Experiments were performed in 3T3-L1 preadipocytes differentiated in vitro into adipocytes. Cells were treated with olanzapine and a 5-lipoxygenase (5-LOX) activating protein (FLAP) inhibitor MK-886. Lipid content was measured using an Oil Red O assay; 5-LOX and FLAP mRNA content was measured using quantitative real-time PCR; the corresponding protein contents were measured using quantitative Western blot assay. Olanzapine did not affect the cell content of 5-LOX mRNA and protein; it decreased FLAP mRNA and protein content at day five but not 24 hours after olanzapine addition. In the absence of MK-886, low concentrations of olanzapine increased lipid content only slightly, whereas a 56% increase was induced by 50？μM olanzapine. A 5-day cotreatment with 10？μM MK-886 potentiated the lipid increasing action of low concentrations of olanzapine. In contrast, in the presence of 50？μM olanzapine nanomolar and low micromolar concentrations of MK-886 reduced lipid content. These data suggest that FLAP system in adipocytes is affected by olanzapine and that it may modify how these cells respond to the second-generation antipsychotic drugs (SGADs). Clinical studies could evaluate whether the FLAP/5-LOX system could play a role in setting a variable individual susceptibility to the metabolic side effects of SGADs. 1. Introduction Serious side effects hamper pharmacological treatment of psychiatric illnesses such as schizophrenia and bipolar disorder. All currently used second-generation antipsychotic drugs (SGADs) including olanzapine are capable of triggering significant weight gain associated with adverse metabolic alterations [1, 2]. It has been proposed that these side effects are caused by a combination of factors including increased fat deposition [3] and appetite stimulation [4]. Interestingly, it was noted that SGADs are capable of increasing adiposity even in the absence of significant body weight gain [5–7] presumably by drug-impaired lipolysis [7, 8] and/or a direct stimulatory action of SGADs on adipocytes [9–11]. In the therapy of psychiatric patients with SGADs, a better understanding of the mechanisms that lead to this clinical problem is needed to identify the risk factors that facilitate and exacerbate these side effects of SGADs and to develop methods and therapies to prevent and/or treat their occurrence. Recently, an in vitro model of 3T3-L1 cells has been developed to study the effects of olanzapine on peripheral adipogenesis [10]. Unrelated studies with this cell culture model have shown that the enzymatic pathway of 5-lipoxygenase (5-LOX),
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