Imaging brown adipose tissue and monitoring browning

Massachusetts General Hospital, Boston MA

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Abstract

The clinical significance of brown adipose tissue (BAT) has been certainly validated through a large-scale clinical analysis of PET-CT images. This recent analysis undoubtedly indicates that BAT mass levels inversely correlate with body-mass index (BMI), suggesting that BAT bears undeniable responsibility for metabolic disorders such as obesity and diabetes. BAT has been considered as ?good fat,? and plays important roles in metabolism and energy expenditure, yet it is a considerably new drug target for obesity and diabetes. PET imaging with 18F-FDG is currently the most commonly used method for visualizing BAT. However, only a very small number of adults' BAT depots could be clearly visualized with 18F-FDG if no cold or drug stimulation is applied. Conversely, studies evidently suggest that almost every adult owns BAT depots at many locations under stimulation. This dramatic discrepancy strongly suggests that imaging probes that can consistently detect BAT mass are highly desirable. In addition, `browning,' a process of turning white adipose tissue (WAT) into BAT (?bad to good? fat), is believed to be a potential approach for fighting obesity and diabetes. However, current imaging methods, including PET with 18F-FDG, are incapable of monitoring the browning process. Results from our research indicated that BAT could be successfully imaged in mice with near infrared fluorescence (NIRF) curcumin analogues. Mechanism studies in cells suggested that probe uptake was mediated (at least partially) by CD36, a transporter highly expressed in BAT. In this application, we propose to optimize the leads to increase BAT selectivity. The top candidates will be tested for monitoring BAT activation/suppression, mass changes, and browning of WAT. BAT is highly vascularized, and its activation is tightly associated with a significant increase of blood flow. We reason that spectral unmixing imaging can be used to differentiate BAT mass and BAT activation, because the to-be-tested NIRF probe will display different spectra in oil droplets of BAT and in blood flow. Our preliminary data indicates that this strategy is feasible. In this 5-year proposal, we will primarily focus on cost efficient NIRF imaging to identify highly BAT selective probes. At the end of this proposal, if possible, we will explore the feasibility of PET tracer development. We believe that our imaging technologies will greatly assist drug discovery and basic research related to BAT.