Synergistic interaction between neuropeptide Y1 and Y5 receptor pathways in regulation of energy homeostasis.

Abstract 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.