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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 387, Issue 2, pp 185–195 | Cite as

Chronic treatment with olanzapine increases adiposity by changing fuel substrate and causes desensitization of the acute metabolic side effects

  • Elodie M. Girault
  • Bruno Guigas
  • Anneke Alkemade
  • Ewout Foppen
  • Mariëtte T. Ackermans
  • Susanne E. la Fleur
  • Eric Fliers
  • Andries Kalsbeek
Original Article

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.

Keywords

Body fat composition Energy expenditure Glucose metabolism Locomotor activity Respiratory exchange ratio Food intake 

Notes

Acknowledgments

The project was founded by a grant of Top Institute Pharma (TIPharma; T2-105). TIPharma had no role in study design, collection, analyses and interpretation of data, in writing the report and in the decision to submit the article for publication.

Conflict of interest

All authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Elodie M. Girault
    • 1
  • Bruno Guigas
    • 4
    • 5
  • Anneke Alkemade
    • 2
  • Ewout Foppen
    • 1
    • 2
  • Mariëtte T. Ackermans
    • 3
  • Susanne E. la Fleur
    • 2
  • Eric Fliers
    • 2
  • Andries Kalsbeek
    • 1
    • 2
  1. 1.Hypothalamic Integration MechanismsNetherlands Institute for NeuroscienceAmsterdamThe Netherlands
  2. 2.Department of Endocrinology and Metabolism, Academic Medical Center (AMC)University of AmsterdamAmsterdamThe Netherlands
  3. 3.Laboratory of Endocrinology, Department of Clinical Chemistry, Academic Medical Center (AMC)University of AmsterdamAmsterdamThe Netherlands
  4. 4.Department of Molecular Cell BiologyLeiden University Medical CenterLeidenThe Netherlands
  5. 5.Department of ParasitologyLeiden University Medical CenterLeidenThe Netherlands

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