Studies in animal models indicate that brown adipose tissue (BAT) has a protective effect against the pathological consequences of obesity, a medical condition complicating life-threatening diseases. The unique function of brown adipocytes in energy dissipation through adaptive thermogenesis opposes the action of white adipocytes, hypertrophy and hyperplasia of which are responsible for obesity. In addition to this explanation for the beneficial effect of BAT, transdifferentiation of white adipocytes into brown adipocytes has been shown to take place in response to cold or other symphatetic nervous system stimuli in rodents. Recently, functional BAT in adult humans has been detected by positron emission tomography (PET), outlining new avenues in treatment of obesity and the associated disorders. Most adults appear to have BAT revealed by biopsy, however it is often metabolically inactive in obese and aging individuals and is undetectable by PET. Therefore, distribution of BAT in humans remains incompletely characterized, and the establishment of approaches for reliable localization and quantification of BAT depots is necessary. The goal of this project is to establish an approach to assess BAT depots irrespective of their metabolic activity. We propose to identify probes targeting markers differentially expressed in adult BAT vasculature and to use them for non-invasive localization of BAT. First, we will use the mouse model to isolate ligands (small peptides) that bind to receptors specifically expressed in the BAT vasculature. BAT-homing ligands will be isolated by integrating a screen of a phage-displayed combinatorial peptide library in vivo with the bioinformatics platform established by our group. Next, we will use these BAT-homing peptides to test and optimize non-invasive imaging of BAT with a peptide-conjugated near-infrared (NIR) dye in the mouse model. BAT localization of systemically administered peptide conjugates will be validated via conventional PET, computed tomography, and tissue immunostaining for BAT markers. Genetic background-specific modulation of BAT amount and metabolic activity in these experiments will establish the sensitivity of our approach and the properties of BAT depots compatible with detection. This non-invasive BAT imaging through ligand-directed imaging agent delivery will be advantageous because it is not based on tissue metabolic activity. Eventually, BAT probes isolated in this study could be used for identification of the targeted receptors and their validation as BAT biomarkers. Subsequently, improved vectors could be designed to target these biomarkers in BAT. Because vascular ligand/receptor systems uncovered through combinatorial peptide library screens tend to be conserved among mammals, we predict that peptides isolated in mice will cross-react with human vascular BAT receptors that are likely to also be differentially expressed. The long-term goal of this study is to translate the tools developed here for designing a method for quantifying BAT depots in humans that will be robust, affordable and potentially highly specific.
The novel approach to non-invasive imaging of BAT developed here will have significant advantages to currently practiced BAT detection with PET: it will not depend on BAT metabolic activity, is likely to produce less non-specific false positive signals in other metabolically active organs, and will be cheaper and more generally available. Based on the BAT-targeting probes generated in our study, new pharmacological approaches to convert white adipose tissue to BAT could be developed as a prospective strategy to treat obesity.
|Azhdarinia, Ali; Daquinag, Alexes C; Tseng, Chieh et al. (2013) A peptide probe for targeted brown adipose tissue imaging. Nat Commun 4:2472|
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