A novel thermoregulatory role for PDE 10A in mouse and 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.

Using genome wide association studies to identify common QTL regions in three different genetic backgrounds based on Iberian pig breed

“…1 ). The PDE10A encodes for a phosphodiesterase implicated in the regulation of energy homeostasis and it has been proposed as a promising candidate target for the treatment of obesity and diabetes [ 53 ]. One SNP within the gene was detected in the mentioned RNA-Seq analysis segregating in all three backcrosses, rs321518792 , following Sscrofa10.2 annotation, however in the new Sscrofa11 is not mapped.…”

Brown and Beige Adipose Tissues in Health and Disease

“…The cAMP/PKA pathway is negatively regulated by phosphodiesterases (PDEs) that degrade cAMP. Pharmacological inhibition of PDE10A or deletion of PDE10A increases beige adipogenesis and energy expenditure in mice (115, 218). Furthermore, activation of α2 adrenergic receptors, unlike β adrenergic receptors, inhibits brown adipocyte thermogenesis (367).…”

Dissociation Between Brown Adipose Tissue 18F-FDG Uptake and Thermogenesis in Uncoupling Protein 1–Deficient Mice

“…Small-animal PET/MRI (Mediso Medical Imaging Systems) was performed as previously described (10). Overnight fasted mice received intraperitoneal injections of either CL 316, 243 (1 mg/kg) (4) or 0.9% saline along with an intraperitoneal injection of 18.8 6 0.4 MBq of 18 F-FDG (Department of Nuclear Medicine, University Hospital Leipzig).…”