EVIDENCE FOR THE KEY ROLE OF THE ADIPOCYTE CGMP-INHIBITED CAMP-PHOSPHODIESTERASE IN THE ANTILIPOLYTIC ACTION OF INSULIN

Enhancement of cAMP degradation by increased cGMP-inhibited cAMP phosp hodiesterase (cGI-PDE) activity is thought to be an important componen t of the mechanism whereby insulin counteracts catecholamine-induced l ipolysis in adipocytes. In this study the selective cGI-PDE inhibitor OPC3911 was used to evaluate this role of cGI-PDE activation in intact rat adipocytes with special reference to changes in cAMP levels measu red as cAMP-dependent protein kinase (cAMP-PK) activity ratios. OPC391 1 completely blocked (IC50 = 0.3 mu M) the maximal inhibitory effect o f insulin on noradrenaline-induced lipolysis and the net dephosphoryla tion of hormone-sensitive lipase and other intracellular target protei ns for insulin action, whereas insulin-induced lipogenesis was not cha nged. The effect of OPC3911 on cAMP-PK activity ratios at different le vels of lipolysis achieved by noradrenaline stimulation revealed that the reduction of cAMP-PK caused by 1 nM insulin was completely blocked by 3 mu M OPC3911. The effect of OPC3911 was not due to an excessive increase in cellular cAMP resulting in 'supramaximal' lipolysis unresp onsive to insulin. These data demonstrate that reduction in cAMP level s by the activation of cGI-PDE may be sufficient to account for the an tilipolytic action of insulin.