title: Olanzapine-induced changes in glucose metabolism are independent of the melanin-concentrating hormone system.
abstract: Atypical antipsychotic drugs such as Olanzapine (Ola) induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these undesired side-effects are currently unknown. Chagnon et al. showed that the common allele rs7973796 of the prepro-melanin-concentrating hormone (PMCH) gene is associated with a greater body mass index in Ola-treated schizophrenic patients. As PMCH encodes for the orexigenic neuropeptide melanin-concentrating hormone (MCH), it was hypothesized that MCH is involved in Ola-induced metabolic changes. We have recently reported that the intragastric infusion of Ola results in hyperglycaemia and insulin resistance in male rats. In order to test in vivo the possible involvement of the PMCH gene in the pathogenesis of Ola side-effects, we administered Ola intragastrically in wild-type (WT) and PMCH knock-out (KO) rats. Our results show that glucose and corticosterone levels, as well as endogenous glucose production, are elevated by the infusion of Ola in both WT and KO animals. Thus, the lack of MCH does not seem to affect the acute effects of Ola on glucose metabolism. On the other hand, these effects might be obliterated by compensatory changes in other hypothalamic systems. In addition, possible modulatory effects of the MCH KO on the long term effects of Ola, i.e. increased adiposity, body weight gain, have not been investigated yet.
authors.affiliation: Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Science, Amsterdam, The Netherlands. Electronic address: elodie.m.girault@gmail.com.
authors.forename: Elodie M
authors.initials: EM
authors.lastname: Girault
authors.forename: Pim W
authors.initials: PW
authors.lastname: Toonen
authors.forename: Leslie
authors.initials: L
authors.lastname: Eggels
authors.forename: Ewout
authors.initials: E
authors.lastname: Foppen
authors.forename: Mariëtte T
authors.initials: MT
authors.lastname: Ackermans
authors.forename: Susanne E
authors.initials: SE
authors.lastname: la Fleur
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.forename: Andries
authors.initials: A
authors.lastname: Kalsbeek
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D001569:Benzodiazepines / Q000009:adverse effects* / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D055786:Gene Knockout Techniques; D005838:Genotype; D044882:Glucose Metabolism Disorders / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D007028:Hypothalamic Hormones / Q000235:genetics*; D007328:Insulin / Q000097:blood; D008297:Male; D008543:Melanins / Q000235:genetics*; D000077152:Olanzapine; D010907:Pituitary Hormones / Q000235:genetics*; D051381:Rats
chemical_list: D014150:Antipsychotic Agents; D001786:Blood Glucose; D007028:Hypothalamic Hormones; D007328:Insulin; D008543:Melanins; D010907:Pituitary Hormones; D001569:Benzodiazepines; C019463:melanin-concentrating hormone; D000077152:Olanzapine; D003345:Corticosterone
keywords: Atypical antipsychotics; Body weight gain; Corticosterone; Endogenous glucose production; Glucose metabolism; Insulin resistance; MCH; Olanzapine; PMCH KO; Schizophrenia