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...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2016-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201506085 |
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| author | 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 Wiebke K Fenske |
| author_facet | 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 Wiebke K Fenske |
| author_sort | Mohammed K Hankir |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9dcbc0c76f9f453e9ca5c9c465a135fb |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9dcbc0c76f9f453e9ca5c9c465a135fb2025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-05-018779681210.15252/emmm.201506085A novel thermoregulatory role for PDE10A in mouse and human adipocytesMohammed K Hankir0Mathias Kranz1Thorsten Gnad2Juliane Weiner3Sally Wagner4Winnie Deuther‐Conrad5Felix Bronisch6Karen Steinhoff7Julia Luthardt8Nora Klöting9Swen Hesse10John P Seibyl11Osama Sabri12John T Heiker13Matthias Blüher14Alexander Pfeifer15Peter Brust16Wiebke K Fenske17Integrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigInstitute of Radiopharmaceutical Cancer Research, Helmholtz‐Zentrum Dresden‐Rossendorf, NeuroradiopharmaceuticalsInstitute of Pharmacology and Toxicology, University Hospital, University of BonnIntegrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigInstitute of Radiopharmaceutical Cancer Research, Helmholtz‐Zentrum Dresden‐Rossendorf, NeuroradiopharmaceuticalsInstitute of Radiopharmaceutical Cancer Research, Helmholtz‐Zentrum Dresden‐Rossendorf, NeuroradiopharmaceuticalsIntegrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigDepartment of Nuclear Medicine, University Hospital, University of LeipzigDepartment of Nuclear Medicine, University Hospital, University of LeipzigIntegrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigIntegrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigMolecular NeuroImaging, LLCIntegrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigIntegrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigIntegrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigInstitute of Pharmacology and Toxicology, University Hospital, University of BonnInstitute of Radiopharmaceutical Cancer Research, Helmholtz‐Zentrum Dresden‐Rossendorf, NeuroradiopharmaceuticalsIntegrated Research and Treatment Centre for Adiposity Diseases, University Hospital, University of LeipzigAbstract 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.https://doi.org/10.15252/emmm.201506085adipose tissueenergy expenditureobesityPDE10APET |
| spellingShingle | 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 Wiebke K Fenske A novel thermoregulatory role for PDE10A in mouse and human adipocytes EMBO Molecular Medicine adipose tissue energy expenditure obesity PDE10A PET |
| title | A novel thermoregulatory role for PDE10A in mouse and human adipocytes |
| title_full | A novel thermoregulatory role for PDE10A in mouse and human adipocytes |
| title_fullStr | A novel thermoregulatory role for PDE10A in mouse and human adipocytes |
| title_full_unstemmed | A novel thermoregulatory role for PDE10A in mouse and human adipocytes |
| title_short | A novel thermoregulatory role for PDE10A in mouse and human adipocytes |
| title_sort | novel thermoregulatory role for pde10a in mouse and human adipocytes |
| topic | adipose tissue energy expenditure obesity PDE10A PET |
| url | https://doi.org/10.15252/emmm.201506085 |
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