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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.

SUBMITTER: Hankir MK

PROVIDER: S-EPMC4931292 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Hankir Mohammed K MK Kranz Mathias M Gnad Thorsten T Weiner Juliane J Wagner Sally S Deuther-Conrad Winnie W Bronisch Felix F Steinhoff Karen K Luthardt Julia J Klöting Nora N Hesse Swen S Seibyl John P JP Sabri Osama O Heiker John T JT Blüher Matthias M Pfeifer Alexander A Brust Peter P Fenske Wiebke K WK

EMBO molecular medicine 20160701 7

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 i ...[more]

PMID: 27247380

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Project description:Chronic activation of innate immunity takes place in obesity and initiated by the hypertrophic adipocytes which obtain a pro-inflammatory phenotype. The corticotrophin-releasing factor (CRF) family of neuropeptides and their receptors (CRF1 and CRF2) affect stress response and innate immunity. Adipose tissue expresses a complete CRF system. The aim of this study was to examine the role of CRF neuropeptides in the immune phenotype of adipocytes assessed by their expression of the toll-like receptor-4 (TLR4), the production of inflammatory cytokines IL-6, TNF-? and IL-1?, chemokines IL-8, monocyte attractant protein-1 (MCP-1) and of the adipokines adiponectin, resistin and leptin. Our data are as follows: (a) CRF, UCN2 and UCN3 are expressed in human white adipocytes as well as CRFR1a, CRFR2a and CRFR2b but not CRFR2c. 3T3L1 pre-adipocytes and differentiated adipocytes expressed both CRF1 and CRF2 receptors and UCN3, while UCN2 was detected only in differentiated adipocytes. CRF2 was up-regulated in mouse mature adipocytes. (b) CRF1 agonists suppressed media- and LPS-induced pre-adipocyte differentiation while CRF2 receptor agonists had no effect. (c) In mouse pre-adipocytes, CRF2 agonists suppressed TLR4 expression and the production of IL-6, CXCL1 and adiponectin while CRF1 agonists had no effect. (d) In mature mouse adipocytes LPS induced IL-6 and CXCL1 production and suppressed leptin. (e) In human visceral adipocytes LPS induced IL-6, TNF-?, IL-8, MCP-1 and leptin production and suppressed adiponectin and resistin. (f) In mouse mature adipocytes CRF1 and CRF2 agonists suppressed basal and LPS-induced production of inflammatory cytokines, TLR4 expression and adiponectin production, while in human visceral adipocytes CRF and UCN1 suppressed basal and LPS-induced IL-6, TNF-?, IL-8 and MCP-1 production. In conclusion, the effects of the activation of CRF1 and CRF2 may be significant in ameliorating the pro-inflammatory activity of adipocytes in obesity.

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

Publications

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

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