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. 1998 Jun 1;101(11):2387–2393. doi: 10.1172/JCI2496

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

M H Fisher 1, A M Amend 1, T J Bach 1, J M Barker 1, E J Brady 1, M R Candelore 1, D Carroll 1, M A Cascieri 1, S H Chiu 1, L Deng 1, M J Forrest 1, B Hegarty-Friscino 1, X M Guan 1, G J Hom 1, J E Hutchins 1, L J Kelly 1, R J Mathvink 1, J M Metzger 1, R R Miller 1, H O Ok 1, E R Parmee 1, R Saperstein 1, C D Strader 1, R A Stearns 1, D E MacIntyre 1, et al.
PMCID: PMC508828  PMID: 9616210

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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Selected References

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