Adenosine is an ubiquitous autacoid that exerts its effects on four G protein-coupled receptors, A1, A2A, A2B and A3. Although adenosine is generally perceived as an emergency signal it plays also some roles in basic physiology. This is partly evidenced by the fact that the adenosine receptor antagonist caffeine has clear effects on e.g. wakefulness and renal function already under basal conditions. We have used mice that lack adenosine A1 receptors (A1R-/-) to probe the roles of this receptor in the regulation of intermediary metabolism. Fat cells from A1R(-/-) mice showed a higher basal and stimulated lipolysis and cAMP production, but did not show any response to adenosine analogues, adenosine deaminase or methyl xanthines. Fat cells from A1R (+/­) mice, which have half the number of receptors, required twice as high dose of adenosine for any given antilipolytic effect. There were no compensatory increases in the potency of nicotinic acid, prostaglandin E2 or insulin as antilipolytic agents in A1R (-/-) adipocytes. Insulin release from pancreas was increased in A1R (-/-) mice. In particular pulsatile insulin release during the later phase of secretion was markedly influenced. Insulin-stimulated glucose uptake was slightly but not significantly reduced in A1R (-/-) muscle and adipocytes. Glucose tolerance was unaltered in young fed mice. Thus, adenosine, via A1 receptors play a physiological role in regulation of metabolism. Adenosine, glucose tolerance, adipose tissue, pancreas.