title: A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. mike_fisher@merck.com
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
authors.forename: A M
authors.initials: AM
authors.lastname: Amend
authors.forename: T J
authors.initials: TJ
authors.lastname: Bach
authors.forename: J M
authors.initials: JM
authors.lastname: Barker
authors.forename: E J
authors.initials: EJ
authors.lastname: Brady
authors.forename: M R
authors.initials: MR
authors.lastname: Candelore
authors.forename: D
authors.initials: D
authors.lastname: Carroll
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: S H
authors.initials: SH
authors.lastname: Chiu
authors.forename: L
authors.initials: L
authors.lastname: Deng
authors.forename: M J
authors.initials: MJ
authors.lastname: Forrest
authors.forename: B
authors.initials: B
authors.lastname: Hegarty-Friscino
authors.forename: X M
authors.initials: XM
authors.lastname: Guan
authors.forename: G J
authors.initials: GJ
authors.lastname: Hom
authors.forename: J E
authors.initials: JE
authors.lastname: Hutchins
authors.forename: L J
authors.initials: LJ
authors.lastname: Kelly
authors.forename: R J
authors.initials: RJ
authors.lastname: Mathvink
authors.forename: J M
authors.initials: JM
authors.lastname: Metzger
authors.forename: R R
authors.initials: RR
authors.lastname: Miller
authors.forename: H O
authors.initials: HO
authors.lastname: Ok
authors.forename: E R
authors.initials: ER
authors.lastname: Parmee
authors.forename: R
authors.initials: R
authors.lastname: Saperstein
authors.forename: C D
authors.initials: CD
authors.lastname: Strader
authors.forename: R A
authors.initials: RA
authors.lastname: Stearns
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008066:Lipolysis / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D011412:Propanolamines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; C112650:L 755507; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; C033394:CGP 12177