Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status

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Abstract

Neuropeptide Y is a widely distributed neuropeptide that elicits a plethora of physiological effects via interaction with six different receptors (Y1–y6). Recent attention has focused on the role of neuropeptide Y in the regulation of energy homeostasis. Neuropeptide Y stimulates food intake, inhibits energy expenditure, increases body weight and increases anabolic hormone levels by activating the neuropeptide Y Y1 and Y5 receptors in the hypothalamus. Based on these findings, several neuropeptide Y Y1 and Y5 receptor antagonists have been developed recently as potential anti-obesity agents. In addition, mice lacking neuropeptide Y, the neuropeptide Y Y1 receptor or the neuropeptide Y Y5 receptor have been generated. The data obtained to date with these newly developed tools suggests that neuropeptide Y receptor antagonists, particularly neuropeptide Y Y1 receptor antagonists, may be useful anti-obesity agents. However, the redundancy of the neurochemical systems regulating energy homeostasis may limit the effect of ablating a single pathway. In addition, patients in whom the starvation response is activated, such as formerly obese patients who have lost weight or patients with complete or partial leptin deficiency, may be the best candidates for treatment with a neuropeptide Y receptor antagonist.

Introduction

Neuropeptide Y is a 36-amino acid neuropeptide that was discovered in 1982 in a directed search for C-terminally amidated peptides (Tatemoto et al., 1982). Neuropeptide Y is a member of the pancreatic polypeptide family; other members of this family are the structurally related peptides, peptide YY and pancreatic polypeptide (Tatemoto et al., 1982). Neuropeptide Y is widely distributed in both the central and peripheral nervous systems and is one of the most abundant neuropeptides known. In the periphery, neuropeptide Y is localized in post-ganglionic sympathetic neurons, adrenal medulla, enteric neurons, cardiac non-sympathetic neurons, certain non-adrenergic perivascular neurons and parasympathetic neurons Grundemar and Hakanson, 1993, McDermott et al., 1993. In sympathetic neurons and adrenal medulla, the peptide is co-localized with the classical sympathetic neurotransmitter noradrenaline (Lundberg et al., 1982). In the brain, neuropeptide Y-containing neuronal cell bodies are found primarily in the locus coeruleus, the nucleus of the solitary tract and the arcuate nucleus of the hypothalamus. These neuropeptide Y-containing neuronal cell bodies also typically contain other neurotransmitters such as noradrenaline and send projections throughout the brain; hence, neuropeptide Y can be found in most brain regions, particularly in the cortex, hippocampus, thalamus, hypothalamus and brainstem (Chronwall et al., 1985).

Since it was one of the first neuropeptides to be discovered and is ubiquitously distributed, a great deal is now known about the biology of neuropeptide Y. Neuropeptide Y has been implicated in a wide variety of physiological effects; hence, neuropeptide Y and its receptors have sparked a great deal of basic research and drug development interest. This review will focus on the role played by neuropeptide Y and neuropeptide Y receptors in the regulation of energy homeostasis. The reader is referred to other excellent reviews for a more comprehensive discussion of the biology of neuropeptide Y Cerda-Reverter and Larhammar, 2000, Grundemar and Bloom, 1997, Wettstein et al., 1995.

Section snippets

Neuropeptide Y receptors

Neuropeptide Y, peptide YY and pancreatic polypeptide elicit their physiological effects by interacting with at least six distinct G protein-coupled receptors designated Y1, Y2, Y3, Y4, Y5 and y6 (Michel et al., 1998). With the exception of the neuropeptide Y Y3 receptor, genes and/or cDNAs encoding each of these neuropeptide Y receptors have been cloned. In contrast to other families of G protein-coupled receptors, the neuropeptide Y receptors share only modest primary sequence homology

Effect of exogenous neuropeptide Y on energy intake and energy expenditure

Neuropeptide Y has potent effects on a variety of behavioral, physiological and endocrine systems that are critical in the modulation of energy homeostasis. Neuropeptide Y is the most potent orexigenic peptide identified to date. Nearly two decades ago, it was discovered that administration of exogenous neuropeptide Y directly to the brains of rats causes a tremendous increase in food consumption, even under conditions of satiation Clark et al., 1984, Stanley and Leibowitz, 1984. Injection of

Development of non-peptide neuropeptide Y receptor antagonists as therapeutic agents for the treatment of obesity

Within the pharmaceutical industry, there has been great interest in the development of neuropeptide Y Y1 and Y5 receptor antagonists as potential drugs for obesity management. There is now a significant body of primary and patent literature describing potent and selective neuropeptide Y Y1 receptor antagonists, and an even larger body of literature devoted to neuropeptide Y Y5 receptor antagonists. The following discussion focuses on the pharmacology of non-peptidic neuropeptide Y receptor

Summary and perspective

Data from mice lacking neuropeptide Y or the neuropeptide Y1 receptor suggest that activation of the neuropeptide Y Y1 receptor by neuropeptide Y plays a role in maintaining normal food intake as well as food intake after deprivation. Studies with selective neuropeptide Y Y1 receptor antagonists also suggest a role for neuropeptide Y Y1 receptors in maintaining food intake under conditions of real or apparent deprivation (e.g., food-deprived animals and genetically obese animals in which leptin

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