Abstract
Olanzapine is a widely used atypical antipsychotic medication for treatment of schizophrenia and is often associated with serious metabolic abnormalities including weight gain and impaired glucose tolerance. These metabolic side effects are severe clinical problems but the underpinning mechanism remains poorly understood. Recently, growing evidence suggests that Wnt signaling pathway has a critical role in the pathogenesis of schizophrenia and molecular cascades of antipsychotics action, of which Wnt signaling pathway key effector TCF7L2 is strongly associated with glucose homeostasis. In this study, we aim to explore the characteristics of metabolic disturbance induced by olanzapine and to elucidate the role of TCF7L2 in this process. C57BL/6 mice were subject to olanzapine (4 mg/kg/day), or olanzapine plus metformin (150 mg/kg/day), or saline, respectively, for 8 weeks. Metabolic indices and TCF7L2 expression levels in liver, skeletal muscle, adipose, and pancreatic tissues were closely monitored. Olanzapine challenge induced remarkably increased body weight, fasting insulin, homeostasis model assessment-insulin resistance index, and TCF7L2 protein expression in liver, skeletal muscle, and adipose tissues. Notably, these effects could be effectively ameliorated by metformin. In addition, we found that olanzapine-induced body weight gain and insulin resistance actively influence the expression of TCF7L2 in liver and skeletal muscle, and elevated level of insulin determines the increased expression of TCF7L2 in adipose tissue. Our results demonstrate that TCF7L2 participates in olanzapine-induced metabolic disturbance, which presents a novel mechanism for olanzapine-induced metabolic disturbance and a potential therapeutic target to prevent the associated metabolic side effects.
Highlights
Schizophrenic patients possess an approximately 20% shortened lifespan compared with the general population
As indicated in the figure, the increase of mean body weight in mice was significantly higher in olanzapine group than control group at week 1 and week 8, treatment with metformin plus olanzapine significantly ameliorated the mean body weight increase induced by olanzapine at week 1 and week 8 (p = 0.032 and p = 0.018, respectively)
We explored the possible relationship between olanzapineinduced metabolic disturbance and TCF7L2 expression
Summary
Schizophrenic patients possess an approximately 20% shortened lifespan compared with the general population. One of the main causes of premature mortality is metabolic syndrome (MetS) (Hennekens et al, 2005; Raedler, 2010), which is twice higher in schizophrenia patients, featuring insulin resistance, glucose intolerance, dyslipidemia, hypertension, type 2 diabetes mellitus (T2DM), cardiovascular disease, and obesity (Rethelyi and Sawalhe, 2011). Due TCF7L2 and Olanzapine-Induced MetS to MetS (Ryan et al, 2003; Mathieu et al, 2009; Rheaume et al, 2009), the first-episode, drug-naïve patients present impaired glucose tolerance, insulin resistant, higher levels of plasma glucose (Ryan et al, 2003; Spelman et al, 2007), and increased visceral fat distribution (Thakore et al, 2002; Ryan et al, 2004). MetS is associated with increased risk of cardiovascular diseases and all-cause mortality (Lakka et al, 2002)
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