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Research Article Free access | 10.1172/JCI2496

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

M H Fisher, A M Amend, T J Bach, J M Barker, E J Brady, M R Candelore, D Carroll, M A Cascieri, S H Chiu, L Deng, M J Forrest, B Hegarty-Friscino, X M Guan, G J Hom, J E Hutchins, L J Kelly, R J Mathvink, J M Metzger, R R Miller, H O Ok, E R Parmee, R Saperstein, C D Strader, R A Stearns, and D E MacIntyre

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

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Published June 1, 1998 - More info

Published in Volume 101, Issue 11 on June 1, 1998
J Clin Invest. 1998;101(11):2387–2393. https://doi.org/10.1172/JCI2496.
© 1998 The American Society for Clinical Investigation
Published June 1, 1998 - Version history
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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.

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