Importance of orexigenic counter-regulation for multiple targeted feeding inhibition

Objective: Central feeding regulation involves both anorectic and orexigenic pathways. This Study examined whether targeting both systems could enhance feeding inhibition induced by anorectic neuropeptides. Research Methods and Procedures: Experiments were carried out in 24-hour fasted rats. Intracerebroventricular (ICV) injections were accomplished through stereotaxically implanted cannulae aimed at the lateral cerebral ventricle. Food intake of standard rat chow pellets was subsequently recorded for 2 hours. Results: Blockade of orexigenic central opioids and neuropeptide Y (NPY) by ICV naloxone (25 mug) or the NPY receptor antagonist [D-Trp(32)]NPY (NPY-Ant; 10 mug) powerfully augmented the feeding suppression induced by ICV glucagon-like peptide 1 (7-36)-amide (GLP-1; 10 mug) or xenin-25 (xenin; 15 mug) in 24-hour fasted rats. Most importantly, in combination with naloxone or NPY-Ant, even a low and ineffective dose of GLP-1 (5 mug) caused a 40% reduction of food intake, which was augmented further when both antagonists were given in combination with GLP-1. The combination of GLP-1 (5 mug) and xenin (110 mug) at individually ineffective doses caused a 46% reduction of food intake, which was abolished at a 10-fold lower dose. This ineffective dose, however, reduced food intake by 72% when administered in combination with naloxone and NPY-Ant. Discussion: Targeting up to four pathways of feeding regulation in the central nervous system by blockade of endogenous feeding stimuli and simultaneous administration of anorectic neuropeptides potentiated reduction of food intake. This raises a promising perspective for treatment of obesity.