specificity and agonist/antagonist properties, we will gain better understanding of the regulation of human NST and resting EE. The second phase of the study focuses on measuring anti-obesity drugs potential effect on basal metabolic rate. The rationale is that previous studies of drug effect on EE in humans have not always rigorously enforced the use of thermoneutrality, thus may have increased variability and underestimated effects, contributing to inconclusive findings. This new protocol will begin in FY14.

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Lee, Paul; Smith, Sheila; Linderman, Joyce et al. (2014) Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63:3686-98
Lee, Paul; Linderman, Joyce D; Smith, Sheila et al. (2014) Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 19:302-9
Lee, P; Linderman, J; Smith, S et al. (2013) Fibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans? Osteoporos Int 24:3053-7
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