A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice

Akane Ishihara, Akio Kanatani, Satoshi Mashiko, Takeshi Tanaka, Masayasu Hidaka, Akira Gomori, Hisashi Iwaasa, Naomi Murai, Shin Ichiro Egashira, Takashi Murai, Yuko Mitobe, Hiroko Matsushita, Osamu Okamoto, Nagaaki Sato, Makoto Jitsuoka, Takahiro Fukuroda, Tomoyuki Ohe, Xiaoming Guan, Douglas J. MacNeil, Lex M.T. Van Der PloegMasaru Nishikibe, Yasuyuki Ishii, Masaki Ihara, Takehiro Fukami

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Abstract

Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Among five NPY receptors described, the NPY Y5 receptor (Y5R) is a prime candidate to mediate some of the effects of NPY on energy homeostasis, although its role in physiologically relevant rodent obesity models remains poorly defined. We examined the effect of a potent and highly selective Y5R antagonist in rodent obesity and dietary models. The Y5R antagonist selectively ameliorated diet-induced obesity (DIO) in rodents by suppressing body weight gain and adiposity while improving the DIO-associated hyperinsulinemia. The compound did not affect the body weight of lean mice fed a regular diet or genetically obese leptin receptor-deficient mice or rats, despite similarly high brain Y5R receptor occupancy. The Y5R antagonist acts in a mechanism-based manner, as the compound did not affect DIO of Y5R-deficient mice. These results indicate that Y5R is involved in the regulation and development of DIO and suggest utility for Y5R antagonists in the treatment of obesity.

Original languageEnglish
Pages (from-to)7154-7158
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number18
DOIs
Publication statusPublished - 2006 May 2

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Keywords

  • Antiobesity effect
  • Receptor occupancy
  • Y5R-deficient mice

ASJC Scopus subject areas

  • General

Cite this

Ishihara, A., Kanatani, A., Mashiko, S., Tanaka, T., Hidaka, M., Gomori, A., Iwaasa, H., Murai, N., Egashira, S. I., Murai, T., Mitobe, Y., Matsushita, H., Okamoto, O., Sato, N., Jitsuoka, M., Fukuroda, T., Ohe, T., Guan, X., MacNeil, D. J., ... Fukami, T. (2006). A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice. Proceedings of the National Academy of Sciences of the United States of America, 103(18), 7154-7158. https://doi.org/10.1073/pnas.0510320103