Antiobesity effect of a melanin-concentrating hormone 1 receptor antagonist in diet-induced obese mice.
Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus, which plays an important role in regulating energy balance. To elucidate the physiological role of MCH in obesity development, the present study examined the effect of a selective MCH1 receptor (MCH1R) antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinity and selectivity for MCH-1R and potently inhibits intracerebroventricularly injected MCH-induced food intake in Sprague Dawley rats. Chronic intracerebroventricular infusion of the MCH1R antagonist (7.5 microg/d) completely suppressed body weight gain in diet-induced obese mice during the treatment periods and significantly decreased cumulative food intake, by 14%. Carcass analysis showed that the MCH1R antagonist resulted in a selective decrease of body fat in the diet-induced obese mice. In addition, the MCH1R antagonist ameliorated the obesity-related hypercholesterolemia, hyperinsulinemia, hyperglycemia, and hyperleptinemia. These results indicate that MCH has a major role in the development of diet-induced obesity in mice and that a MCH1R antagonist might be a useful candidate as an antiobesity agent.
Mashiko
Satoshi
S
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan.
Ishihara
Akane
A
Gomori
Akira
A
Moriya
Ryuichi
R
Ito
Makoto
M
Iwaasa
Hisashi
H
Matsuda
Masao
M
Feng
Yue
Y
Shen
Zhu
Z
Marsh
Donald J
DJ
Bednarek
Maria A
MA
MacNeil
Douglas J
DJ
Kanatani
Akio
A
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004032:Diet; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects; D006801:Humans; D007028:Hypothalamic Hormones / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008543:Melanins / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D010907:Pituitary Hormones / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000172:deficiency; D015430:Weight Gain / Q000187:drug effects
D007028:Hypothalamic Hormones; C103263:MCHR1 protein, human; D008543:Melanins; D010907:Pituitary Hormones; D017481:Receptors, Somatostatin; C019463:melanin-concentrating hormone