Differences in functional cyclic AMP compartments mediating lipolysis by isoprenaline and BRL 37344 in four adipocyte types

Triglyceride mobilization and adenylyl cyclase activation in adipocytes from Wistar rats, lean Zucker (Fa/?) rats, obese Zucker (fa/fa) rats and humans were investigated in concentration-response studies with (-)-isoprenaline and the atypical beta-3-adrenoceptor selective agonist BRL 37344. Maximum FFA production by both agonists was identical in Wistar rat and lean Zucker rat adipocytes, while obese Zucker rat adipocytes and human adipocytes produced significantly less FFA, especially with BRL 37344. Maximum adenylyl cyclase activation by (-)-isoprenaline was similar for all types of adipocyte ghosts, whereas BRL 37344 was a partial agonist in all cases with the lowest intrinsic activity in human adipocytes. For (-)-isoprenaline the relationship between cAMP and lipolysis was steepest with Wistar rat adipocytes, followed by human and lean Zucker rat adipocytes, while obese Zucker rat cells showed a shallow relationship. For BRL 37344, the relationship was very steep and similar for all four adipocyte types, despite the marked differences in maximal lipolysis and cyclic AMP production. The results strongly argue in favour of cyclic AMP compartmentalization, the activity ratio between the functional and the non-functional compartment being least favourable in obese Zucker rat adipocytes. The atypical beta-3-adrenoceptor agonist BRL 37344 very efficiently directs the generated cyclic AMP into the functional compartment in all four adipocytes types investigated.