Regulation of energy homeostasis by bombesin receptor subtype-3: selective receptor agonists for the treatment of obesity.
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.
Guan
Xiao-Ming
XM
Merck Research Laboratories, Rahway, NJ 07065, USA. xiaoming_guan@merck.com
Chen
Howard
H
Dobbelaar
Peter H
PH
Dong
Yan
Y
Fong
Tung M
TM
Gagen
Karen
K
Gorski
Judith
J
He
Shuwen
S
Howard
Andrew D
AD
Jian
Tianying
T
Jiang
Michael
M
Kan
Yanqing
Y
Kelly
Theresa M
TM
Kosinski
Jennifer
J
Lin
Linus S
LS
Liu
Jian
J
Marsh
Donald J
DJ
Metzger
Joseph M
JM
Miller
Randy
R
Nargund
Ravi P
RP
Palyha
Oksana
O
Shearman
Lauren
L
Shen
Zhu
Z
Stearns
Ralph
R
Strack
Alison M
AM
Stribling
Sloan
S
Tang
Yui Sing
YS
Wang
Sheng-Ping
SP
White
Amanda
A
Yu
Hong
H
Reitman
Marc L
ML
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*
D019440:Anti-Obesity Agents; D008024:Ligands; D010455:Peptides; D018004:Receptors, Bombesin; C000617994:bantag-1; C107120:bombesin receptor subtype 3