Atypical antipsychotic drugs (AA) can cause rapid onset weight gain, insulin resistance, dyslipidemia and NAFLD. Although AA metabolic effects are often associated with obesity, acute AA treatment can cause whole body and hepatic insulin resistance in the absence of weight gain pre-clinically, indicating mechanisms distinct from chronic obesogenic effects of AA. Our aim was to identify pathways involved in AA-associated side effects by correlating differentially expressed traits common to acute AA-exposed mice and drug-exposed human cells using a multi-omic approach. C57BL/6J mice fed chow were treated daily with low, clinically relevant doses of risperidone (RIS; 1 mg/kg BW), olanzapine (OLAN; 5 mg/kg BW) or drug vehicle (VEH; 0.1% acetic acid) for 28 days. Drug treatment had no effect on body weight gain vs. VEH (P>0.05); however, hepatic steatosis was readily observed. Proteomic signatures were generated from hearts and livers of each treatment group, and differentially expressed (DE) proteins (P<0.05; RIS or OLAN vs. VEH) were catalogued. Drug-associated expression signatures consistent with immune disruption, insulin resistance, NAFLD, type 1 and type 2 diabetes occurred with both drugs. Significant (P<0.05) transcriptomic changes between human neuroblastoma cells exposed to 100 nM RIS or VEH were accessed from the Gene Expression Omnibus Database (GSE149611), and overlaid onto proteomic changes of RIS- and OLAN-treated mice. Over 65 pathways associated with metabolic and immune function, insulin resistance, and diabetes were disrupted in both the human and murine systems in the absence of weight gain. These data indicate that AA medications contribute directly to drug-induced immune dysregulation, NAFLD, and metabolic syndrome in patients, potentially via universal mechanisms of systemic dysregulation conserved across species.
M. May: None. M. Beauchemin: None. C. Vary: None. C. Bouchard: None. K. L. Houseknecht: None.
National Institutes of Health (DK095143)