Format

Send to

Choose Destination
See comment in PubMed Commons below
EMBO Mol Med. 2016 Jul 1;8(7):796-812. doi: 10.15252/emmm.201506085. Print 2016 Jul.

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

Author information

1
Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany.
2
Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Neuroradiopharmaceuticals, Leipzig, Germany.
3
Institute of Pharmacology and Toxicology, University Hospital University of Bonn, Bonn, Germany.
4
Department of Nuclear Medicine, University Hospital University of Leipzig, Leipzig, Germany.
5
Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany Department of Nuclear Medicine, University Hospital University of Leipzig, Leipzig, Germany.
6
Molecular NeuroImaging, LLC, New Haven, CT, USA.
7
Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany wiebkekristin.fenske@medizin.uni-leipzig.de.

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 [(18)F]-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.

KEYWORDS:

PDE10A; PET; adipose tissue; energy expenditure; obesity

PMID:
27247380
PMCID:
PMC4931292
DOI:
10.15252/emmm.201506085
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center