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Effects of a Novel Y5 Antagonist in Obese Mice: Combination With Food Restriction or Sibutramine
Author(s) -
Mashiko Satoshi,
Ishihara Akane,
Iwaasa Hisashi,
Moriya Ryuichi,
Kitazawa Hidefumi,
Mitobe Yuko,
Ito Junko,
Gomori Akira,
Matsushita Hiroko,
Takahashi Toshiyuki,
MacNeil Douglas J.,
Ploeg Lex H.T.,
Fukami Takehiro,
Kanatani Akio
Publication year - 2008
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1038/oby.2008.223
Subject(s) - sibutramine , antagonist , endocrinology , diet induced obese , weight loss , rimonabant , medicine , leptin , insulin resistance , insulin , obesity , receptor , cannabinoid receptor
Objective: To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet‐induced obese (DIO) mice. Methods and Procedures: Male C57BL/6 or Npy5r −/− mice were adapted to high‐fat (HF) diet for 6–10 months and were submitted to three experimental treatments. First, the Y5 antagonist at a dose of 10 or 30 mg/kg was administered for 1 month to DIO C57BL/6 or Npy5r −/− mice. Second, the Y5 antagonist at 30 mg/kg was administered for 1.5 months to DIO C57BL/6 mice, and insulin sensitivity was evaluated using an insulin tolerance test. After a recovery period, nuclear magnetic resonance measurement was performed to evaluate body composition. Third, DIO mice were treated with the Y5 antagonist alone, or in combination with 10% food restriction, or with another anorectic agent, sibutramine at 10 mg/kg, for 1.5 months. Plasma glucose, insulin, and leptin levels, and adipose tissue weights were quantified. Results: The spironolactone Y5 antagonist significantly reduced body weight in C57BL DIO mice, but not in Npy5r −/− DIO mice. The Y5 antagonist produced a fat‐selective loss of body weight, and ameliorated obesity‐associated insulin resistance in DIO mice. In addition, the Y5 antagonist combined with either food restriction or sibutramine tended to produce greater body weight loss, as compared with single treatment. Discussion: These findings demonstrate that the Y5 receptor is an important mediator of energy homeostasis in rodents.