A1-adenosine receptor-mediated inhibition of adipocyte adenylate cyclase and lipolysis in Zucker rats

Abstract

Hormone-stimulated lipolysis is reduced in genetically obese rodents and may contribute to the increased adiposity characteristic of the obese state. Endogenously released adenosine, acting via the A1 receptor coupled to the inhibitory guanosine 5'-triphosphate binding protein, Gi, provides a tonic inhibition of lipolysis in rat adipocytes. Removal of this inhibition by the addition of adenosine deaminase frequently results in maximal lipolytic activity. Adipocytes isolated from lean Zucker (Fa/?) rats responded normally to adenosine deaminase, where lipolysis in adipocytes from obese Zucker (fa/fa) rats remained approximately 50% inhibited. Adipocyte adenylate cyclase was equally responsive to activation by forskolin, but lipolytic hormones were significantly less effective in stimulating adenosine 3',5'-cyclic monophosphate (cAMP) production in the obese adipocytes. These cells also exhibited an increased sensitivity to inhibition by the adenosine agonist, N6-(L-2-phenylisopropyl)-adenosine, either in combination with forskolin or beta-adrenergic hormone stimulation. Treatment of isolated adipocytes with pertussis toxin, which uncouples receptor-mediated Gi function, had little effect in cells from lean rats but increased isoproterenol stimulated cAMP production of cells from obese rats to levels observed in the lean cells. In addition, the adenosine A1 antagonist, 8-phenyltheophylline, increased cAMP and lipolytic activity in the obese adipocytes while having little significant effect in the lean adipocytes. These results suggest that hormonal control of lipolysis is altered in the obese Zucker rat because of an alteration in A1-adenosine receptor-mediated inhibition of adenylate cyclase.