title: Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation.
abstract: The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance.
authors.affiliation: Dr. Einar Martens' Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, Bergen, Norway. johan.ferno@uib.no
authors.forename: Johan
authors.initials: J
authors.lastname: Fernø
authors.forename: Luis
authors.initials: L
authors.lastname: Varela
authors.forename: Silje
authors.initials: S
authors.lastname: Skrede
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Vázquez
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.forename: Vidar M
authors.initials: VM
authors.lastname: Steen
authors.forename: Miguel
authors.initials: M
authors.lastname: López
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D003024:Clozapine / Q000008:administration & dosage / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006963:Hyperphagia / Q000097:blood / Q000139:chemically induced*; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology*; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D000077152:Olanzapine; D000068797:Orexins; D010766:Phosphorylation / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D054369:Agouti-Related Protein; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D009479:Neuropeptides; D000068797:Orexins; D012265:Ribonucleotides; D001569:Benzodiazepines; D000620:Aminoimidazole Carboxamide; D011333:Pro-Opiomelanocortin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D003024:Clozapine; D000077152:Olanzapine