Imaging adipose tissue browning using the TSPO-18kDa tracer [18F]FEPPA

Abstract

Objectives The browning of white adipose tissue (WAT) into beige has been proposed as a strategy to enhance energy expenditure to combat the growing epidemic of obesity. Research into browning strategies are hampered by the lack of sensitive, translatable, imaging tools capable of detecting beige fat mass non-invasively. [ 18 F]FDG is able to detect activated beige fat but provides little information on unstimulated beige fat mass. We have assessed the use of [ 18 F]FEPPA, a tracer for the TSPO-18KDa found on the outer mitochondrial membrane, as an alternative imaging agent capable of detecting unstimulated brown fat (BAT) and beige fat. Methods Female Balb/c mice (n = 5) were treated for 7 days with the β3 adrenergic agonist CL-316,243 to induce the browning of inguinal WAT (beige fat). Animals were imaged longitudinally with [ 18 F]FDG and [ 18 F]FEPPA and uptake in interscapular BAT and inguinal WAT assessed. The browning of inguinal WAT was confirmed using H&E and immunohistochemical detection of UCP-1 and TSPO. Results Repeated dosing with β3-adrenergic agonist CL-316,243 caused a significant increase in [ 18 F]FDG uptake in both interscapular BAT and inguinal WAT associated with the increased metabolic activity of brown and beige adipocytes respectively. [ 18 F]FEPPA uptake was likewise increased in inguinal WAT but showed no increase in BAT uptake due to stimulation over the same time course. Furthermore, inguinal WAT uptake was unaffected by pharmacological blockade, indicating that [ 18 F]FEPPA uptake is associated with the expression of mitochondria in BAT and beige adipocytes and independent of activation. Conclusion These data show that [ 18 F]FEPPA can detect BAT and newly formed beige fat under non-stimulated, thermoneutral conditions and that uptake after stimulation is linked to mitochondrial expression as opposed to activation.

Comparative [18F]FDG and [18F]DPA714 PET imaging and time-dependent changes of brown adipose tissue in tumor-bearing mice

“…In fact, many proteins, including TSPO (expressed on the outer mitochondrial membrane), are also potential targets of BAT imaging. In contrast, WAT shows less mitochondria number and TSPO expression than BAT (including unstimulated BAT and beige fat) [ 25 ]. Recent studies have confirmed that TSPO specific tracers, such as 11 C-PBR28 and [ 18 F]FEPPA, can be used for the imaging of BAT and to detect the browning of WAT [ 19 , 25 ].…”

“…In contrast, WAT shows less mitochondria number and TSPO expression than BAT (including unstimulated BAT and beige fat) [ 25 ]. Recent studies have confirmed that TSPO specific tracers, such as 11 C-PBR28 and [ 18 F]FEPPA, can be used for the imaging of BAT and to detect the browning of WAT [ 19 , 25 ]. However, to the best of our knowledge, there is no published report about studying BAT activity with [ 18 F]DPA714, a mitochondrial TSPO-based imaging tracer.…”

Molecular Imaging of Brown Adipose Tissue Mass

“…In addition, other groups have demonstrated the feasibility of TSPO PET tracers for BAT imaging. Goggi et al reported that 18 F-FEPPA was able to detect inguinal WAT browning but not BAT activation in mice after dosing with β3-adrenergic agonist CL-316,243 [60]. Their results indicated 18 F-FEPPA could be a promising tracer for BAT mass detection, independent of its metabolic state.…”

Imaging Metabolically Active Fat: A Literature Review and Mechanistic Insights

“…The short (2 min) half-life of 15 O allows for repeat PET scanning with another tracer on the same day [77,79]. Investigational radiotracer currently include the mitochondrial outer membrane translocator protein, visualized with 18 F-FEPPA PET/CT and 11 C-PBR28 PET/CT, the cannabinoid type 1 receptor, visualized with 18 F-FMPEP-d2 PET/CT [80,81,82,83], and PD-L1, visualized with radiolabeled antibodies [84,85].…”