Effects of a novel Y5 antagonist in obese mice: combination with food restriction or sibutramine.
OBJECTIVE
To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet-induced obese (DIO) mice.


METHODS
Male C57BL/6 or Npy5r(-/-) mice were adapted to high-fat (HF) diet for 6-10 months and were submitted to three experimental treatments. First, the Y5 antagonist at a dose of 10 or 30 mg/kg was administered for 1 month to DIO C57BL/6 or Npy5r(-/-) mice. Second, the Y5 antagonist at 30 mg/kg was administered for 1.5 months to DIO C57BL/6 mice, and insulin sensitivity was evaluated using an insulin tolerance test. After a recovery period, nuclear magnetic resonance measurement was performed to evaluate body composition. Third, DIO mice were treated with the Y5 antagonist alone, or in combination with 10% food restriction, or with another anorectic agent, sibutramine at 10 mg/kg, for 1.5 months. Plasma glucose, insulin, and leptin levels, and adipose tissue weights were quantified.


RESULTS
The spironolactone Y5 antagonist significantly reduced body weight in C57BL DIO mice, but not in Npy5r(-/-) DIO mice. The Y5 antagonist produced a fat-selective loss of body weight, and ameliorated obesity-associated insulin resistance in DIO mice. In addition, the Y5 antagonist combined with either food restriction or sibutramine tended to produce greater body weight loss, as compared with single treatment.


CONCLUSIONS
These findings demonstrate that the Y5 receptor is an important mediator of energy homeostasis in rodents.
Mashiko
Satoshi
S
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan.
Ishihara
Akane
A
Iwaasa
Hisashi
H
Moriya
Ryuichi
R
Kitazawa
Hidefumi
H
Mitobe
Yuko
Y
Ito
Junko
J
Gomori
Akira
A
Matsushita
Hiroko
H
Takahashi
Toshiyuki
T
MacNeil
Douglas J
DJ
Van der Ploeg
Lex H T
LH
Fukami
Takehiro
T
Kanatani
Akio
A
D050154:Adiposity; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001067:Appetite Depressants / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D031204:Caloric Restriction; D003131:Combined Modality Therapy; D003503:Cyclobutanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004435:Eating / Q000187:drug effects; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000178:diet therapy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology*; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology*; D013997:Time Factors
C544692:3-oxo-N-(5-phenylpyrazinyl)spiro(isobenzofuran-1(3H),4'-piperidine)-1'-carboxamide; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D001786:Blood Glucose; D003503:Cyclobutanes; D007328:Insulin; D020738:Leptin; D017476:Receptors, Neuropeptide Y; D013141:Spiro Compounds; C100568:neuropeptide Y5 receptor; D013148:Spironolactone; C058254:sibutramine