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.