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 Y1 and Y5 receptors in feeding regulation by employing selective neuropeptide Y1 and Y5 receptor antagonists in C57BL/6 and neuropeptide Y1 receptor knockout mice fed a high-fat diet. A single-dose of a neuropeptide Y1 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 Y5 receptor antagonist did not significantly reduce food intake or body weight. Coadministration of a neuropeptide Y1 receptor antagonist with a neuropeptide Y5 receptor antagonist further suppressed food intake and reduced body weight. Next, we evaluated the chronic efficacy of a neuropeptide Y5 receptor antagonist in high-fat diet-fed neuropeptide Y1 receptor knockout mice in order to mimic chronic combination treatment with neuropeptide Y1 and Y5 receptor antagonists. The neuropeptide Y5 receptor antagonist produced greater body weight reductions in high-fat diet-fed neuropeptide Y1 receptor knockout mice than in wild-type C57BL/6 mice. These findings confirm an interaction between neuropeptide Y1 and Y5 receptors in the regulation of energy homeostasis, as blockade of both the neuropeptide Y1 and Y5 receptors produced a greater anti-obesity effect than blocking either receptor alone.