Preclinical PET/MR: Defining novel roles for phosphodiesterase 10A in brain and brown adipose tissue (BAT) in the regulation of energy homeostasis

OBJECTIVES: Phosphodiesterase type 10A (PDE10A) is highly enriched in the striatum and a potential therapeutic target for brain diseases. It is suggested that PDE10A is also involved in the regulation of food intake. By using the novel selective radioligand 18F-AQ28A [1] we evaluated expression of PDE10A in brain and BAT of lean, diet-induced (DIO) and genetically obese mice. As BAT activation could be visualized by using small animal PET/MR using 18F-FDG [2], we also assessed whether inhibition of PDE10A modulates BAT activity.
METHODS: Female CD1 and C57BL/6 mice were studied with either 18F-AQ28A or 18F-FDG. After anesthesia (1.8% isoflurane in 60%O2/40% air) and i.v injection of the tracer, a 1 h PET/MR scan was done for all groups. After image coregistration volumes of interest were created for striatum, hypothalamus, interscapular BAT and skeletal muscle. The selectivity of 18F-AQ28A towards PDE10A was proven by baseline (n=3) and blocking (n=3) experiments with the PDE10A inhibitor MP-10. DIO in CD1 mice was achieved by 16 weeks free access to a high-fat, high-sugar diet. Leptin-deficient ob/ob C57BL/6 mice (n=5) were used as a genetic model of obesity. The first set of CD1 mice (n=10) was divided into lean (n=5) and DIO (n=5) and received 18F-AQ28A. A second group (n=10) of lean CD1 mice were fasted and housed overnight under thermoneutral conditions and received either i.p. injection of MP-10 (n=5) or vehicle (n=5) followed 30 min later by i.v. injection of FDG. After a recovery period, the second group received either an i.p. injection of MP-10 (n=5) or vehicle (n=5) and 2 h later were sacrificed and BAT, hypothalamus and striatum were collected. Relative mRNA expression of PDE10A and thermoregulatory genes in BAT and neuropeptides in striatum and hypothalamus as well as the indirect neuronal activity marker Fos were analyzed by real-time quantitative PCR.
RESULTS: Blocking with MP-10 showed selectivity of 18F-AQ28A towards PDE10A (SUV15min striatum blocking/baseline: 0.54±0.08/1.02±0.19; p<0.01). A 7-fold higher mRNA expression of PDE10A in striatum compared to hypothalamus was found (p<0.001). In lean mice, 18F-AQ28A showed selective symmetrical accumulation in BAT (SUV55min: 0.44±0.04) with low uptake in the adjacent skeletal muscle (SUV55min: 0.20±0.02; p<0.01). Higher PDE10A levels (p<0.05) in striatum and BAT were found for DIO (SUV15min:1.36±0.10 / SUV55min:0.82±0.08) and for ob/ob mice (SUV15min:1.91±0.08 / SUV55min:0.77±0.04) compared to normal weight mice. Acute administration of MP-10 to lean mice resulted in significantly higher FDG uptake by BAT (SUV55min: 0.40±0.01) compared to vehicle administration (SUV55min: 0.25±0.02; p<0.01) and an increase in Pgc1alpha (2-fold), Ucp1 (1.6-fold) and Cidea (1.6-fold) mRNA expression (p<0.01, p<0.05 and p<0.05, respectively) was found. In striatum, acute administration of MP-10 increased expression of Fos (4-fold) and preproenkephalin (2.9-fold) (p<0.0001 and p<0.05 respectively) whereas in hypothalamus there were no changes in gene expression found.
CONCLUSION: A novel thermoregulatory role for PDE10A was demonstrated and related to obesity. PDE10A selectively regulates gene expression in striatum. The data suggest that PDE10A inhibitors offer the potential to treat obesity by increasing thermogenesis and reducing hedonic feeding through recruiting BAT and striatal circuits.