A SELECTIVE HUMAN BETA(3) ADRENERGIC-RECEPTOR AGONIST INCREASES METABOLIC-RATE IN RHESUS-MONKEYS

Activation of beta(3) adrenergic receptors on the surface of adipocyte s leads to increases in intracellular cAMP and stimulation of lipolysi s. In brown adipose tissue, this serves to upregulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductan ce pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta(3) a gonists in nonprimate species leads to uncoupling protein 1 up-regulat ion and weight loss, the relevance of this mechanism to energy metabol ism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and se lective partial agonist for both human and rhesus beta(3) receptors, w e now demonstrate that acute exposure of rhesus monkeys to a beta(3) a gonist elicits lipolysis and metabolic rate elevation, and that chroni c exposure increases uncoupling protein 1 expression in rhesus brown a dipose tissue. These data suggest a role for beta(3) agonists in the t reatment of human obesity.