Effects of Age on β Adrenergic Subtype Activation of Adenylyl Cyclase in Brown Adipose Tissue

Abstract

Abstract

Thermogenesis in brown adipose tissue (BAT) is believed to be mediated mainly by p₃ adrenergic receptors. We previously demonstrated that the specific p₃ 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 p₃ adrenergic signal transduction are impaired with age. To investigate whether β₁ or p₃ adrenergic function is decreased with age, we assessed β₁ and β₃ adrenergic receptor mRNA levels and the ability of β₁ and β₃ adrenergic receptors to activate adenylyl cyclase in BAT membranes from 4- and 24-month-old F-344 rats. Both β₁ and p₃ adrenergic receptor mRNA levels decreased by 50% with age. Adenylyl cyclase stimulated by the nonspecific agonist, isoproterenol, and by the specific β₃ 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 β₁ and β₃ adrenergic receptors. The V_max for both β₁ and β₃ adrenergic receptors decreased by 50% with age. However, stimulation of adenylyl cyclase by NaF and forskolin was also diminished by the same amount as β 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 β₁ and β₃ adrenergic receptors and adenylyl cyclase catalytic units are deficient with age in rodent BAT.