Desensitization of beta3-adrenergic receptor-stimulated adenylyl cyclase activity and lipolysis in XXXX .

@entity563 @entity3047 @entity653 @entity5483 @entity35 @entity56137
The beta3-adrenergic receptor is an integral membrane protein consisting of seven transmembrane domains. Unlike the beta1 and beta2 receptors, this subtype lacks the consensus phosphorylation sites required for desensitization by @entity563 kinases. Using the rodent specific beta3 agonist @entity56137 , our initial data indicated that beta3 receptor-mediated @entity653 levels progressively decreased following daily oral doses of 5 mg/kg. Therefore, we initiated studies designed to delineate the possible mechanism(s) for this decreased response. Within 3 hours following a single oral dose of @entity56137 , serum @entity653 levels and @entity5483 (uncoupling protein) RNA levels were significantly increased whereas beta3 RNA levels were significantly decreased. @entity35 were dosed daily for 5 days with either vehicle or @entity56137 (5 mg/kg, p.o.) and blood samples were collected for @entity653 analysis. Adipose tissue was excised for lipolysis and adenyl cyclase measurements. In addition, @entity5483 and beta3 receptor RNA levels were assessed. No effect on adipocyte @entity3047 -stimulated adenylyl cyclase activity was observed 3 hours following the initial dose of @entity56137 . Although a slight decrease (approximately 25%) in adenylyl cyclase activity could be observed 24 hours following the initial dose, it wasn't until day 4 of dosing that a significant decrease (50%) was observed. In contrast, beta3- stimulated lipolysis in adipocytes from @entity56137 -treated @entity35 was decreased 85% within 24 hours and this decrease persisted through four days of treatment. These data indicate that the lipolytic response to beta3 receptor activation is decreased after only a single oral dose of @entity56137 , whereas receptor-mediated adenylyl cyclase activation, although initially unaffected, also desensitizes by day four of treatment.
