Olanzapine-Induced Activation of Hypothalamic Astrocytes and Toll-Like Receptor-4 Signaling via Endoplasmic Reticulum Stress Were Related to Olanzapine-Induced Weight Gain.

Meng He,Ying Zhang,Kun Qian,Hao Xie,Guanbin Gao,Chao Deng,Xu-Feng Huang,Jing Li,Baohua Zhang,Taolei Sun

doi:10.3389/fnins.2020.589650

Abstract

The antipsychotic drug olanzapine is associated with serious obesity side effects. Hypothalamic astrocytes and associated toll-like receptor-4 (TLR4) signaling play an essential role in obesity pathogenesis. This study investigated the effect of olanzapine on astrocytes and TLR4 signaling both in vitro and in the rat hypothalamus and their potential role in olanzapine-induced weight gain. We found that olanzapine treatment for 24 h dose-dependently increased cell viability, increased the protein expression of astrocyte markers including glial fibrillary acidic protein (GFAP) and S100 calcium binding protein B (S100B), and activated TLR4 signaling in vitro. In rats, 8- and 36-day olanzapine treatment caused weight gain accompanied by increased GFAP and S100B protein expression and activated TLR4 signaling in the hypothalamus. These effects still existed in pair-fed rats, suggesting that these effects were not secondary effects of olanzapine-induced hyperphagia. Moreover, treatment with an endoplasmic reticulum (ER) stress inhibitor, 4-phenylbutyrate, inhibited olanzapine-induced weight gain and ameliorated olanzapine-induced changes in hypothalamic GFAP, S100B, and TLR4 signaling. The expression of GFAP, S100B, and TLR4 correlated with food intake and weight gain. These findings suggested that olanzapine-induced increase in hypothalamic astrocytes and activation of TLR4 signaling were related to ER stress, and these effects may be related to olanzapine-induced obesity.

Highlights

Antipsychotics, in particular olanzapine, are the most commonly used medications in the treatment of schizophrenia (Lieberman et al, 2005)
To further investigate whether olanzapine’s effects on astrocytes were specific for astrocytes or systematic effects, we have examined the effect of olanzapine treatment on the cell viability of PC12 cells
In order to investigate whether changes in the hypothalamic astrocytes and toll-like receptor-4 (TLR4) signaling were secondary to the elevated food intake induced by olanzapine, we examined the expression of astrocyte markers and TLR4 signaling in pair-fed rats treated with olanzapine or vehicle

Summary

Introduction

Antipsychotics, in particular olanzapine, are the most commonly used medications in the treatment of schizophrenia (Lieberman et al, 2005). Olanzapine treatment induces significant weight gain/obesity side effects (Albaugh et al, 2006; Salviato Balbao et al, 2014; Li et al, 2018). Chemogenetic selective activation of astrocytes in the dorsomedial hypothalamus (DMH) counter mediated ghrelin-induced hyperphagia (Yang et al, 2015). Activated astrocytes have been detected in the hypothalamus of high-fat diet (HFD)-induced obesity rodents (Thaler et al, 2012; Buckman et al, 2013, 2015) and were related to weight gain (Thaler et al, 2012). To further understand the causes of olanzapine-induced obesity and develop novel effective therapeutics in preventing this side effect, it is crucial to understand the role of hypothalamic astrocytes in olanzapineinduced obesity

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Results

Conclusion