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A natural Nrf2 activator glucoraphanin improves hepatic steatosis in high-fat diet-induced obese male mice associated with AMPK activation

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Abstract

Genetic and pharmacological activation of the transcription factor nuclear factor, erythroid derived 2, like 2 (Nrf2) alleviates high-fat diet (HFD)-induced obesity in mice; however, synthetic Nrf2 activators are not clinically available due to safety concerns. Dietary glucoraphanin (GR), a naturally occurring compound found in cruciferous vegetables that activates Nrf2 and induces its target antioxidant genes. We previously demonstrated that GR increased thermogenesis and mitigated HFD-induced obesity in lean healthy mice. In this study, we investigated the therapeutic effects of GR on pre-existing obesity and associated metabolic disorders, such as hepatic steatosis, with or without low-fat dietary intervention. Eight-week-old male C57BL/6J mice were fed an HFD for 9 weeks to induce obesity. Subsequently, these obese mice were fed either the HFD or a normal chow diet, supplemented with or without GR, for an additional 11 weeks. GR supplementation did not decrease the body weight of HFD-fed mice; however, it significantly reduced plasma alanine aminotransferase and aspartate aminotransferase levels and hepatic triglyceride accumulation. These improvements in liver damage by GR were associated with decreased expression levels of fatty acid synthesis genes and proinflammatory chemokine genes, suppressed c-Jun N-terminal kinase activation, and reduced proinflammatory phenotypes of macrophages in the liver. Moreover, metabolome analysis identified increased hepatic levels of adenosine 5′-monophosphate (AMP) in HFD-GR mice compared with those in HFD mice, which agreed with increased phosphorylation levels of AMP-activated protein kinase. Our results show that GR may have a therapeutic potential for treating obesity-associated hepatic steatosis.

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Acknowledgements

The authors would like to thank Dr. Tsuguhito Ota for kindly supporting this project. The authors thank H Akutsu (Asahikawa Medical University, Asahikawa, Japan) for technical assistance of GC-MS analysis. The authors also thank M Ishiguro and C Hasegawa (Asahikawa Medical University, Asahikawa, Japan), M Nakayama and K Hara (Kanazawa University, Kanazawa, Japan) for technical assistance and the care of animals. Parts of the data in this article were presented at IDF conference December 2021 (IDF21-0354).

Funding

This work was supported by a grant Grant-in-Aid for Scientific Research (C) (15K00813 for N.N.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Division of Diabetes, Department of Internal Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa, 078-8510, Japan

    Suratsawadee Promsuwan, Kazuki Sawamoto & Yumi Takiyama

  2. School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Liang Xu

  3. Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, Kanazawa, 920-0942, Japan

    Mayumi Nagashimada

  4. Department of Cellular and Molecular Function Analysis, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8640, Japan

    Naoto Nagata

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  1. Suratsawadee Promsuwan
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  2. Kazuki Sawamoto
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  4. Mayumi Nagashimada
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Contributions

SP, KS, MN, and LX performed experiments and collected and analyzed data. SP and KS wrote first draft of the manuscript. SP, NN and YT contributed to discussions and edited the manuscript. YT supervised the project. All authors reviewed and accepted the final version of the manuscript.

Corresponding author

Correspondence to Yumi Takiyama.

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Conflict of interest

Y.T. was supported by several foundational grants, including grants from Nippon Boehringer Ingelheim Co., Ltd., Taisho Pharmaceutical Co., Ltd., Ono pharmaceutical Co., Ltd. From October 2019 to September 2021, K.S. was belonged to the Division of Diabetes and Lifestyle Diseases Prevention and Therapeutics, an endowed course at Asahikawa Medical University, which was run with donations from Ono pharmaceutical Co., Ltd, Taisho Pharmaceutical Co., Ltd., and Nippon Boehringer Ingelheim Co., Ltd. No other potential conflicts of interest relevant to this article were reported.

Compliance with ethical standards

All animal procedures were approved by the Kanazawa University Animal Care and Use Committee (date of approval: September 5, 2013, approved number: AP-132930) and were performed in accordance with the standards set forth in the guidelines and regulations for the Care and Use of Laboratory Animals at Kanazawa University. This study does not contain any studies with human subjects performed by any of the authors.

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Promsuwan, S., Sawamoto, K., Xu, L. et al. A natural Nrf2 activator glucoraphanin improves hepatic steatosis in high-fat diet-induced obese male mice associated with AMPK activation. Diabetol Int 15, 86–98 (2024). https://doi.org/10.1007/s13340-023-00658-6

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