Article

Olanzapine Activates Hepatic Mammalian Target of Rapamycin: New Mechanistic Insight into Metabolic Dysregulation with Atypical Antipsychotic Drugs

University of Louisville
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.86). 08/2013; 347(1). DOI: 10.1124/jpet.113.207621
Source: PubMed

ABSTRACT Olanzapine (OLZ) is an effective treatment for schizophrenia and other disorders, but causes weight gain and metabolic syndrome. Most studies to date have focused on potential effects of OLZ on CNS mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in systemic effects of OLZ. The purpose of this study was to therefore investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg/d) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for GCxGC-TOF MS metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a 'pseudo-fasted' state, which depleted hepatic glycogen reserves; OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMPK signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mTOR) pathways, and yield new insight into the metabolic side effects of this drug.

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Available from: Robin Schmidt, Dec 23, 2013
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