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Journal of Lipid Research, Vol. 46, 494-503, March 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

The role of cyclic nucleotide phosphodiesterases in the regulation of adipocyte lipolysis

Peter B. Snyder¹, James M. Esselstyn, Kate Loughney, Sharon L. Wolda and Vincent A. Florio

ICOS Corporation, Bothell, WA 98021

¹ To whom correspondence should be addressed. e-mail: psnyder{at}icos.com

This study assessed the effects of selective inhibitors of 3',5'-cyclic nucleotide phosphodiesterases (PDEs) on adipocyte lipolysis. IC224, a selective inhibitor of type 1 phosphodiesterase (PDE1), suppressed lipolysis in murine 3T3-L1 adipocytes (69.6 ± 5.4% of vehicle control) but had no effect in human adipocytes. IC933, a selective inhibitor of PDE2, had no effect on lipolysis in either cultured murine 3T3-L1 adipocytes or human adipocytes. Inhibition of PDE3 with cilostamide moderately stimulated lipolysis in murine 3T3-L1 and rat adipocytes (397 ± 25% and 235 ± 26% of control, respectively) and markedly stimulated lipolysis in human adipocytes (932 ± 7.6% of control). Inhibition of PDE4 with rolipram moderately stimulated lipolysis in murine 3T3-L1 adipocytes (291 ± 13% of control) and weakly stimulated lipolysis in rat adipocytes (149 ± 7.0% of control) but had no effect on lipolysis in human adipocytes. Cultured adipocytes also responded differently to a combination of PDE3 and PDE4 inhibitors. Simultaneous exposure to cilostamide and rolipram had a synergistic effect on lipolysis in murine 3T3-L1 and rat adipocytes but not in human adipocytes.

Hence, the relative importance of PDE3 and PDE4 in regulating lipolysis differed in cultured murine, rat, and human adipocytes.

Abbreviations: AC, adenylyl cyclase; BMI, body mass index; DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; G_s, stimulatory guanine nucleotide binding protein; HSL, hormone-sensitive lipase; IBMX, 3-isobutyl-1-methylxanthine; ISO, isoproterenol; PDE, 3',5'-cyclic nucleotide phosphodiesterase; PDEx, type x phosphodiesterase; PKA, cAMP-dependent protein kinase; RIIß, cAMP-dependent protein kinase regulatory subunit IIß; R_max, maximal response; TG, triglyceride

Supplementary key words cilostamide • rolipram • triglyceride

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