The last several years have witnessed an explosion of information implicating thermogenic brown adipose tissue (BAT) in the regulation of energy expenditure and weight gain. These findings bring hope that BAT may serve as a new target for developing anti-obesity drugs. Most of our knowledge about BAT was derived from studies in rodents. Due to the lack of appropriate tools to study human subjects very little is known about BAT in humans. Currently, FDG PET is the only noninvasive technology available to detect BAT in humans. However, FDG targets glycolysis, which may be secondary to the core thermogenic mechanism. This may explain the variable and non-reproducible FDG BAT uptake reported in human studies. To address these limitations, we propose to develop and validate a technique that will allow for the first time to detect and quantify the core mechanism of thermogenic function of BAT. This technique is based on the novel biomarker, 18F-fluorobenzyl triphenyl phosphonium (FBnTP) and PET imaging. Previous studies have shown that FBnTP, developed in our laboratory, is a highly accurate voltage sensor for monitoring the mitochondria membrane potential ( (m) in vitro and in the intact organ. The uncoupling protein-1 (UCP1), a constituent of the mitochondrial inner membrane, is the key player in BAT thermogenesis that allows an energy-dissipating flux of H+ back to the mitochondrial matrix. (m is the voltage analogue of the proton circuit, and the re-entrance of UCP1-mediated protons is expressed by a proportional decline in (m. Targeting (m may afford a novel approach for direct and reliable quantification of the core mechanism of BAT thermogenesis - UCP1. Preliminary studies in rodents revealed that at room temperature (22OC, RT) BAT is a major target organ of FBnTP concentration, similar to heart and second only to kidney. In a cold environment (4OC, COLD), FBnTP BAT uptake dropped markedly via a noradrenergic-mediated mechanism. FDG demonstrated the opposite behavior. Importantly, FBnTP administration at RT revealed a washout from BAT upon transition to cold temperatures. These findings lend initial support to the above working hypothesis of the proposed project. The preliminary studies were carried out ex vivo, however in vivo PET studies are essential for establishing the potential role and clinical relevance of FBnTP as a noninvasive biomarker for direct detection and quantification of BAT thermogenesis. This project will examine the capacity and accuracy of FBnTP PET not only to detect and localize the thermogenic tissue, but also to quantify the time-dependent kinetics of the thermogenic function (Aims 1 and 2). The animal studies will be expanded to clinical studies in a small number of human subjects (Aim 3).
| Madar, Igal; Isoda, Takuro; Finley, Paige et al. (2011) 18F-fluorobenzyl triphenyl phosphonium: a noninvasive sensor of brown adipose tissue thermogenesis. J Nucl Med 52:808-14 |
