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

  • Proc Natl Acad Sci U S A. 2006 May 2;103(18):7154-8. doi: 10.1073/pnas.0510320103.
Akane Ishihara  1 ,  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 H T Van der Ploeg ,  Masaru Nishikibe ,  Yasuyuki Ishii ,  Masaki Ihara ,  Takehiro Fukami
Affiliations
  • 1. Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba 300-2611, Japan. [email protected]
PMID: 16636293 DOI: 10.1073/pnas.0510320103
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.

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