Abstract
241832
Introduction: China has the highest number of diabetes patients in the world, with more than 90% suffering from type 2 diabetes mellitus (T2DM) [1]. Uncoupling protein-1 (UCP1) located in the inner membrane of mitochondria in brown adipose tissue (BAT) plays an important role in directly converting energy into heat and dissipating consumption when activated. Because UCP1 has been found to decrease membrane potential and increase energy expenditure, is regarded as a candidate biomarker for T2DM, obesity or related-traits[2].
Translocator protein (TSPO, 18 kDa) is considered suitable for imaging BAT as it has low expression in the normal brain, spinal cord, and liver. Therefore, targeted TSPO probes are considered to be iBAT-specific imaging markers[3]. We aim to visualise TSPO and its activation with PET in BAT, and to clarify the relationship with UCP1, which makes it possible for probes targeting TSPO to become an alternative to UCP1 for PET imaging. It will further support the importance of UCP1 probes in the diagnosis and prediction of various diseases such as obesity, diabetes and metabolic disorders.
In this study, we conducted research on the usefulness of PET imaging for TSPO, which are highly expressed in brown adipose tissue. ZDF rats (Fatty and Lean) was used as an experimental animal model for T2DM and performed PET/CT imaging by administering the PET probe [18F]FEDAC for TSPO. We compared and examined the imaging of interscapular (IS) and paravertebral (PV) BAT in diabetic conditions and control animals.
Methods: The model animals in this experiment are 8-week Zucker diabetic fatty rats (ZDF-Leprfa/CrlCrlj), which are divided into Fatty group (Leprfa/Leprfa, Symptoms of type II diabetes) and Lean group (Leprfa/+ or +/+, normal range of blood sugar values). CL316243 were administered to some of the rats in each group from 10-week to 12-week (1 mg/kg/day) in CL group, and continuous saline administration in control group simultaneously. After 2 weeks, Fatty group and Lean group rats (n=6) received tail vein injections of 11~17MBq/head (in 0.16~0.25mL PBS) [18F]FEDAC. PET images were acquired from 0 – 30 minutes post injection (p.i.). Then, the BAT tissues from each group of rats were isolated for Western Blotting and HE staining.
Results: The uptake of [18F]FEDAC into IS BAT and PV BAT was low in Fatty-Cont but significantly higher in Lean-Cont. When PK11195（3mg/kg，an inhibitor of TSPO）was pre-administered (3 mg/kg, 1 min before tracer administration), the uptake of [18F]FEDAC into IS BAT and PV BAT significantly decreased confirming the distribution of TSPO expression. The activation of brown fat is reflected in the increased uptake of TSPO ligand. The heavily stained TSPO and UCP1 were observed on the same cell confirming that both are expressed. TSPO and UCP1 in Lean-Cont, except for UCP1 in IS BAT, were present at a similar ratio as Lean-CL and Fatty-CL. The HE staining of Lean-Cont showed lipid droplets in the cells of IS BAT. There was less intracellular fat, and the tissue appearance resembled that of the CL-treated group, with both TSPO and UCP1 clearly expressed. It was confirmed that PV BAT in Lean-Cont was in an activated state.
Conclusions: By investigating the interscapular and paraspinal BAT in T2DM model rats, it was found that the activation state varies depending on the location of BAT. TSPO PET imaging using [18F]FEDAC probe reflects the activation state of UCP1 in BAT. These tools offer an opportunity to identify pharmacologic modulators of UCP1 expression and uncover regulatory pathways that impact BAT-mediated thermogenesis.
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