Y2, Y4 receptors and obesity

Abstract

The neuropeptide Y system -comprising neuropeptide Y, peptide YY, pancreatic polypeptide and the Y receptors through which they act (Y1, Y2, Y4, Y5 and y6) -has been at the center of attention with regards to regulation of feeding behavior and its possible involvement in obesity. In the past, research has focused mainly on the orexigenic and obesogenic action of this system, with Y1 and Y5 receptors being prime candidates as mediators of neuropeptide Y-induced hyperphagia and obesity. However, in recent years, the role of other members of the neuropeptide Y family, peptide YY, pancreatic polypeptide and the Y2 and Y4 receptors through which they predominantly act, have commanded increasing attention on account of their effects to mediate satiety and promote weight loss via actions in key brain structures, such as the arcuate nucleus of the hypothalamus and the brain stem. This review focuses on the role of peptide YY-and pancreatic polypeptide-like compounds as possible antiobesity drugs, taking into account their effects, not only on energy balance, but also in the regulation of bone formation, and highlights potential benefits of using Y2 and/or Y4 antagonists (as opposed to agonists such as peptide YY or pancreatic polypeptide) in the treatment of obesity.

Synergistic attenuation of obesity by Y2- and Y4-receptor double knockout in ob/ob mice

“…We previously reported that the synergy between Y2 and Y4 receptors in reducing adiposity may be related to differential effects on the hypothalamo-pituitary-somatotropic and -gonadotropic axes [23,24], both of which are inhibited by NPY [3]. In two conditions of elevated hypothalamic NPY expression (24-h fasting and leptin-deficient obesity) [12], germline or hypothalamus-specific Y2-but not Y4-receptor deletion prevents the associated decrease in activity of the somatotropic axis, whereas Y4-but not Y2-receptor deletion prevents the associated decrease in activity of the gonadotropic axis [13,14,23].…”

Role of the Autonomic Nervous System and Neuropeptides in the Development of Obesity in Humans: Targets for Therapy?

“…In part, this may be due to the redundancy of the peptides mediating energy homeostasis, thereby limiting the approach of targeting a single pathway in an attempt to reduce food intake and body weight. In addition, central and peripheral Y receptors can have opposing actions on parameters that affect energy homeostasis [54], so it is important to consider which receptor pool a pharmacological agent reaches. Agents that target more than one Y receptor, such as the Y2 and Y4 receptors, may prove to be more effective in inducing weight loss in clinical studies [12].…”

Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists

“…Of these, Y1 and Y5 are generally believed to be involved in both food intake and energy expenditure, although recent literature suggests the involvement of the Y2 and Y4 subtypes as well. 14 The pharmacology of the Y1 receptor has been studied using potent and selective Y1 receptor antagonists (Figure 1). The effect of NPY administration in Y5 knockout mice was completely blocked by coinjection of the peptidic Y1 antagonist, 1229U91.…”

“…Five NPY receptors (Y1–Y5) have been cloned and expressed. Of these, Y1 and Y5 are generally believed to be involved in both food intake and energy expenditure, although recent literature suggests the involvement of the Y2 and Y4 subtypes as well . The pharmacology of the Y1 receptor has been studied using potent and selective Y1 receptor antagonists (Figure ).…”