Behavioural PharmacologySynergistic interaction between neuropeptide Y1 and Y5 receptor pathways in regulation of energy homeostasis
Introduction
Several lines of evidence have shown that the hypothalamus plays a key role in energy homeostasis and that a number of hypothalamic neuropeptides are involved in energy balance. Neuropeptide Y, a 36-amino acid peptide neurotransmitter, is one of the most potent orexigenic peptides identified to date. The physiological functions of neuropeptide Y are mediated by activation of G-protein-coupled receptors. Five types of neuropeptide Y receptors, Y1, Y2, Y4, Y5 and mY6, have been cloned, with Y1, Y2 and Y5 receptors being abundantly expressed in the hypothalamus (Parker et al., 2002) and playing a role in feeding regulation. Neuropeptide Y1 and Y5 receptor selective agonists stimulate feeding (Gerald et al., 1996, Mullins et al., 2001), while neuropeptide Y2 receptor selective agonists inhibit feeding (Batterham et al., 2002). Thus, neuropeptide Y1 and Y5 receptors mediate orexigenic effects, while neuropeptide Y2 receptors mediate anorexigenic effects.
We previously reported that neuropeptide Y-induced food intake was reduced in neuropeptide Y1 receptor knockout mice, but not in neuropeptide Y5 receptor knockout mice, indicating that the neuropeptide Y1 receptor plays a major role in neuropeptide Y-induced feeding (Kanatani et al., 2000b). Interestingly, despite the limited efficacy of the neuropeptide Y5 receptor-preferring agonists at the neuropeptide Y1 receptor, human pancreatic polypeptide-induced food intake was significantly diminished in neuropeptide Y1 receptor knockout mice (Kanatani et al., 2000b). This indicates that the neuropeptide Y1 receptor modulates the action of the neuropeptide Y5 receptor. In addition, both neuropeptide Y1 and Y5 receptor knockout mice paradoxically develop late-onset obesity (Pedrazzini et al., 1998, Marsh et al., 1998). Compensatory changes of the remaining neuropeptide Y receptors, such as neuropeptide Y5 or Y1 receptor, may occur in neuropeptide Y1 and Y5 receptor knockout mice, and these changes may contribute to the obese phenotypes of these knockout mice. We thus hypothesized that there are interactions among neuropeptide Y receptor subtypes, particularly neuropeptide Y1 and Y5 receptors.
In the present study, we conducted experiments in order to clarify the interactions between neuropeptide Y1 and Y5 receptors in feeding regulation by using selective neuropeptide Y1 (Kanatani et al., 2001) and Y5 receptor antagonists (Mashiko et al., 2008). We previously reported that a neuropeptide Y1 receptor antagonist suppressed spontaneous food intake in db/db and C57BL/6 mice (Kanatani et al., 2001), while a neuropeptide Y5 receptor antagonist specifically produced anti-obesity effects in high-fat diet-fed obesity animals (Ishihara et al., 2006, Mashiko et al., 2008). Therefore, we initially examined the acute anorexigenic effects of combined treatment of neuropeptide Y1 and Y5 receptor antagonists in high-fat diet-fed obese C57BL/6 mice. Next, we examined the chronic effects of neuropeptide Y5 receptor antagonist in high-fat diet-fed obese neuropeptide Y1 receptor knockout mice in order to mimic chronic exposure to combined treatment with neuropeptide Y1 and Y5 receptor antagonists.
Section snippets
Materials
Neuropeptide Y1 receptor antagonist, [(−)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl) ethylamino]-6-[2-(-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4morpholinopyridine] (Kanatani et al., 2001), and neuropeptide Y5 receptor antagonist, 3-oxo-N-(5-phenylpyrazinyl) spiro (isobenzofuran-1(3H), 4′-piperidine)-1′-carboxamide (Mashiko et al., 2008), were synthesized at Banyu Pharmaceutical Co., Ltd. (Tsukuba, Japan).
Acute anorexigenic effects of neuropeptide Y1 and Y5 receptor antagonists on spontaneous food intake in high-fat diet-fed obese C57BL/6 mice
Single intraperitoneal administration of the neuropeptide Y1 receptor antagonist dose-dependently suppressed 24-h spontaneous food intake and reduced body weight in high-fat diet-fed obese C57BL/6 mice (Fig. 1). The neuropeptide Y1 receptor antagonist at 10 and 30 mg/kg suppressed food intake by 23 and 70%, and reduced body weight by 0.60 and 1.49 g, respectively. Doses of 10 and 30 mg/kg of the neuropeptide Y1 receptor antagonist were selected for the combination study with the neuropeptide Y5
Discussion
In the present study, we conducted experiments in order to clarify the interaction between the neuropeptide Y1 and Y5 receptors in energy homeostasis. We evaluated the acute anorexigenic effects of a combination of neuropeptide Y1 and Y5 receptor antagonists in high-fat diet-fed obese mice, and the chronic anti-obesity effects of a neuropeptide Y5 receptor antagonist in neuropeptide Y1 receptor knockout mice. The neuropeptide Y1 and Y5 receptor antagonists used here are highly selective for
Conflict of interest statement
The authors are employees of Banyu Pharmaceutical Co., Ltd. and declare no conflicts of interest relating to the published contents.
Acknowledgements
We would like to thank Dr. Douglas J. MacNeil for his valuable criticism and suggestions for the preparation of this manuscript.
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