The ketogenic diet increases mitochondrial uncoupling protein levels and activity

Ann Neurol. 2004 Apr;55(4):576-80. doi: 10.1002/ana.20062.


Fatty acids are known to enhance mitochondrial uncoupling protein (UCP) activity. We asked whether a high-fat ketogenic diet (KD) increases UCP levels and activity in hippocampi of juvenile mice. Maximum mitochondrial respiration rates were significantly (p < 0.001) higher in KD- versus standard diet (SD)-treated animals, indicating increased UCP-mediated proton conductance that can reduce reactive oxygen species (ROS) production. Western blots showed significant (p < 0.05) or borderline significant increases in UCP2, UCP4, and UCP5 protein levels, and increased immunoreactivity to these three UCP isoforms was most prominently seen in the dentate gyrus of KD-fed mice. Finally, we found that oligomycin-induced ROS production was significantly (p < 0.05) lower in KD-fed mice than in SD controls. Collectively, our data suggest that a KD may exert neuroprotective effects by diminishing ROS production through activation of mitochondrial UCPs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / biosynthesis*
  • Carrier Proteins / genetics
  • Dietary Fats / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Ion Channels
  • Ketones / pharmacology*
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C3H
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Mitochondrial Proteins
  • Reactive Oxygen Species / metabolism
  • Uncoupling Protein 1


  • Carrier Proteins
  • Dietary Fats
  • Ion Channels
  • Ketones
  • Membrane Proteins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Uncoupling Protein 1