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J Clin Invest. 1998 Jun 1;101(11):2387-93.

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

Author information

1
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. mike_fisher@merck.com

Abstract

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.

PMID:
9616210
PMCID:
PMC508828
DOI:
10.1172/JCI2496
[Indexed for MEDLINE]
Free PMC Article

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