REGULATION OF BROWN FAT TRANSMEMBRANE SIGNALLING

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The principal function of brown adipose tissue (BAT) is the generation of heat in response to stimulation by the sympathetic nervous system. The stimulation of adenylyl cyclase by norepinephrine is central to the control of BAT function. Our work has shown that chronic neural stimulation regulates the adenylyl cyclase system in BAT by altering the genetic expression and activity of the components of the adenylyl cyclase system, including receptors and GTP-binding proteins. This work has established BAT as a model system for assessing the role of the nervous system in the coordinated regulation of signal-transducing proteins. Using combined pharmacological and molecular biological approaches, we have found that BAT contains the recently-discovered beta3 receptor and, in addition, appears to contain related novel atypical receptors. Atypical receptors appear to be important new therapeutic targets for obesity and obesity-related diseases, including diabetes, hypertension and cardiovascular disease. However, very little is known about the tissue distribution or regulation of atypical beta receptors, including the beta3 receptor. We have developed highly sensitive and specific assays for measuring typical and atypical beta receptor gene expression so that these studies can now be undertaken. Our specific aims are: 1) To examine the neural regulation of the molecular components of the adenylyl cyclase system in neonatal BAT and to determine how changes in the expression of these components alters adenylyl cyclase activity during the perinatal period. 2) To examine the functional relationship between beta receptor stimulation, G (sa) mRNA levels and G (sa) protein levels in brown adipocytes using in vivo and in vitro analyses. 3) To clone and pharmacologically characterize typical and atypical beta receptors, including the beta3 receptor. 4) To identify tissues that express atypical beta receptors and to examine the neural and endocrine regulation of beta receptor gene expression, with a focus upon atypical beta receptors.