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

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.

• Authors: 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 H T Van der Ploeg, Masaru Nishikibe, Yasuyuki Ishii, Masaki Ihara, Takehiro Fukami
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 18 Pg. 7154-8 (May 02 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16636293 (Publication Type: Journal Article)

Chemical References

• Anti-Obesity Agents
• Blood Glucose
• Cyclohexanes
• Insulin
• L 152804
• Neuropeptide Y
• Receptors, Neuropeptide Y
• Xanthenes
• neuropeptide Y5 receptor

Topics

• Adipose Tissue (anatomy & histology, metabolism)
• Animals
• Anti-Obesity Agents (metabolism)
• Blood Glucose (metabolism)
• Body Weight
• Cyclohexanes (chemistry, metabolism)
• Diet
• Insulin (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neuropeptide Y
• Obesity (genetics, metabolism)
• Organ Size
• Rats
• Rats, Zucker
• Receptors, Neuropeptide Y (agonists, genetics, metabolism)
• Weight Gain
• Xanthenes (chemistry, metabolism)