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This version published online on April 7, 2005
Endocrinology, doi:10.1210/en.2004-1150
A more recent version of this article appeared on July 1, 2005
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Submitted on August 30, 2004
Accepted on March 31, 2005

Anti-obesity Effect of an MCH1R Antagonist in Diet-Induced Obese Mice Anti-obesity effect of MCH1R antagonist

Satoshi Mashiko, Akane Ishihara*, Akira Gomori, Ryuichi Moriya, Makoto Ito, Hisashi Iwaasa, Masao Matsuda, Yue Feng, Zhu Shen, Donald J. Marsh, Maria A. Bednarek, Douglas J. MacNeil, and Akio Kanatani

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan; Departments of Metabolic Disorders and Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA

* To whom correspondence should be addressed. E-mail: akane_ishihara{at}merck.com.

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 MCH1R antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinity and selectivity for the MCH-1 receptor, and potently inhibits ICV-injected MCH-induced food intake in SD rats. Chronic ICV infusion of the MCH1R antagonist (7.5 µg/day) completely suppressed body weight gain in diet-induced obese (DIO) 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 DIO 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 anti-obesity agent.
Key words: Obesity • melanin-concentrating hormone(MCH) • MCH1R




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