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.


METHODS
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 microg) or the NPY receptor antagonist [D-Trp32]NPY (NPY-Ant; 10 micro g) powerfully augmented the feeding suppression induced by ICV glucagon-like peptide 1 (7-36)-amide (GLP-1; 10 microg) or xenin-25 (xenin; 15 microg) in 24-hour fasted rats. Most importantly, in combination with naloxone or NPY-Ant, even a low and ineffective dose of GLP-1 (5 microg) 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 microg) and xenin (10 microg) 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.


CONCLUSIONS
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.
Schusdziarra
Volker
V
Department of Nutritional Medicine, Else-Kröner-Fresenius Center of Nutritional Medicine, Technical University of Munich, Munich, Germany.
Zimmermann
Jens P
JP
Schick
Rafael R
RR
D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage*; D004435:Eating / Q000187:drug effects* / Q000502:physiology*; D005934:Glucagon / Q000008:administration & dosage; D052216:Glucagon-Like Peptide 1; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors; D009479:Neuropeptides / Q000008:administration & dosage*; D009496:Neurotensin; D010446:Peptide Fragments / Q000008:administration & dosage; D010455:Peptides / Q000008:administration & dosage; D011498:Protein Precursors / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors
D001067:Appetite Depressants; D009292:Narcotic Antagonists; D009478:Neuropeptide Y; D009479:Neuropeptides; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D017476:Receptors, Neuropeptide Y; C077659:xenin 25; D009270:Naloxone; D009496:Neurotensin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon