Abstract
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.
Highlights
This study assessed the effects of selective inhibitors of 3,5-cyclic nucleotide phosphodiesterases (PDEs) on adipocyte lipolysis
We investigated whether a combination of a PDE3 inhibitor and a PDE4 inhibitor would be more effective than either inhibitor alone. 3T3-L1 cells were exposed to various concentrations of cilostamide in the absence or presence of a fixed concentration of rolipram (1 M)
Because PDE3 and PDE4 appeared to have somewhat different roles in regulating lipolysis in cultured murine and human adipocytes, we examined the effects of PDE3 and PDE4 inhibitors on lipolysis in cultured adipocytes from a third species
Summary
This study assessed the effects of selective inhibitors of 3,5-cyclic nucleotide phosphodiesterases (PDEs) on adipocyte lipolysis. The size of adipose TG stores is dynamically regulated by endocrine signals in response to energy intake and metabolic demands Anabolic hormones, such as insulin, stimulate adipocyte TG synthesis (lipogenesis), whereas catabolic hormones, such as epinephrine, glucagon, and corti-. Adipocytes from HSL knockout mice retain considerable TG lipase activity, and lipolysis in these cells is partially responsive to the -adrenoceptor agonist isoproterenol (ISO), suggesting that other lipases besides HSL play a role in lipolysis [3,4,5] Another layer of regulation of lipolysis is revealed by the observation that lipolytic stimuli cause translocation of HSL from the cytosol to the surface of lipid droplets, allowing HSL access to substrate [6].
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