Thermoregulatory role for PDE10A in mouse & human adipocytes

Authors: Mohammed K Hankir, Mathias Kranz, Thorsten Gnad, Juliane Weiner, Sally Wagner, Winnie Deuther-Conrad, Felix Bronisch, Karen Steinhoff, Julia Luthardt, Nora Klöting, Swen Hesse, John P Seibyl, Osama Sabri, John T Heiker, Matthias Blüher, Alexander Pfeifer, Peter Brust, and Wiebke K Fenske

Thermoregulatory role for PDE10A in mouse & human adipocytes

ABSTRACT:

Phosphodiesterase type 10A (PDE10A) is highly enriched in striatum and is under evaluation as a drug target for several psychiatric/neurodegenerative diseases. Preclinical studies implicate PDE10A in the regulation of energy homeostasis, but the mechanisms remain unclear.

By utilizing small-animal PET/MRI and the novel radioligand [18F]-AQ28A, we found marked levels of PDE10A in interscapular brown adipose tissue (BAT) of mice. Pharmacological inactivation of PDE10A with the highly selective inhibitor MP-10 recruited BAT and potentiated thermogenesis in vivo. In diet-induced obese mice, chronic administration of MP-10 caused weight loss associated with increased energy expenditure, browning of white adipose tissue, and improved insulin sensitivity.

Analysis of human PET data further revealed marked levels of PDE10A in the supraclavicular region where brown/beige adipocytes are clustered in adults. Finally, the inhibition of PDE10A with MP-10 stimulated thermogenic gene expression in human brown adipocytes and induced browning of human white adipocytes.

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 and diabetes.