Orexin and NPY interactions in feeding behavior.

Abstract

Obesity results from an imbalance between energy intake and energy expenditure. The central nervous system (CNS) has a complex interconnected circuitry that regulates feeding behavior. The hypothalamus is the principal region in the central nervous system regulating energy intake and energy expenditure. Important advances have been made identifying hypothalamic neuronal networks, neuropeptide transmitters and the discovery of circulating peptides that send signals to the brain regarding the body’s nutritional status. However, the full set of neuronal pathways that initiate changes in ingestive behavior or energy expenditure remain undefined. This dissertation examines the roles of two specific neuropeptides, orexin A (OXA) and neuropeptide Y (NPY) in food regulation. Several lines of evidence suggest that orexin and NPY interact in modulating feeding behavior and these dissertation studies further substantiate this premise. Previous research conducted in this laboratory showed that subthreshold doses of OXA and NPY agonists stimulate feeding when administered simultaneously. The current set of studies shows effects of individual and simultaneous central administration of subthreshold doses of NPY and OXA antagonists on feeding. The first study established dose-response parameters for both OXA and NPY antagonists. The OXA antagonist was injected into the lateral hypothalamic area (LHa) whereas the NPY antagonist was injected into the hypothalamic paraventricular nucleus (PVN). The objective was to ascertain sub-threshold doses for both of these neuropeptides antagonists within these brain sites. The study showed that the subthreshold dose for both the NPY and the orexin antagonist was 100 pmol. The second study was the central administration of both subthreshold doses of the NPY antagonist and the orexin antagonist simultaneously, within the PVN and LHA respectively. Individual administration of subthreshold doses of the orexin and NPY antagonists in the LHA and PVN respectively caused no inhibition of food intake, whereas simultaneous administration of subthreshold doses of the orexin and NPY antagonists significantly inhibited food intake. Significant differences (p < 0.001) were obtained at all time points (0-1 h, 0-2 h, 0-4 h and 0-24 h) comparatively with vehicle. The experiments conducted further substantiate the premise of a functional relationship between OXA and NPY that involves corresponding pathways between the LHA and the PVN.