Abstract
Hypoxia inducible factor alpha (HIF1α) is associated with neuroprotection conferred by diet-induced ketosis, but the underlying mechanism remains unclear. In this study, we use a ketogenic diet in rodents to induce a metabolic state of chronic ketosis, as measured by elevated blood ketone bodies. Chronic ketosis correlates with neuroprotection in both aged and following focal cerebral ischemia and reperfusion (via middle cerebral artery occlusion, MCAO) in mouse and rat models. Ketone bodies are known to be used efficiently by the brain, and metabolism of ketone bodies is associated with increased cytosolic succinate levels that inhibits prolyl hydroxylases allowing HIF1α to accumulate. Ketosis also regulates inflammatory pathways, and HIF1α is reported to be essential for gene expression of interleukin 10 (IL10). Therefore, we hypothesized that ketosis-stabilized HIF1α modulates the expression of inflammatory cytokines orchestrating neuroprotection. To test changes in cytokine levels in rodent brain, 8-week-rats were fed either the standard chow diet (SD) or the KG diet for 4 weeks before ischemia experiments (MCAO) were performed and the brain tissues were collected. Consistent with our hypothesis, immunoblotting analysis shows IL10 levels were significantly higher in KG diet rat brain compared to SD, whereas the TNFα and IL6 levels were significantly lower in the brains of KG diet-fed group.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Puchowicz MA, Zechel JL, Valerio J et al (2008) Neuroprotection in diet-induced ketotic rat brain after focal ischemia. J Cereb Blood Flow Metab 28(12):1907–1916
Xu K, Ye L, Sharma K et al (2017) Diet-induced ketosis protects against focal cerebral ischemia in mouse. Adv Exp Med Biol 977:205–213
Zhang Y, Xu K, Kerwin T et al (2018) Impact of aging on metabolic changes in the ketotic rat brain: glucose, oxidative and 4-HNE metabolism. Adv Exp Med Biol 1072:21–25
Gasior M, Rogawski MA, Hartman AL (2006) Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol 17(5–6):431–439
Gibson CL, Murphy AN, Murphy SP (2012) Stroke outcome in the ketogenic state – a systematic review of the animal data. J Neurochem 123(Suppl 2):52–57
Sethuraman A, Brown M, Seagroves TN et al (2016) SMARCE1 regulates metastatic potential of breast cancer cells through the HIF1A/PTK2 pathway. Breast Cancer Res 18(1):81
Sethuraman A, Brown M, Krutilina R et al (2018) BHLHE40 confers a pro-survival and pro-metastatic phenotype to breast cancer cells by modulating HBEGF secretion. Breast Cancer Res 20(1):117
Cai Z, Luo W, Zhan H et al (2013) Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. Proc Natl Acad Sci U S A 110(43):17462–17467
Garcia JM, Stillings SA, Leclerc JL et al (2017) Role of Interleukin-10 in acute brain injuries. Front Neurol 8:244
Schaefer E, Wu W, Mark C et al (2017) Intermittent hypoxia is a proinflammatory stimulus resulting in IL-6 expression and M1 macrophage polarization. Hepatol Commun 1(4):326–337
Lobo-Silva D, Carriche GM, Castro AG et al (2016) Balancing the immune response in the brain: IL-10 and its regulation. J Neuroinflammation 13(1):297
Gurung P, Li B, Subbarao Malireddi RK et al (2015) Chronic TLR stimulation controls NLRP3 inflammasome activation through IL-10 mediated regulation of NLRP3 expression and caspase-8 activation. Sci Rep 5:14488
Verma R, Balakrishnan L, Sharma K et al (2016) A network map of Interleukin-10 signaling pathway. J Cell Commun Signal 10(1):61–67
Hutchins AP, Diez D, Miranda-Saavedra D (2013) The IL-10/STAT3-mediated anti-inflammatory response: recent developments and future challenges. Brief Funct Genomics 12(6):489–498
Acknowledgments
This study was supported by NIH grant R01 NS 38632; Mouse Metabolic Phenotyping Consortium (P&F 20497-21, MMPC).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Switzerland AG
About this chapter
Cite this chapter
Sethuraman, A., Rao, P., Pranay, A., Xu, K., LaManna, J.C., Puchowicz, M.A. (2021). Chronic Ketosis Modulates HIF1α-Mediated Inflammatory Response in Rat Brain. In: Nemoto, E.M., Harrison, E.M., Pias, S.C., Bragin, D.E., Harrison, D.K., LaManna, J.C. (eds) Oxygen Transport to Tissue XLII. Advances in Experimental Medicine and Biology, vol 1269. Springer, Cham. https://doi.org/10.1007/978-3-030-48238-1_1
Download citation
DOI: https://doi.org/10.1007/978-3-030-48238-1_1
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-48236-7
Online ISBN: 978-3-030-48238-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)