The principal function of brown adipose tissue (BAT) is to generate heat in response to sympathetic nerve stimulation. Recent work indicates that BAT plays an important role not only during cold exposure, but also in overall energy homeostasis. Because of its ability to dissipate lipid energy as heat, BAT is receiving attention as a therapeutic target for anti-obesity drugs, including beta3-receptor agonists. The principal investigator has found that the beta3 receptor is abundantly expressed in human BAT, and therefore up-regulation of BAT metabolism may be a consequence of treatment with a beta3-agonist in man. This research group has also shown that the beta1 and beta3 receptor subtypes control different functions in brown adipocytes, possibly by differentially interacting with G-protein subtypes. The focus of this proposal is to understand the transmembrane mechanisms that control BAT function in response to adrenergic stimulation. Recent work from this laboratory has shown that adrenergic stimulation regulates the genetic expression and activity of key signalling proteins in BAT, including receptors, G-proteins and adenylate cyclase. The principal investigator has recently demonstrated that neural stimulation dramatically induces expression of type III adenylate cyclase (AC-III) in BAT. It is proposed that AC-III plays a central role in the adaptation of BAT to chronic adrenergic stimulation by integrating signals from the alpha1- and beta3-adrenergic pathways. Therefore, an integrative analysis of AC-III and alpha-receptors in BAT function could lead to the design of novel drugs which optimally activate BAT thermogenesis.
The specific aims are as follows: (1) To examine the functional organization of beta- receptor signalling in brown adipocytes, including interactions with G-proteins and cellular distribution. (2) To analyze the physiological and cellular mechanisms of adrenergic induction of type III adenylate cyclase (AC-III) in BAT. (3) To examine the regulation of alpha1-receptor subtypes in adult and neonatal BAT. (4) To provide an integrative analysis of the roles of AC-III and alpha1-receptors in BAT function.
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