title: Regulation of energy homeostasis by bombesin receptor subtype-3: selective receptor agonists for the treatment of obesity.
abstract: Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake and body weight, whereas agonists increased metabolic rate and reduced food intake and body weight. Prolonged high levels of receptor occupancy increased weight loss, suggesting a lack of tachyphylaxis. BRS-3 agonist effectiveness was absent in Brs3(-/Y) (BRS-3 null) mice but was maintained in Npy(-/-)Agrp(-/-), Mc4r(-/-), Cnr1(-/-), and Lepr(db/db) mice. In addition, Brs3(-/Y) mice lost weight upon treatment with either a MC4R agonist or a CB1R inverse agonist. These results demonstrate that BRS-3 has a role in energy homeostasis that complements several well-known pathways and that BRS-3 agonists represent a potential approach to the treatment of obesity.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA. xiaoming_guan@merck.com
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Guan
authors.forename: Howard
authors.initials: H
authors.lastname: Chen
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dobbelaar
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Karen
authors.initials: K
authors.lastname: Gagen
authors.forename: Judith
authors.initials: J
authors.lastname: Gorski
authors.forename: Shuwen
authors.initials: S
authors.lastname: He
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.forename: Tianying
authors.initials: T
authors.lastname: Jian
authors.forename: Michael
authors.initials: M
authors.lastname: Jiang
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Kan
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Kelly
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kosinski
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: Randy
authors.initials: R
authors.lastname: Miller
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.forename: Oksana
authors.initials: O
authors.lastname: Palyha
authors.forename: Lauren
authors.initials: L
authors.lastname: Shearman
authors.forename: Zhu
authors.initials: Z
authors.lastname: Shen
authors.forename: Ralph
authors.initials: R
authors.lastname: Stearns
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.forename: Sloan
authors.initials: S
authors.lastname: Stribling
authors.forename: Yui Sing
authors.initials: YS
authors.lastname: Tang
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.forename: Amanda
authors.initials: A
authors.lastname: White
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Marc L
authors.initials: ML
authors.lastname: Reitman
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D010455:Peptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018004:Receptors, Bombesin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019440:Anti-Obesity Agents; D008024:Ligands; D010455:Peptides; D018004:Receptors, Bombesin; C000617994:bantag-1; C107120:bombesin receptor subtype 3