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HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor

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Abstract

Objective

Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits. This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet (HFD) and explored the involvement of endoplasmic reticulum (ER) stress.

Methods

Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine (3 mg/kg/day) and the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 1 and 0.5 g/kg/day) for 8 days. Changes in body weight, food intake, and plasma lipids were assessed. Hepatic fat accumulation was evaluated using oil red O staining. Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), and proopiomelanocortin (POMC) in the hypothalamus or liver.

Results

Compared to olanzapine alone, olanzapine+HFD induced greater weight gain, increased hyperlipidemia, and enhanced hepatic fat accumulation (P<0.05). Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects (P<0.05). Further mechanistic investigations revealed that olanzapine alone activated ER stress, upregulated NLRP3 expression in the hypothalamus and liver, and downregulated hypothalamic POMC expression. The HFD exacerbated these effects by 50%–100%. Moreover, co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress, NLRP3, and POMC expression in the hypothalamus and liver (P<0.05).

Conclusion

HFD worsened olanzapine-induced weight gain and lipid metabolic disorders, possibly through ER stress-POMC and ER stress-NLRP3 signaling. ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.

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Authors and Affiliations

  1. School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, 430070, China

    Yu-feng Zuo, Ming-rui Guo, Ben-ben Li, Bao-cui Wang, Deng Duan, Yu-xin Wang, Jing Xi, Meng He & Tao-lei Sun

  2. The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital & the Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China

    Bao-hua Zhang

  3. Hubei Key Laboratory of Nanomedicine for Neurodegenerative Diseases, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, China

    Meng He & Tao-lei Sun

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  1. Yu-feng Zuo
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Correspondence to Meng He or Tao-lei Sun.

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This work was supported by grants from the Natural Science Foundation of Hubei Province (No. 2021CFB301 and No. 2021CFB299), and the State Key Laboratory of Advanced Technology for Materials Synthesis and Processing (WUT) (No. 2022-KF-27).

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Zuo, Yf., Zhang, Bh., Guo, Mr. et al. HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor. CURR MED SCI 43, 1116–1132 (2023). https://doi.org/10.1007/s11596-023-2781-y

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