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Chronic high-fat diet consumption exacerbates pyroptosis- and necroptosis-mediated HMGB1 signaling in the brain after ischemia and reperfusion injury

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Abstract

Obesity is categorized as a common comorbidity found in people who experience an ischemic stroke. However, the mechanisms to explain this correlation have still not been elucidated fully. Pyroptosis and necroptosis are novel forms of programmed cell death that occur upon intracellular danger signals. The major feature of pyroptosis and necroptosis is damage to the lipid membrane, which consequently results in lytic cell death and allows the release of high mobility group box protein 1 (HMGB1) into the extracellular space. We aimed to investigate the influences of high-fat diet (HFD) consumption on cerebral ischemia and reperfusion (I/R) injury and hypothesized that HFD consumption exacerbated the activation of pyroptosis, necroptosis, and HMGB1 signaling pathways. All rats received normal diet (ND) or HFD for 16 weeks. Subsequently, both groups were divided into either a sham- or an I/R-operated group. Twenty-four hours after the surgery, all rats were evaluated for neurological deficits and then sacrificed. After I/R injury, there were more severe functional deficits and larger brain infarcts in the HFD compared with the ND group. The histological observation revealed an increase in tissue abnormalities in the HFD group, consistent with the massive reduction of intact neurons along the peri-infarct region. Furthermore, cerebral I/R injury dramatically activated the pyroptotic, necroptotic, and HMGB1 signaling pathways in HFD-fed rats compared with ND-fed rats. These findings suggest that chronic HFD consumption worsens ischemic brain pathology and leads to poor post-stroke outcomes by exacerbating pyroptotic and necroptotic cell death.

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Funding

This study was supported by Functional Food Research Center for Well-Being, Chiang Mai University and the Royal Golden Jubilee PhD program (grant number PHD/0104/2561).

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Nuttapong Yawoot, Wijitra Chumboatong & Jiraporn Tocharus

  2. Graduate School, Chiang Mai University, Chiang Mai, 50200, Thailand

    Nuttapong Yawoot

  3. Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Jirakhamon Sengking & Chainarong Tocharus

  4. Functional Food Research Center for Well-Being, Chiang Mai University, Chiang Mai, 50200, Thailand

    Jiraporn Tocharus

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  1. Nuttapong Yawoot
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Contributions

The authors declare that all data were generated in-house and that no paper mill was used. Jiraporn Tocharus designed the conception in this study; Nuttapong Yawoot performed experiments and collected data; Wijitra Chumboatong and Jirakhamon Sengking performed experiments; Nuttapong Yawoot, Chainarong Tocharus, and Jiraporn Tocharus performed data analysis and investigation; Nuttapong Yawoot performed an original draft of manuscript; Nuttapong Yawoot, Chainarong Tocharus, and Jiraporn Tocharus edited and reviewed the manuscript. All authors read and approved for the final draft of the manuscript.

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Correspondence to Jiraporn Tocharus.

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All experimental procedures in animals were carried out according to a protocol approved by the Laboratory Animal Center, Chiang Mai University, Thailand, following the guidelines established by the National Institutes of Health.

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Key points

1. Obesity promoted an increase in brain infarct volume and worsened neurological outcomes after cerebral ischemia and reperfusion injury.

2. Obesity exacerbated pyroptotic and necroptotic cell death after cerebral ischemia and reperfusion injury.

3. Obesity exacerbated the HMGB1/TLR4/NF-κB signaling pathway after cerebral ischemia and reperfusion injury.

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Yawoot, N., Chumboatong, W., Sengking, J. et al. Chronic high-fat diet consumption exacerbates pyroptosis- and necroptosis-mediated HMGB1 signaling in the brain after ischemia and reperfusion injury. J Physiol Biochem 78, 833–844 (2022). https://doi.org/10.1007/s13105-022-00906-4

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