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Molecular Pharmacology

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Research ArticleArticle

PDE3 and PDE4 Isozyme-Selective Inhibitors Are Both Required for Synergistic Activation of Brown Adipose Tissue

Stephen M. Kraynik, Robert S. Miyaoka and Joseph A. Beavo
Molecular Pharmacology June 2013, 83 (6) 1155-1165; DOI: https://doi.org/10.1124/mol.112.084145
Stephen M. Kraynik
Department of Pharmacology (S.M.K., J.A.B.) and Department of Radiology (R.S.M.), University of Washington, Seattle, Washington
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Robert S. Miyaoka
Department of Pharmacology (S.M.K., J.A.B.) and Department of Radiology (R.S.M.), University of Washington, Seattle, Washington
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Joseph A. Beavo
Department of Pharmacology (S.M.K., J.A.B.) and Department of Radiology (R.S.M.), University of Washington, Seattle, Washington
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Abstract

Brown adipose tissue (BAT) is a highly thermogenic organ that converts lipids and glucose into heat. Many of the metabolic and gene transcriptional hallmarks of BAT activation, namely increased lipolysis, uncoupling protein-1 (UCP1) mRNA, and glucose uptake, are regulated by the adrenergic second messenger, cAMP. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the breakdown of cAMP, thereby regulating the magnitude and duration of this signaling molecule. In the absence of adrenergic stimulus, we found that it required a combination of a PDE3 and a PDE4 inhibitor to fully induce UCP1 mRNA and lipolysis in brown adipocytes, whereas neither PDE inhibitor alone had any substantial effect under basal conditions. Under submaximal β-adrenoceptor stimulation of brown adipocytes, a PDE3 inhibitor alone could potentiate induction of UCP1 mRNA, whereas a PDE4 inhibitor alone could augment lipolysis, indicating differential roles for each of these two PDEs. Neither induction of UCP1 nor lipolysis was altered by inhibition of PDE1, PDE2, or PDE8A. Finally, when injected into mice, the combination of PDE3 and PDE4 inhibitors stimulated glucose uptake in BAT under thermoneutral and fasted conditions, a response that was further potentiated by the global ablation of PDE8A. Taken together, these data reveal that multiple PDEs work in concert to regulate three of the important pathways leading to BAT activation, a finding that may provide an improved conceptual basis for the development of therapies for obesity-related diseases.

Footnotes

    • Received November 29, 2012.
    • Accepted March 14, 2013.
  • This work was supported by the University of Washington Department of Medicinal Chemistry, Pharmacological Sciences Training [Grant GM08392]; the UW Diabetes Research Center Samuel and Althea Stroum Endowed Diabetes Fellowship [P30 DK017047]; and the National Institutes of Health [Grants GM083926 and P30 CA15704].

  • dx.doi.org/10.1124/mol.112.084145.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (6)
Molecular Pharmacology
Vol. 83, Issue 6
1 Jun 2013
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Research ArticleArticle

Multiple PDE Inhibitors Are Required for BAT Activation

Stephen M. Kraynik, Robert S. Miyaoka and Joseph A. Beavo
Molecular Pharmacology June 1, 2013, 83 (6) 1155-1165; DOI: https://doi.org/10.1124/mol.112.084145

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Research ArticleArticle

Multiple PDE Inhibitors Are Required for BAT Activation

Stephen M. Kraynik, Robert S. Miyaoka and Joseph A. Beavo
Molecular Pharmacology June 1, 2013, 83 (6) 1155-1165; DOI: https://doi.org/10.1124/mol.112.084145
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