title: A novel thermoregulatory role for PDE10A 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 [(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.
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany.
authors.forename: Mohammed K
authors.initials: MK
authors.lastname: Hankir
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Kranz
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Gnad
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Weiner
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Sally
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Bronisch
authors.affiliation: Department of Nuclear Medicine, University Hospital University of Leipzig, Leipzig, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Steinhoff
authors.affiliation: Department of Nuclear Medicine, University Hospital University of Leipzig, Leipzig, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Luthardt
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: 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.
authors.forename: Swen
authors.initials: S
authors.lastname: Hesse
authors.affiliation: Molecular NeuroImaging, LLC, New Haven, CT, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Seibyl
authors.affiliation: 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.
authors.forename: Osama
authors.initials: O
authors.lastname: Sabri
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany.
authors.forename: John T
authors.initials: JT
authors.lastname: Heiker
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Institute of Pharmacology and Toxicology, University Hospital University of Bonn, Bonn, Germany.
authors.forename: Alexander
authors.identifier: 0000-0001-8805-6831
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf Neuroradiopharmaceuticals, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital University of Leipzig, Leipzig, Germany wiebkekristin.fenske@medizin.uni-leipzig.de.
authors.forename: Wiebke K
authors.identifier: 0000-0002-3457-1114
authors.initials: WK
authors.lastname: Fenske
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008820:Mice, Obese; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D022722:Thermogenesis
chemical_list: C545121:2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011804:Quinolines; C119843:PDE10A protein, human; C492284:Pde10a protein, mouse; D010727:Phosphoric Diester Hydrolases
keywords: PDE10A; PET; adipose tissue; energy expenditure; obesity