Acute effects of orexigenic antipsychotic drugs on lipid and carbohydrate metabolism in rat

Abstract

ObjectiveThis study aims to investigate whether orexigenic antipsychotic drugs may induce dyslipidemia and glucose disturbances in female rats through direct perturbation of metabolically active peripheral tissues, independent of prior weight gain.MethodsIn the current study, we examined whether a single intraperitoneal injection of clozapine or olanzapine induced metabolic disturbances in adult female outbred Sprague–Dawley rats. Serum glucose and lipid parameters were measured during time-course experiments up to 48 h. Real-time quantitative PCR was used to measure specific transcriptional alterations in lipid and carbohydrate metabolism in adipose tissue depots or in the liver.ResultsOur results demonstrated that acute administration of clozapine or olanzapine induced a rapid, robust elevation of free fatty acids and glucose in serum, followed by hepatic accumulation of lipids evident after 12–24 h. These metabolic disturbances were associated with biphasic patterns of gluconeogenic and lipid-related gene expression in the liver and in white adipose tissue depots.ConclusionOur results support that clozapine and olanzapine are associated with primary effects on carbohydrate and lipid metabolism associated with transcriptional changes in metabolically active peripheral tissues prior to the development of drug-induced weight gain.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2397-y) contains supplementary material, which is available to authorized users.

Acute effects of oral olanzapine treatment on the expression of fatty acid and cholesterol metabolism-related gene in rats

“…Since olanzapine was prepared with the cookie dough in this study, a most likely explanation for the delay of drug absorption was due to a prolonged release of olanzapine from the cookie mix and/or delayed gastrointestinal absorption (Mauri et al, 2007). Another explanation is that olanzapine could be absorbed faster at the higher dose (5-6 mg/kg) used in previous reports (Aravagiri et al 1999;Jassim et al 2012). In the current study, the volume of distribution and clearance characteristics of olanzapine resulted in an elimination half-life of 3.5 h, which was slightly longer than the 2.5 h reported in male rats by Aravagiri (Aravagiri et al 1999).…”

“…In an earlier study, a rapid absorption was observed and the peak appeared within 45 min after an oral gavage of 6 mg/kg olanzapine (Aravagiri et al 1999). In another study, after a single intraperitoneal dose of 5 mg/kg, the serum level of olanzapine peaked at 1 h after injection (Jassim et al 2012). Since olanzapine was prepared with the cookie dough in this study, a most likely explanation for the delay of drug absorption was due to a prolonged release of olanzapine from the cookie mix and/or delayed gastrointestinal absorption (Mauri et al, 2007).…”

“…However, it is very interesting that a different (biphasic) expression pattern of lipogenic genes and cholesterol metabolism genes was reported previously in female rats: an i.p. injection of olanzapine (5mg/kg) or clozapine (25mg/kg or 50mg/kg) induced an initial upregulation of SREBP-controlled gene expression followed (at around 1 h post-treatment) by a marked downregulation of SREBPs target genes in rats (Fernø et al 2009;Jassim et al 2012). Although the initial upregulated expression of SREBPs target genes may be explained by the parallel peak concentration of serum drug concentration observed in these studies, the following downregulation could not be well explained by the serum drug concentration.…”

“…Although the unexpected biphasic expression pattern of lipogenic SREBP target genes may be partly explained by its parallel with the peak serum concentrations of clozapine and short half-life of these SGAs (Jassim et al 2012), considering the high dosages of clozapine and olanzapine used in these studies, the biphasic expression pattern is more likely a nonphysiological activation followed by a compensatory rebound effect. Therefore, it is necessary to investigate the acute effects of these SGAs at a clinical equivalent dosage on the expression of SREBPs and their target genes in relation to lipogenesis/cholesterogenesis in the liver and WAT.…”

“…However, in contrast to the findings, acute studies in female rats found that a single intraperitoneal (i.p.) injection of clozapine (25 or 50 mg/kg) or olanzapine (5 mg/kg) causes an initial upregulation of lipogenic SREBP target genes followed by a marked and sustained downregulation of these genes in the liver and WAT (Fernø et al 2009;Jassim et al 2012).…”