The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model

PLoS One. 2015 Jun 17;10(6):e0130357. doi: 10.1371/journal.pone.0130357. eCollection 2015.


Background: The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.

Methods: To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.

Results: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

Conclusions: The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 4 / genetics
  • Aquaporin 4 / metabolism
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / diet therapy
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases / genetics
  • Carbonic Anhydrases / metabolism
  • Cell Membrane Permeability
  • Diet, Ketogenic*
  • Disease Models, Animal
  • Female
  • Glioma / blood supply
  • Glioma / diet therapy*
  • Glioma / metabolism*
  • Glioma / pathology
  • Hypoxia / diet therapy
  • Hypoxia / metabolism*
  • Hypoxia / pathology
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Immunoenzyme Techniques
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / diet therapy
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Zonula Occludens-1 Protein / genetics
  • Zonula Occludens-1 Protein / metabolism


  • Aqp4 protein, mouse
  • Aquaporin 4
  • Biomarkers, Tumor
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NF-kappa B
  • RNA, Messenger
  • Tjp1 protein, mouse
  • Vascular Endothelial Growth Factor A
  • Zonula Occludens-1 Protein
  • Matrix Metalloproteinase 2
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • Car9 protein, mouse

Grants and funding

This work was supported by an unrestricted grant from Students Supporting Brain Tumor Research ( The authors also received a grant-in-kind from Nutricia Advanced Medical Nutrition through Nutricia North America (, who provided KetoCal and the Remi Savioz GLUT1 Foundation ( who provided the blood analysis equipment. The funders had no role in data collection and analysis, decision to publish or preparation of the manuscript, or the study design. No additional external funding was received for this study.