Effects of age on beta adrenergic subtype activation of adenylyl cyclase in brown adipose tissue.

Thermogenesis in brown adipose tissue (BAT) is believed to be mediated mainly by beta3 adrenergic receptors. We previously demonstrated that the specific beta3 adrenergic agonist CGP-12177 increases whole body oxygen consumption and BAT GDP binding to a greater extent in young than in senescent rats. In contrast, the forskolin-induced increases were maintained with age, suggesting that early events in beta3 adrenergic signal transduction are impaired with age. To investigate whether beta1 or beta3 adrenergic function is decreased with age, we assessed beta1 and beta3 adrenergic receptor mRNA levels and the ability of beta1 and beta3 adrenergic receptors to activate adenylyl cyclase in BAT membranes from 4- and 24-month-old F-344 rats. Both beta1 and beta3 adrenergic receptor mRNA levels decreased by 50% with age. Adenylyl cyclase stimulated by the nonspecific agonist, isoproterenol, and by the specific beta3 agonist, BRL 37344, also declined by 50% with age, whereas glucagon stimulation decreased by more than 70%. The isoproterenol-stimulated adenylyl cyclase activation curves were resolved by two-site regression analysis to determine the contribution of beta1 and beta3 adrenergic receptors. The Vmax for both beta1 and beta3 adrenergic receptors decreased by 50% with age. However, stimulation of adenylyl cyclase by NaF and forskolin was also diminished by the same amount as beta adrenergic stimulation, suggesting that the activation with age may be limited by the amount of adenylyl cyclase catalytic unit rather than by receptor number. These data suggest both beta1 and beta3 adrenergic receptors and adenylyl cyclase catalytic units are deficient with age in rodent BAT.