Investigating the various roles of neuropeptide Y in the periphery and the central nervous system in mice

Abstract

Neuropeptide Y (NPY) exhibits a diverse range of actions in the central and peripheral nervous systems. The role of NPY is still not fully elucidated. The aims of this thesis were to investigate the putative role of NPY in audition, its role in insulin release and the roles of NPY's Y1 and Y5 receptors in the regulation of food intake and energy homeostasis. This thesis shows that NPY does not play a direct role in murine audition. Further, in vitro studies show that since the MIN6 cell-line lacks Y1 receptors, unlike beta pancreatic cells, they are an unsuitable cell line in which to study the mechanism of insulin release. Importantly however, this thesis presents novel findings regarding the role of Y1 and Y5 receptors in feeding and obesity. Germline deletion of Y1 and Y5 receptors reduces both spontaneous food intake and re-feeding after a period of fasting. However, deletion also results in early-onset obesity, due to the combination of decreased energy expenditure and secondary effects of increased serum insulin concentration. It was hypothesized that the effects of reduced feeding observed in germline Y1Y5-/- mice, but not the effects of increased adiposity, would be recapitulated in adult mice whereby Y1 and Y5 receptors are deleted at the paraventricular hypothalamic nuclei (PVN). Deletion of Y1 and Y5 receptors at the PVN by injecting cre-recombinase using brain surgery, results in Y1Y5Hyp mice. Y1Y5Hyp male mice show reduced food consumption after fasting and exhibit a decrease in adiposity. These mice exhibit decreased energy expenditure indicating Y1 and Y5 receptors at the PVN play a significant role in maintaining energy homeostasis. These mice also exhibit normal glucose responses to an intraperitoneal glucose tolerance test, demonstrating that PVN Y1 and Y5 receptors do not modulate glucose homeostasis. This thesis demonstrates that Y1 and Y5 receptors play a synergistic role in regulating food intake. This is novel data that shows that deletion of hypothalamic Y1 and Y5 receptors reduces food intake after a fast and decreases adiposity in male mice.