THE BETA(3)-ADRENERGIC RECEPTOR IN THE OBESITY AND DIABETES-PRONE RHESUS-MONKEY IS VERY SIMILAR TO HUMAN AND CONTAINS ARGININE AT CODON-64

The beta(3)-adrenergic receptor (ADR beta(3)) is a seven-membrane span ning, G-protein linked receptor expressed in brown adipose tissue in r odents, and visceral adipose tissue in humans. Stimulation of the rece ptor by norepinephrine leads to lipolysis and thermogenesis. In rodent models of obesity and diabetes, administration of beta(3)-agonists re sults in weight loss and improved glucose tolerance. Studies indicate that the pharmacological properties of the ADR beta(3) differ markedly between rodents and humans, making generalizations of rodent studies to humans difficult. We hypothesized that the obesity and diabetes pro ne rhesus monkey (Macaca mulatta) would provide an excellent animal mo del to study the role of the ADR beta(3) in the development of obesity and diabetes as well as for assessment of the therapeutic efficacy of beta(3)-agonists. We sequenced the entire coding region of the rhesus ADR beta(3) gene. Like humans, the rhesus ADR beta(3) has two exons. There is 89% amino acid (aa) identity between human and rhesus compare d to 82% aa identity between human and mouse. A single base deletion r esults in divergence of the intracellular carboxy terminus accounting for 26 of the 45 aa changes and 10 additional aa. Of the 15 rhesus mon keys studied, all were homozygous for Arg(64). In humans, Arg(64) (rat her than Trp) is associated with increased body mass index, insulin re sistance, and an earlier onset of type II diabetes mellitus. We conclu de that the rhesus ADR beta(3) is more similar to the human ADR beta(3 ) than to the rodent ADR beta(3) suggesting that this primate model ma y be more appropriate for physiologic and therapeutic studies of the A DR beta(3) axis, and that Arg(64) may influence susceptibility in this species to obesity, insulin resistance, and type II diabetes.