A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice.
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.
Ishihara
Akane
A
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba 300-2611, Japan. akane_ishihara@merck.com
Kanatani
Akio
A
Mashiko
Satoshi
S
Tanaka
Takeshi
T
Hidaka
Masayasu
M
Gomori
Akira
A
Iwaasa
Hisashi
H
Murai
Naomi
N
Egashira
Shin-ichiro
S
Murai
Takashi
T
Mitobe
Yuko
Y
Matsushita
Hiroko
H
Okamoto
Osamu
O
Sato
Nagaaki
N
Jitsuoka
Makoto
M
Fukuroda
Takahiro
T
Ohe
Tomoyuki
T
Guan
Xiaoming
X
MacNeil
Douglas J
DJ
Van der Ploeg
Lex H T
LH
Nishikibe
Masaru
M
Ishii
Yasuyuki
Y
Ihara
Masaki
M
Fukami
Takehiro
T
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*
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