GENETIC ANALYSIS OF B3 ADRENERGIC RECEPTOR FUNCTION

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Obesity is a prevalent disorder that often leads to diabetes and cardiovascular disease. We have recently found that transgenic mice engineered to have brown fat deficiency become markedly obese, suggesting that brown fat protects against the development of obesity. We now seek to better understand the mechanisms by which brown fat is regulated, specifically the role of beta/3-adrenergic receptors (beta/3-ARs). The activity of brown fat is controlled predominantly by the sympathetic nervous system. Norepinephrine, released from sympathetic nerves, activates brown fat by binding to adrenergic receptors. Recently, brown fat has been found to possess a highly specialized beta-adrenergic receptor (beta-AR), termed the beta/3-AR. This receptor is the most abundant beta-AR in adipose tissue and is decreased by 70-98% in genetic models of obesity. Pharmaceutical companies have synthesized "atypical" beta-AR agonists which stimulate beta/3-ARs, and these compounds hold promise as anti-obesity, anti-diabetes agents. For these reasons, there is great interest in the beta/3-AR, and the drugs which stimulate it. However, the function of beta/3-ARs in normal physiology, and the mechanisms by which atypical beta-AR agonists produce their effects, are incompletely understood. To address these issues, a genetic analysis of beta/3-AR function has been undertaken. Using homologous recombination, we have generated mice which completely lack beta/3-ARs. These animals will be used to determine the function of beta/3-ARs in normal physiology and to define the receptor through which atypical beta-AR agonists produce their many effects. By reexpressing beta/3-ARs transgenically in selected tissues of deficient mice, it will be possible to establish the sites of action for these various effects. Finally, by transgenically reconstituting beta/3-AR deficient mice with human receptors, it will be possible to determine the capacity of activated human beta/3-ARs to augment thermogenesis. Given the high specificity of this genetic approach, information obtained from these mice concerning the function of this receptor, should be definitive in nature.