Sensitive and Specific detection of BAT Tissue and Activity by Magnetic Resonance with Hyperpolarized Xe-129

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 DESCRIPTION (provided by applicant): Brown Adipose Tissue (BAT) is a tissue present in all mammals and is specialized for non-shivering thermogenesis (NST). Recent studies showed that BAT plays a regulatory role in human energy balance and glucose homeostasis and may have a protective role against obesity and diabetes. As the biochemical mechanisms that trigger the differentiation and the activity of BAT are being discovered, and as new therapeutic treatments that specifically target this tissue are being developed, non-invasive detection of BAT tissue and thermogenic activity remains challenging. BAT is especially difficult to detect in animals and in humans that are overweight and obese, in which this tissue is present but metabolically inactive. In addition, BAT thermogenic activity can be detected non-invasively only indirectly, either through measurement of tissue uptake of potential NST substrates or through measurements of physiological changes that may correlate with NST. Preliminary magnetic resonance studies with HyperPolarized 129Xe gas (HP 129Xe) in rodents and humans show that stimulation of NST leads to a selective downstream accumulation of inhaled HP 129Xe gas into BAT, whether or not stimulation of NST is followed by BAT activation. At the same time, when xenon dissolves in BAT, the temperature dependence of its chemical shift can be used to directly measure BAT temperature and thermogenic activity in real time and with high accuracy. The objective of the proposed work is to validate this novel methodology for the non-invasive detection of brown adipose tissue and for the characterization of its function. Specifically, the first aim will establish whether 129Xe MRI can quantify BAT tissue volume and mass with better accuracy and sensitivity than conventional imaging methodologies like 18FDG-PET, 1H MRI, and contrast ultrasound in animals with different BAT functional states, while using histology as ground truth. In the second aim, absolute accuracy of HP xenon MR thermometry of BAT will be assessed in vivo by direct comparison with temperature probes in murine animal models with different thermogenic capacity. With the third aim, sensitivity and specificity of HP 129Xe MR with respect to 18FDG-PET will be assessed in humans. Reliable identification of BAT by HP129Xe MR, coupled with direct measurement of its thermogenic activity, will enhance the success of preclinical research studies aiming at understanding the primary factors that regulate the development, the differentiation and the activation of this tissue. In the clinical research setting, such a tool will allow us to correctly assess, in a larger number of human subjects, normal and abnormal BAT function, and to determine the efficacy of new anti-obesity and anti-diabetes therapies that specifically target this tissue.