Novel Magnetic Resonance Approach to Detect BAT Distribution and Temperature

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DESCRIPTION (provided by applicant): The recent detection of brown adipose tissue (BAT) in humans suggests a radically different strategy for obesity control, if BAT can play the same role in humans that it plays in animals for regulation of body weight. Arguably the largest obstacle to answering this question is the lack of a non-invasive means to detect BAT presence and activity in humans. The only technology currently available to detect human BAT (18FDG- PET) is prone to false negatives, is subject to high scan-rescan variability, and causes significant radiation exposure, which limits repeated studies on the same subject necessary to test the efficacy of new drugs. The long-term goal of the proposed research is to develop a non-invasive MRI based method that allows the detection of both BAT presence and BAT activity in humans. The objective of this application is to develop and optimize this method pre-clinically and then to validate it through comparison with histology and more established 18FDG-PET scans. The proposed approach uses a novel proton Magnetic Resonance Imaging (MRI) method (detection of intermolecular zero-quantum coherences, or iZQCs) which exploits structural differences between BAT and White Adipose Tissue (WAT). The central hypothesis is that the proposed method is sensitive to tissue microstructure and can differentiate BAT depots from WAT. Moreover, since this method is sensitive to BAT temperature it can be used to monitor tissue activity. This hypothesis has been formulated on the basis of preliminary results from the investigator's laboratory, which identify a marker for BAT in the NMR spectra that arises from the iZQC signal between spins that are 100 microns apart. Guided by strong preliminary data, the research will test the central hypothesis by pursuing two Specific Aims: 1) Develop, optimize, and validate this method for BAT localization in vivo in mice; and 2) Optimize and accelerate BAT temperature measurement to monitor BAT activity in mice. The proposed approach is innovative because it exploits the unique sensitivity of iZQC to tissue structure to detect the presence of small BAT depots that are mixed with other tissues and its sensitivity to temperature to monitor BAT activity. The proposed research is significant because increasing the ability to measure BAT mass and BAT activity in humans in vivo will allow for a better understanding of BAT's role in physiology and its potential as a therapeutic target in the treatment of obesity. The approach is noninvasive; the signal is intrinsic, and does not even require contrast agent administration. It thus allows repeated scanning on the same subject, which is critical to test the efficacy of new drugs that are developed to increase BAT tissue mass or to boost BAT activity. PUBLIC HEALTH RELEVANCE: The proposed study will develop an MRI-based imaging technique to detect Brown Adipose Tissue (BAT) in vivo and to monitor its metabolic state. Such a technique will provide an invaluable tool to study the occurrence of BAT in humans and monitor its metabolic state over time. The proposed research has relevance to public health because new tools for non-invasive detection of BAT will show the connection between BAT occurrence and obesity and ultimately accelerate the process of developing better treatments for obesity.