A denylate cyclase of human fat cell ghosts shows a biphasic response towards prostaglandin E2 with inhibition occurring at nanomolar concentrations of the hormone and stimulation at concentrations beyond 10(-6) mol/liter. The expression of the inhibitory effect is critically dependent on GTP. Under the conditions employed (1 mmol/liter ATP, 5 mmol/liter Mg2+, 30 degrees C) the inhibitory component of prostaglandin E2 became apparent at GTP concentrations exceeding 10(-6) mol/liter. The prostaglandin E2-induced inhibition displayed characteristic features of prostaglandin action in intact fat cells with respect to the effective concentrations and degree of inhibition. It is concluded that prostaglandin E2 is capable of inducing antagonistic effects upon lipolysis via interaction with the membrane-bound adenylate cyclase.