Effect of N6-methyladenosine on fat-cell glucose metabolism : Evidence for two modes of action

N 6-Methyladenosine strongly stimulates [1- 14C]glucose oxidation in rat adipocytes [J.E. Souness and V. Chagoya de Sanchez, Fedn Eur. Biochem. Soc. Lett. 125, 249 (1981)]. The effect of the adenosine analogue is largely independent of its action as an R-site agonist. Removal of endogenous adenosine was a prerequisite for the manifestation of the effect of N 6-methyladenosine. Nucleoside uptake inhibitors, dipridamole and nitrobenzylthioinosine, did not block the action of N 6-methyladenosine on [1- 14C]glucose oxidation. The effect of the adenosine analogue was not greatly influenced by N 6-phenylisopropyladenosine, nicotinic acid or theophylline. Although N 6-methyladenosine stimulated 3- O-methylglucose uptake into fat cells, it is uncertain whether this was its only effect on glucose metabolism, in view of the comparable enhancement of hexose transport elicited by N 6-phenylisopropyladenosine, a much weaker stimulator of glucose oxidation. That hexose transport is not the sole site of action of N 6-methyladenosine was supported by the finding that, under conditions which have been proposed to make glucose transport rate limiting, the adenosine analogue only weakly enhanced [1- 14C]glucose oxidation. The conversion of glucose carbon 1 to 14CO 2 was enhanced by N 6-methyladenosine to a greater degree than that of carbon 6, suggesting an increase in pentose phosphate shunt activity. Mechanisms by which this could arise are discussed. Although similarities exist between the effects of insulin and N 6-methyladenosine on adipocyte glucose metabolism, the mechanisms by which they stimulate glucose oxidation appear to be distinct, in view of the additivity of their actions on [1- 14C]glucose conversion to 14CO 2. The results indicate that N 6-methyladenosine affects fat-cell glucose metabolism via two different mechanisms: (1) a weak R-site-dependent mode of action related to stimulation of glucose transport and inhibition of lipolysis, and (2) a strong R-site-independent effect of unknown mechanism.