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: 3.97). 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.

Download full-text

Full-text

Available from: Robin Schmidt, Dec 23, 2013
  • Source
    • "When antipsychotic blood levels decrease, their direct actions on cholesterol biosynthesis enzymes are reversed resulting in a increased synthesis of cholesterol (Canfran-Duque et al., 2013; Lauressergues et al., 2011, 2010). The effect of antipsychotics in cholesterol biosynthesis in liver might also be related to the activation of AMPactivated protein kinase and mammalian target of rapamycin, which regulate nutrient metabolism in general (Schmidt et al., 2013). At the adipose tissue level, atypical antipsychotics stimulate the accumulation of cholesterol (Jassim et al., 2012), and adipocytes are a regulated source of cholesterol transfer to HDL both in vitro (3T3-L1 cells) and in vivo (mice) (Zhang et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of antipsychotic drugs for the treatment of mood disorders and psychosis has increased dramatically over the last decade. Despite its consumption being associated with beneficial neuropsychiatric effects in patients, atypical antipsychotics (which are the most frequently prescribed antipsychotics) use is accompanied by some secondary adverse metabolic effects such as weight gain, dyslipidemia and glucose intolerance. The molecular mechanisms underlying these adverse effects are not fully understood but have been suggested to involve a dysregulation of adipose tissue homeostasis. As such, the aim of this paper is to review and discuss the role of adipose tissue in the development of secondary adverse metabolic effects induced by atypical antipsychotics. Data analyzed in this article suggest that atypical antipsychotics may increase adipose tissue (particularly visceral adipose tissue) lipogenesis, differentiation/hyperplasia, pro-inflammatory mediator secretion and insulin resistance and decrease adipose tissue lipolysis. Consequently, patients receiving antipsychotic medication could be at risk of developing obesity, type 2 diabetes and cardiovascular disease. A better knowledge of the impact of these drugs on adipose tissue homeostasis may unveil strategies to develop novel antipsychotic drugs with less adverse metabolic effects and to develop adjuvant therapies (e.g. behavioral and nutritional therapies) to neuropsychiatric patients receiving antipsychotic medication. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.
    Full-text · Article · Dec 2014 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1–12: early acceleration, day 13–28: middle new equilibrium, and day 29–36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity.
    Full-text · Article · Apr 2014 · Psychoneuroendocrinology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Olanzapine is a second generation antipsychotic. A common side effect in humans is weight gain, but the mechanisms are mostly unknown. Aim To study the effects of subchronic olanzapine treatment on body weight, fasting plasma glucose (FPG), fasting insulin (FINS), C-peptide, insulin sensitivity index (ISI), and expression of glucose transporter 2 (GLUT2) in rat pancreatic β cells. Materials and methods Female Sprague-Dawley rats were randomly divided into two groups: the olanzapine-treated group and the control group (each n = 8). Rats in the olanzapine-treated group intragastrically received olanzapine 5 mg/kg/day for 28 days; the rats in the control group received the same volume of vehicle. FPG and body weight were measured on the 1st, 7th, 14th and 28th day. FINS and C-peptide were measured using immunoradiometric assays at baseline and on the 28th day. GLUT2 mRNA and protein expressions in pancreatic β cells were analyzed by RT-PCR and western blot. Results Olanzapine-treated rats had higher body weight (227.4 ± 8.9 vs. 211.0 ± 9.9 g), FPG (5.86 ± 0.42 vs. 4.24 ± 0.29 mmol/L), FINS (17.34 ± 3.64 vs. 10.20 ± 1.50 µIU/mL), and C-peptide (0.154 ± 0.027 vs. 0.096 ± 0.009 ng/mL) than those in controls (all P < 0.05) at the 28th day. Pancreatic β cells of the olanzapine-treated group showed lower ISI (−4.60 ± 0.23 vs. −3.76 ± 0.20) and GLUT2 levels (mRNA: 1.12 ± 0.02 vs. 2.00 ± 0.03; protein: 0.884 ± 0.134 vs. 1.118 ± 0.221) than those in controls (all P < 0.05). Conclusions Subchronic olanzapine treatment inhibited expression of GLUT2 in rat pancreatic β cells. Therefore, it may disturb glucose metabolism via the insulin resistance of β cells, but confirmation in humans is needed.
    No preview · Article · Jun 2014 · Journal of endocrinological investigation
Show more