Molecular Insights into Divergent Effects of Second-Generation Antipsychotics on Human Adipocyte Metabolism

Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effect (e.g. obesity and type 2 diabetes). We investigated the effects of SGAs on adipocyte differentiation and metabolism. The presence of therapeutic concentrations of aripiprazole (ARI) or its active metabolite dehydroaripiprazole (DARI) during human adipocyte differentiation impaired adipocyte glucose metabolism while the expression of gene markers of fatty acid oxidation was increased. Additionally, supra-therapeutic concentration of ARI inhibited adipocyte differentiation. Furthermore, OLA, a highly obesogenic SGA, directly increased leptin mRNA expression but did not affect adipocyte differentiation and metabolism. These molecular insights are novel, and suggest that ARI, but not OLA, may directly act via alterations in adipocyte differentiation and by causing a switch from glucose to lipid utilization in human adipocytes. Additionally, SGAs may affects crosstalk with other organs, such as the brain, to exert their adverse metabolic effects.