Effects of adenosine nucleosides on adenylate cyclase, phosphodiesterase, cyclic adenosine monophosphate accumulation, and lipolysis in fat cells.

Adenosine and 2’-deoxyadenosine at concentrations in the range of S to 50 pM inhibited the activation of adenylate cyclase activity in fat cell “ghosts” by norepinephrine. Z’, 5’Dideoxyadenosine was more potent than adenosine while arabinosyl adenosine, 3’-deoxyadenosine, and Z-fluoroadenosine were equi-potent to adenosine as inhibitors of adenylate cyclase. Adenine was inactive as an inhibitor of adenylate cyclase along with nucleosides such as phenylisopropyl adenosine, inosine, 2’-deoxyinosine, guanosine, and 2’-deoxyguanosine. Adenosine, 2’-deoxyadenosine, and 2fluoroadenosine were also inhibitors of the low K, phosphodiesterase found in the supernatant fraction obtained after centrifugation of fat cell homogenates. The large accumulation of cyclic adenosine 3’,5’-monophosphate (cyclic AMP) seen in fat cells incubated for 5 min with catecholamines plus theophylline was markedly inhibited by 2’,5’-dideoxyadenosine, adenosine, and Z-fluoroadenosine. The small increase in cyclic AMP due to norepinephrine or theophylline alone was also blocked by adenosine and Z/,5’-dideoxyadenosine. However, there was no correlation between the effects of the nucleosides on cyclic AMP accumulation and lipolysis since 2’,5’-dideoxyadenosine did not inhibit lipolysis. Adenosine inhibited the lipolytic action of theophylline or low concentrations of norepinephrine but did not inhibit the lipolytic action of higher concentrations of norepinephrine under conditions in which it virtually abolished the increase in cyclic AMP accumulation due to norepinephrine. These data indicate that marked inhibition by nucleosides of the increase in total cyclic AMP accumulation seen 5 min after the addition of theophylline, norepinephrine, or norepinephrine plus theophylline IS not necessarily associated with any decrease in lipolysis. Apparently most of the increased cyclic AMP accumulation seen in the presence of lipolytic agents is unrelated to the regulation of lipolysis. The effect of adenosine and related nucleosides on cyclic AMP accumulation suggest that they may play a physiological role as feedback regulators of fat cell adenylate cyclase.