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. 2013 Jan 15;3(1):e208.
doi: 10.1038/tp.2012.138.

Haloperidol and olanzapine mediate metabolic abnormalities through different molecular pathways

V Mondelli  1 , C Anacker, A C Vernon, A Cattaneo, S Natesan, M Modo, P Dazzan, S Kapur, C M Pariante
Affiliations

Haloperidol and olanzapine mediate metabolic abnormalities through different molecular pathways

V Mondelli et al. Transl Psychiatry. .

Abstract

The pathogenesis of antipsychotic-induced disturbances of glucose homeostasis is still unclear. Increased visceral adiposity has been suggested to be a possible mediating mechanism. The aim of this study was to investigate, in an animal model, the differential effects of olanzapine and haloperidol on visceral fat deposition (using magnetic resonance imaging(MRI)) and on critical nodes of the insulin signaling pathway (liver-protein levels of IRS2 (insulin receptor substrate 2), GSK3α (glycogen synthase kinase-3α), GSK3β, GSK3α-Ser21, GSK3β-Ser9). To this end, we studied male Sprague-Dawley rats treated with vehicle (n=8), haloperidol (2 mg kg(-1) per day, n=8), or olanzapine (10 mg kg(-1)per day, n=8), using osmotic minipumps, for 8 weeks. The haloperidol group showed a higher percentage of visceral fat than both the olanzapine group and the vehicle group, whereas there was no difference between the olanzapine and the vehicle group. In terms of insulin signaling pathway, the olanzapine group showed significantly reduced IRS2 levels, reduced phosphorylation of GSK3α and increased phosphorylation of GSK3β, whereas there was no difference between the haloperidol and the vehicle group. Our data suggest that different molecular pathways mediate the disturbances of glucose homeostasis induced by haloperidol and olanzapine with a direct effect of olanzapine on the insulin molecular pathway, possibly partly explaining the stronger propensity of olanzapine for adverse effects on glucose regulation when compared with haloperidol in clinical settings.

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Figures

Figure 1
Figure 1
Visceral fat assessed by T2-weighted MRI in vehicle, olanzapine- and haloperidol-treated rats.
Figure 2
Figure 2
Hepatic IRS2 protein levels in olanzapine and vehicle group (P=0.02), and in haloperidol and vehicle group (P>0.05). IRS2 blots were normalized to beta-actin.
Figure 3
Figure 3
Hepatic levels of GSK3α, phosphorylated Ser21-GSK3α, GSK3β and phosphorylated Ser9-GSK3β in olanzapine and vehicle group. Olanzapine group showed significantly reduced phosphorylation of GSK3α (P=0.05), and increased phosphorylation of GSK3β (P=0.05) when compared with vehicle group. Blots for GSK3α and GSK3β were normalized to beta-actin. Blots for Ser21-GSK3α and Ser9-GSK3β were normalized to unphosphorylated GSK3α and GSK3β, respectively.
Figure 4
Figure 4
Hepatic levels of GSK3α, phosphorylated Ser21-GSK3α, GSK3β and phosphorylated Ser9-GSK3β in haloperidol and vehicle group. No significant difference was found in GSK3α, GSK3 β, or in phosphorylated Ser21-GSK3α and Ser9-GSK3β between the haloperidol and the vehicle group (P>0.05). Blots for GSK3α and GSK3β were normalized to beta-actin. Blots for Ser21-GSK3α and Ser9-GSK3β were normalized to unphosphorylated GSK3α and GSK3β, respectively.
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