A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.

Cloning, sequencing, and expression of the rhesus monkey beta 2 adrenergic receptor.

The beta 2 adrenergic receptor (beta 2AR) plays a key role in the signal transduction mechanism for epinephrine and norepinephrine. The gene for beta 2 adrenergic receptors has been cloned for several species, but has remained undetermined for rhesus monkey. In this study, we report the isolation of the gene encoding the rhesus beta 2AR from both cDNA and genomic DNA sources. Sequence analysis of the gene reveals an intronless open reading frame that encodes a 415-amino-acid protein. The rhesus receptor is highly homologous to that from other species, especially to the human receptor (97% sequence identity). Functional characterization by ligand binding and agonist-mediated cAMP accumulation indicates that the rhesus beta 2 receptor shares a very similar pharmacological profile with the human beta 2 receptor. Therefore, the rhesus monkey represents a valid animal model for developing therapeutic agents targeted at the corresponding human beta 2 receptor.

Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase.

Three closely related fungal metabolites, zaragozic acids A, B, and C, that are potent inhibitors of squalene synthase have been isolated and characterized. Zaragozic acids A, B, and C were produced from an unidentified sterile fungal culture, Sporormiella intermedia, and Leptodontium elatius, respectively. The structures of the zaragozic acids and their trimethyl esters were determined by a combination of physical and chemical techniques. The zaragozic acids are characterized by a novel 2,8-dioxobicyclo[3.2.1]octane-4,6,7- trihydroxyl-3,4,5-tricarboxylic acid core and differ from each other in the structures of the 6-acyl and 1-alkyl side chains. They were found to be potent competitive inhibitors of rat liver squalene synthase with apparent Ki values of 78 pM, 29 pM, and 45 pM, respectively. They inhibited cholesterol synthesis in Hep G2 cells, and zaragozic acid A was an inhibitor of acute hepatic cholesterol synthesis in the mouse (50% inhibitory dose of 200 micrograms/kg of body weight). Inhibition of squalene synthase in cells and in vivo was accompanied by an accumulation of label from [3H]mevalonate into farnesyl diphosphate, farnesol, and organic acids. These data indicate that the zaragozic acids are a previously unreported class of therapeutic agents with potential for the treatment of hypercholesterolemia.