Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls (p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology.

Mood spectrum disorders and medications used to treat these disorders, such as atypical antipsychotic drugs (AA), are associated with metabolic and endocrine side effects including obesity, dyslipidemia, hyperglycemia and increased risk of fractures. Antidepressant medications, including selective serotonin reuptake inhibitors (SSRI), have also been reported to increase fracture risk in some patients. The pharmacology underlying the increased risk of fractures is currently unknown. Possible mechanisms include alternations in dopaminergic and/or serotonergic signaling pathways. As these medications distribute to the bone marrow as well as to the brain, it is possible that drug-induced fractures are due to both centrally mediated effects as well as direct effects on bone turnover. Given the growing patient population that is prescribed these medications for both on- and off-label indications, understanding the level of risk and the mechanisms underlying drug-induced fractures is important for informing both prescribing and patient monitoring practices.

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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&gt;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&lt;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&lt;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. Disclosure M. May: None. M. Beauchemin: None. C. Vary: None. C. Bouchard: None. K. L. Houseknecht: None. Funding National Institutes of Health (DK095143)

The absence of T‐cell death‐associated gene 51 (TDAG51) in mice results in late‐onset insulin resistance (IR), obesity and hepatic steatosis. In support of these findings, mice fed a high fat diet, which leads to IR and obesity, as well as the leptin‐deficient mouse model, a well‐established genetic model of type 2 diabetes and obesity, show significantly diminished hepatic TDAG51 protein levels. Here we report that hepatic TDAG51 protein levels are reduced in multiple mouse models of liver injury and in liver biopsies from patients with non‐alcoholic steatohepatitis. Given that hepatic TDAG51 protein levels decrease under conditions of fatty liver and correlate with IR, we investigated whether restoring hepatic TDAG51 protein levels would reverse hepatic IR. Hepatic expression of a TDAG51‐GFP fusion protein was increased via a liver‐specific adeno‐associated virus (AAV) in both TDAG51 knockout and leptin‐deficient mice. Restoration of hepatic TDAG51 protein increased insulin sensitivity and reduced weight gain compared to mice injected with a control AAV vector encoding only GFP. Specifically, TDAG51 knockout mice expressing ectopic TDAG51 demonstrated: 1) improved Akt473 phosphorylation, 2) reduced expression of diacylglycerol O‐acyltransferase, which catalyzes the final step in triglyceride biosynthesis, and 3) reduced expression of the SREBP‐1c target genes, fatty acid synthase and stearoyl‐CoA desaturase‐1. These findings demonstrate that restoring hepatic TDAG51 in mouse models of metabolic disease and fatty liver improves hepatic insulin signaling and reduces weight gain. However, this protective effect is lost over time, correlates with fatty liver progression and is accompanied by diminished hepatic TDAG51 protein stability. Taken together, these studies suggest that hepatic TDAG51 is an important factor that mediates insulin signaling and weight gain. Future studies aimed at increasing hepatic TDAG51 protein levels and/or stability may represent a new therapeutic opportunity for the amelioration of obesity and augmentation of insulin sensitivity in non‐alcoholic fatty liver disease.Support or Funding InformationR.C.A is supported by grants from the Heart and Stroke Foundation of Ontario and the Canadian Institutes of Health Research. Financial support from St. Joseph's Healthcare Hamilton is also acknowledged. R.C.A. is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds the Amgen Canada Research Chair in Nephrology. K.N.M acknowledges financial support from the William R. Hummel Homocystinuria Research Fund and holds the Ehst‐Hummel‐Kaufmann Family Endowed Chair in Inherited Metabolic Disease. G.R.S is supported by a Canada Research Chair in Metabolism and Obesity, the J. Bruce Duncan Endowed Chair in Metabolic Diseases and grants from the Canadian Institutes of Health Research and Diabetes Canada.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.