A novel thermoregulatory role for PDE10A in mouse and human adipocytes

Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and a novel drug target for several psychiatric and neurodegenerative diseases. PDE10A has additionally been implicated in the regulation of energy homeostasis, but the mechanisms remain unclear. Here, we showed marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice by utilizing small animal PET/MRI and the novel radioligand [¹⁸F]-AQ28A. In addition to BAT, Pde10a mRNA is also expressed in perigonadal visceral white adipose tissue (VAT). Pharmacological targeting of PDE10A with the selective inhibitor MP-10 increased [¹⁸F]-FDG uptake by BAT and enhanced thermogenesis in vivo. Moreover, acute MP-10 treatment of mouse brown adipocytes stimulated lipolysis and chronic treatment induced browning of primary human white adipocytes. Functional studies on diet induced obese mice further demonstrated that MP-10 produces weight loss independent of changes in food intake associated with increased energy expenditure and browning of VAT. Finally, human PET imaging with the radioligand [¹⁸F]-MNI-659 revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Collectively, our findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity.