Synergistic interaction between neuropeptide Y1 and Y5 receptor pathways in regulation of energy homeostasis.
Neuropeptide Y plays a key role in the physiological control of energy homeostasis. Five neuropeptide Y receptor subtypes have been cloned, and multiple neuropeptide Y receptor subtypes are thought to mediate neuropeptide Y activity. However, interactions among neuropeptide Y receptor subtypes have not been elucidated to date. Herein, we examined the interaction between neuropeptide Y(1) and Y(5) receptors in feeding regulation by employing selective neuropeptide Y(1) and Y(5) receptor antagonists in C57BL/6 and neuropeptide Y(1) receptor knockout mice fed a high-fat diet. A single-dose of a neuropeptide Y(1) receptor antagonist (10-30 mg/kg) suppressed spontaneous food intake and reduced body weight in high-fat diet-fed C57BL/6 mice, while treatment with a neuropeptide Y(5) receptor antagonist did not significantly reduce food intake or body weight. Coadministration of a neuropeptide Y(1) receptor antagonist with a neuropeptide Y(5) receptor antagonist further suppressed food intake and reduced body weight. Next, we evaluated the chronic efficacy of a neuropeptide Y(5) receptor antagonist in high-fat diet-fed neuropeptide Y(1) receptor knockout mice in order to mimic chronic combination treatment with neuropeptide Y(1) and Y(5) receptor antagonists. The neuropeptide Y(5) receptor antagonist produced greater body weight reductions in high-fat diet-fed neuropeptide Y(1) receptor knockout mice than in wild-type C57BL/6 mice. These findings confirm an interaction between neuropeptide Y(1) and Y(5) receptors in the regulation of energy homeostasis, as blockade of both the neuropeptide Y(1) and Y(5) receptors produced a greater anti-obesity effect than blocking either receptor alone.
Mashiko
Satoshi
S
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan.
Moriya
Ryuichi
R
Ishihara
Akane
A
Gomori
Akira
A
Matsushita
Hiroko
H
Egashira
Shinichiro
S
Iwaasa
Hisashi
H
Takahashi
Toshiyuki
T
Haga
Yuji
Y
Fukami
Takehiro
T
Kanatani
Akio
A
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects*; D004734:Energy Metabolism / Q000502:physiology*; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000235:genetics; D013141:Spiro Compounds / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
C544692:3-oxo-N-(5-phenylpyrazinyl)spiro(isobenzofuran-1(3H),4'-piperidine)-1'-carboxamide; D019440:Anti-Obesity Agents; D004041:Dietary Fats; C422269:J 115814; D009025:Morpholines; D011725:Pyridines; D017476:Receptors, Neuropeptide Y; D013141:Spiro Compounds; D013844:Thiazoles; C097212:neuropeptide Y-Y1 receptor; C100568:neuropeptide Y5 receptor