title: Chronic treatment with olanzapine increases adiposity by changing fuel substrate and causes desensitization of the acute metabolic side effects.
abstract: Atypical antipsychotic drugs such as olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these metabolic side-effects are unknown at the moment. In this study, we investigated the metabolic changes induced by a chronic treatment, as well as the influence of a preceding chronic treatment on the acute effects of olanzapine on glucose metabolism. The effect of chronic olanzapine treatment (±6.5 mg/kg/day, administered via drinking water) on body weight, locomotor activity, body temperature, fat distribution and energy expenditure was investigated in male rats. After 5 weeks, the animals received an acute olanzapine challenge (intragastric, IG) at 3 mg/kg/h during 160 min to investigate the acute effects of olanzapine on glucose metabolism. Chronic olanzapine-treated animals showed a slight decrease in nocturnal body temperature, and increased perirenal fat pad weights as well as plasma leptin. In addition, chronic olanzapine-treated animals showed hyperinsulinaemia with unchanged blood glucose concentrations. The acute challenge with IG olanzapine elevated blood glucose levels and endogenous glucose production in control animals, but not in chronic olanzapine-pre-treated rats. Chronic olanzapine-treated animals also showed reduced locomotor activity and a higher respiratory exchange ratio. Thus, chronic treatment with olanzapine in rats causes desensitization to its acute effects on glucose metabolism but promotes adiposity probably due to a shift from lipids to carbohydrates as an energy source. Chronic exposure to olanzapine changes body fat distribution and insulin sensitivity in an unfavourable direction, but it is still unclear what the primary mechanism is.
authors.affiliation: Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands, elodie.m.girault@gmail.com.
authors.forename: Elodie M
authors.initials: EM
authors.lastname: Girault
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
authors.forename: Anneke
authors.initials: A
authors.lastname: Alkemade
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: D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D000077152:Olanzapine; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D020738:Leptin; D001569:Benzodiazepines; D005947:Glucose; D000077152:Olanzapine