MICE EXPRESSING HUMAN BUT NOT MURINE BETA-ADRENERGIC RECEPTORS UNDER THE CONTROL OF HUMAN GENE REGULATORY ELEMENTS

beta(3)-Adrenergic receptors (ARs) are expressed predominantly in adip ose tissue, and beta(3)-selective agonists are effective anti-obesity drugs in rodents. Rodent and human beta(3)-ARs differ with respect to expression in white versus brown adipocytes as well as their ability t o be stimulated by beta(3)-AR-selective agonists. Humans express beta( 3)-AR mRNA abundantly in brown but not white adipocytes, while rodents express beta(3)-AR mRNA abundantly in both sites. To determine the ba sis for this difference, we have transgenically introduced 74 kilobase s (kb) of human beta(3)-AR genomic sequence into gene knockout mice la cking beta(3)-ARs. Importantly, human beta(3)-AR mRNA was expressed on ly in brown adipose tissue (BAT) of transgenic mice, with Little or no expression being detected in white adipose tissue (WAT), liver, stoma ch, small intestine, skeletal muscle, and heart. This pattern of expre ssion differed from that observed in mice bearing a murine beta(3)-AR genomic transgene in which beta(3)-AR mRNA was expressed in both WAT a nd BAT, but not in other sites. Furthermore, we have transgenically in troduced smaller human constructs containing -14.5 and -0.6 kb of upst ream sequence into beta(3)-AR gene knockout mice. Both -14.5 and -0.6 kb constructs were expressed in BAT but not WAT. Thus, human but: not murine cis-regulatory elements direct beta(3)-AR gene expression prefe rentially to brown adipocytes. Identification of responsible cis-regul atory element(s) and relevant trans-acting factor(s) should provide in sight into mechanisms controlling human beta(3)-AR gene expression. In addition, the beta(3)-AR agonist, CGP-12177, stimulated oxygen consum ption in mice expressing human but not murine beta(3)-ARs by 91% compa red with only 49% in control beta(3)-AR gene knockout mice, demonstrat ing that the human beta(3)-AR can functionally couple with energy expe nditure. These ''humanized'' mice should assist us in the development of drugs that may become effective anti-obesity agents in humans.