title: 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.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba 300-2611, Japan. akane_ishihara@merck.com
authors.forename: Akane
authors.initials: A
authors.lastname: Ishihara
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mashiko
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Masayasu
authors.initials: M
authors.lastname: Hidaka
authors.forename: Akira
authors.initials: A
authors.lastname: Gomori
authors.forename: Hisashi
authors.initials: H
authors.lastname: Iwaasa
authors.forename: Naomi
authors.initials: N
authors.lastname: Murai
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Egashira
authors.forename: Takashi
authors.initials: T
authors.lastname: Murai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mitobe
authors.forename: Hiroko
authors.initials: H
authors.lastname: Matsushita
authors.forename: Osamu
authors.initials: O
authors.lastname: Okamoto
authors.forename: Nagaaki
authors.initials: N
authors.lastname: Sato
authors.forename: Makoto
authors.initials: M
authors.lastname: Jitsuoka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuroda
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Guan
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: MacNeil
authors.forename: Lex H T
authors.initials: LH
authors.lastname: Van der Ploeg
authors.forename: Masaru
authors.initials: M
authors.lastname: Nishikibe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
authors.forename: Masaki
authors.initials: M
authors.lastname: Ihara
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism*; D004032:Diet; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009478:Neuropeptide Y; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D051381:Rats; D011924:Rats, Zucker; D017476:Receptors, Neuropeptide Y / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D015430:Weight Gain; D014966:Xanthenes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D003510:Cyclohexanes; D007328:Insulin; C410588:L 152804; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D014966:Xanthenes; C100568:neuropeptide Y5 receptor