The beta3 adrenergic receptor (AR) has been proposed to be a therapeutic target for the treatment of obesity and adult-onset diabetes, and recent work has identified a polymorphism in the human beta3-AR gene that is associated with excess weight gain and insulin resistance. Beta3-AR are expressed almost exclusively in adipocytes where they are co-expressed with beta1-AR. The tissue-specific pattern of beta3-AR gene expression and its co-existence in adipose tissue with beta1-AR has raised several fundamental questions. First, the coexpression of beta1-and beta3-AR in fat cells implies that the beta3-AR subtypes serve different signaling functions in adipocytes, and recent evidence indicates that beta1- and beta3-AR have unique signaling properties and that these receptors activate distinct pathways in adipocytes. The organization of beta1- and beta3-AR signaling in adipocytes will be further characterized and specific hypotheses regarding the biochemical and cellular basis of that organization will be tested. Second, beta1- and beta3-AR exhibit several unique pharmacological and biochemical properties that are amenable to molecular analysis. A panel of epitope- tagged, mutated and chimeric receptors have been created that will allow validation of observations made in adipocyte and further dissection of the molecular bases of beta3-AR subtype-specific signaling properties. These analyses will include examination of the molecular pharmacology of aryloxypropranolamine and phenethanolamine agonists, compounds being developed as selective beta3-AR agonists. An understanding of how these compounds differentially interact with the beta 3-AR subtypes, and the impact of that interaction on receptor signaling is key to understanding their biological actions.
Specific aims are:
Aim 1. To investigate the biochemical organization of beta3-AR signaling in adipocytes.
Aim 2. To further characterize the differential signaling properties of beta1- beta3-AR and to examine the cellular and molecular basis.
Specific Aim 3. To examine the molecular pharmacology of beta3-AR-selective agonists.
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