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Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole

International Journal of Obesity volume 34, pages 970–979 (2010)Cite this article

Subjects

Abstract

Objective:

In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ.

Design and Measurement:

C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg−1 body weight), alone or with APAP (30 mg kg−1 body weight) or THII (4.5 mg kg−1 body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined.

Results:

OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O2 uptake and H2O2 production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT.

Conclusions:

We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment.

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Acknowledgements

We thank Jennifer Schurdak for her technical assistance. This study was supported by NIEHS Center for Environmental Genetics Grant P30 ES06096 (HGS, MBG), and NIEHS training grants T32 ES117051 and T32 ES016646 (ELK). Funded also in part by NARSAD (HGS, MBG), the world's leading charity dedicated to mental health research, and through the University of Cincinnati Medical College Dean's Bridge Funds Program (MBG). Besides funding, there was no additional input from any funding source. All authors have made significant scientific contributions to the planning, experimentation and/or writing of this paper. All authors approved the final paper.

Author contributions: Howard G Shertzer: conceptualized the project, secured funding, and wrote the initial paper; Eric L Kendig: performed much of the experimentation and edited the paper; Henry A Nasrallah: contributed to the conceptualization of the study, and edited the paper; Elisabet Johansson: animal care and treatment, and implementation of experiments; Mary Beth Genter: helped conceive the project, secured funding, implemented experiments, edited and revised the paper.

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Authors and Affiliations

  1. Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA

    H G Shertzer, E L Kendig, E Johansson & M B Genter

  2. Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, OH, USA

    H A Nasrallah

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  1. H G Shertzer
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Correspondence to H G Shertzer.

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Shertzer, H., Kendig, E., Nasrallah, H. et al. Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole. Int J Obes 34, 970–979 (2010). https://doi.org/10.1038/ijo.2009.291

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