The beta3 adrenergic receptor has been proposed to be a therapeutic target for the treatment of obesity and adult-onset diabetes, yet very little is known about the biochemical and pharmacological properties of these receptors. Pharmacological and molecular data indicate that adipose tissues contain both beta1 and beta3 receptors, yet it is unclear why fat cells make both receptor subtypes. Our preliminary data, however, indicate that beta1 and beta3 receptors have distinct signal- transducing properties and are differentially regulated by agonist exposure. We propose to further characterize these differences and examine the molecular bases of those differences. We have discovered that he human beta3 receptor gene contains an intron and a second protein-coding exon. All previous work with the recombinant human beta3 receptor was conducted on a protein that lacked the sequence from the second exon, and thus was incomplete. Furthermore, preliminary data indicates that the newly-discovered exon may play an important role in the pharmacological and regulatory properties of the human receptor. We have also discovered that the rat beta3 receptor gene also contains multiple exons and introns. The sequence of the first intron of the rat gene suggest that it may play a role in fat-specific expression.
Our specific aims are: 1. To characterize, for the first time, the pharmacological properties of the recombinant full-length human beta3 receptor. To further characterize the differential signalling properties of beta1 and beta 3 receptors. 2. To characterize the differential regulation of beta1 and beta3 receptors by agonist exposure and to examine the molecular basis. 3. To evaluate the impact of the differential signalling properties of beta1 and beta3 receptors on physiological responses in adipocytes. 4. To determine the genetic elements that confer adipose tissue-specific expression of the rat beta3 receptor, with a initial focus on the potential role of the first intron. To determine whether the human beta3 receptor gene contains similar elements.
Showing the most recent 10 out of 13 publications
