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Obesity Drives Delayed Infarct Expansion, Inflammation, and Distinct Gene Networks in a Mouse Stroke Model

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Abstract

Obesity is associated with chronic peripheral inflammation, is a risk factor for stroke, and causes increased infarct sizes. To characterize how obesity increases infarct size, we fed a high-fat diet to wild-type C57BL/6J mice for either 6 weeks or 15 weeks and then induced distal middle cerebral artery strokes. We found that infarct expansion happened late after stroke. There were no differences in cortical neuroinflammation (astrogliosis, microgliosis, or pro-inflammatory cytokines) either prior to or 10 h after stroke, and also no differences in stroke size at 10 h. However, by 3 days after stroke, animals fed a high-fat diet had a dramatic increase in microgliosis and astrogliosis that was associated with larger strokes and worsened functional recovery. RNA sequencing revealed a dramatic increase in inflammatory genes in the high-fat diet-fed animals 3 days after stroke that were not present prior to stroke. Genetic pathways unique to diet-induced obesity were primarily related to adaptive immunity, extracellular matrix components, cell migration, and vasculogenesis. The late appearance of neuroinflammation and infarct expansion indicates that there may be a therapeutic window between 10 and 36 h after stroke where inflammation and obesity-specific transcriptional programs could be targeted to improve outcomes in people with obesity and stroke.

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Acknowledgments

This work used the Genome Sequencing Service Center by Stanford Center for Genomics and Personalized Medicine Sequencing Center, supported by NIH S10OD020141.

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke, RO1 NS067132 (Buckwalter) and NRSA F32 NS089162 (Peterson), and by a Brain Health Frontiers Award from the American Heart Association and the Paul Allen Frontiers Group. (Buckwalter)

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Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford School of Medicine, Palo Alto, CA, USA

    Todd C. Peterson, Kendra J. Lechtenberg, Tawaun A. Lucas & Marion S. Buckwalter

  2. Department of Psychology, University of North Carolina Wilmington, Wilmington, NC, USA

    Todd C. Peterson

  3. Department of Genetics, Stanford School of Medicine, Palo Alto, CA, USA

    Brian D. Piening, Eric Wei, Hassan Chaib & Michael Snyder

  4. Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA

    Brian D. Piening & Alexa K. Dowdell

  5. Department of Neurosurgery, Stanford School of Medicine, Palo Alto, CA, USA

    Marion S. Buckwalter

  6. Department of Neurology and Neurological Sciences and Department of Neurosurgery, Stanford University, P209 MSLS Building, 1201 Welch Road, Stanford, CA, 94305, USA

    Marion S. Buckwalter

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  1. Todd C. Peterson
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  2. Kendra J. Lechtenberg
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  9. Marion S. Buckwalter
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Marion S. Buckwalter designed and performed the research, analyzed the data, and wrote the paper. Todd C. Peterson designed and performed the research, analyzed the data, and wrote the paper. Kendra J. Lechtenberg designed and performed the research and analyzed the data. Brian D. Piening designed and performed the research and analyzed the data. Tawaun A. Lucas designed and performed the research and analyzed the data. Eric Wei analyzed the data. Hassan Chaib analyzed the data. Alexa K. Dowdell analyzed the data. Michael Snyder designed the research and analyzed the data.

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Correspondence to Marion S. Buckwalter.

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All applicable international, national, and/or institutional guidelines for the care and use for animals were followed. All use and care of animals was approved by UNCW IACUC protocol number A1819-01.

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Peterson, T.C., Lechtenberg, K.J., Piening, B.D. et al. Obesity Drives Delayed Infarct Expansion, Inflammation, and Distinct Gene Networks in a Mouse Stroke Model. Transl. Stroke Res. 12, 331–346 (2021). https://doi.org/10.1007/s12975-020-00826-9

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  • DOI: https://doi.org/10.1007/s12975-020-00826-9

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