A novel thermoregulatory role for PDE10A in mouse and human adipocytes.

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

doi:10.15252/emmm.201506085

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.

Highlights

Obesity poses a tremendous burden for patients and healthcare systems alike for which safe and effective pharmacotherapies are still lacking
We demonstrated that in addition to striatum, Phosphodiesterase type 10A (PDE10A) is expressed in interscapular brown adipose tissue (BAT) and peri-ovarian visceral white adipose tissue (VAT) in mice
We demonstrated that PDE10A is markedly expressed in human supraclavicular BAT and abdominal subcutaneous white adipose tissue (SAT)

Summary

Introduction

Obesity poses a tremendous burden for patients and healthcare systems alike for which safe and effective pharmacotherapies are still lacking. The discovery of the persistence of thermogenic brown adipose tissue (BAT) in adult humans has rekindled interest in pharmacologically increasing energy expenditure as a means to promote weight loss (Sidossis & Kajimura, 2015). By implementing small-animal PETMRI, we discovered marked and restricted uptake of the specific PDE10A radioligand [18F]-AQ28A (Wagner et al, 2016) by interscapular BAT in mice, indicating for the first time expression of PDE10A in this thermogenic tissue Consistent with this finding, we found that acute pharmacological suppression of PDE10A enzymatic activity with the highly selective inhibitor MP-10, which has over 1,000-fold specificity for PDE10A over other PDEs (Grauer et al, 2009), sufficiently elicits multiple functional responses in BAT in vivo. The inhibition of PDE10A with MP10 caused weight loss in diet-induced obese mice associated with increased energy expenditure and browning of visceral white adipose tissue. Cell culture experiments revealed that the inhibition of PDE10A with MP-10 stimulates thermogenic gene expression in primary human brown adipocytes and causes browning of primary human white adipocytes

Results

Discussion

Materials and Methods