Bimodal effect of insulin on hormone-stimulated lipolysis: relation to intracellular 3',5'-cyclic adenylic acid and free fatty acid levels

The present study was undertaken to determine the relationship between the antilipolytic and lipolytic effects of insulin on hormone-stimulated lipolysis and the mechanisms of these reactions. The dose-response curve of norepinephrine-stimulated lipolysis in rat adipocytes was not sigmoidal but biphasic in nature. Intracellular free fatty acid levels were linearly related to lipolytic rate and also described a biphasic profile in response to increments in norepinephrine concentration. Intracellular 3',5'-cyclic AMP levels measured 10 min after addition of increasing concentrations of norepinephrine showed a rise and a plateau followed by a secondary rise. Insulin was antilipolytic at low concentrations of norepinephrine and distinctly lipolytic at high concentrations. The combined antilipolytic and lipolytic effect of insulin is termed the "bimodal" effect of insulin on hormone-stimulated lipolysis. The bimodal effect of insulin correlated positively with changes in peak intracellular 3',5'-cyclic AMP levels. In the presence of glucose, insulin invariably enhanced lipolysis. It is suggested that the antilipolytic effect of insulin is achieved by both inhibition of adenyl cyclase activity and activation of low-K(m) 3',5'-cyclic AMP phosphodiesterase, the net effect being a low accumulation of 3',5'-cyclic AMP. On the other hand, the lipolytic effect of insulin probably reflects enhancement of adenyl cyclase activity to an extent that overrides any activation of low-K(m) 3',5'-cyclic AMP phosphodiesterase activity, resulting in an increase in peak adipocyte 3',5'-cyclic AMP levels.