Energy Balance During Ketosis in Rat Brain

Summary

Principal Investigator: JOSEPH CHARLES LAMANNA
Abstract: DESCRIPTION (provided by applicant): The uptake and metabolism of ketone bodies in brain have been of interest to researchers and clinicians for decades but how they affect the coupling of blood flow and glucose metabolism, especially during chronic ketotic conditions, remains unclear. Although glucose is considered the primary fuel for brain, ketones supplement brain metabolism, especially under conditions of glucose sparing, such as fasting, starvation or high fat-low carbohydrate diet. The enzymes for ketone metabolism and the monocarboxylate transporters at the blood brain barrier are known to increase with fasting or ketogenic diet. It is known that cerebral ischemia, such as stroke (induced by cardiac arrest and resuscitation), results in altered glucose metabolism, the reduction of intracellular energy metabolites such as ATP, ADP and phosphocreatine and the accumulation of metabolic intermediates, such as lactate and adenosine. Degree of recovery of neurologic function following stroke (oxidative stress) is limited by the ability of the central nervous system to recover from an ischemic event. Based on our experiences we have developed the working hypothesis that ketones are effective against pathology associated with oxidative stress and/or altered glucose metabolism. The rationale is ketosis stabilizes glucose metabolism through the normalization of redox (lactate/pyruvate ratio) in brain. One potential mechanism is that ketone body metabolism differs from glucose such that when oxidized, acetyl-CoA units enter the Krebs-TCA cycle at the level of citrate bypassing glycolysis (the step after pyruvate dehydrogenase complex which is often a metabolic block following oxidative stress) and through feed-back regulation is known to down regulate glycolytic rates at the level of citrate, phosphofructokinase or hexokinase. Another proposed mechanism may be that ketosis facilitates anaplerosis (replenishment of the Krebs-TCA cycle intermediates) after oxidative challenges, a mechanism for neuroprotection. To investigate the effects of ketosis on cerebral metabolic rate for glucose (CMRglu) imaging modalities, such as PET analysis, and an in vivo rat model of ketosis will be used to determine if ketosis improves CMRglu and metabolic outcome following cardiac arrest and resuscitation. PUBLIC HEALTH RELEVANCE: Fasting, prolonged starvation or consumption of high fat-low carbohydrate diet (ketogenic diet) is known to result in ketosis and has been used for the treatment of intractable epilepsy, especially where the seizures are caused by insufficient glucose transport into the brain. Based on animal studies, ketosis has been suggested to possess neuroprotective properties against neurodegenerative diseases such as Alzheimer's, Parkinson's and recovery from focal stroke. However, there has been little progress in developing therapies that optimize ketosis as an approach to the medical treatment of neurodegenerative diseases, and, therefore, we would like to investigate the effects of ketosis on brain metabolism of glucose (CMRglu) using image (PET) analysis in ketotic rat and to determine if there is improved outcome following cardiac arrest and resuscitation.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. ncbi Contribution of brain glucose and ketone bodies to oxidative metabolism
    Yifan Zhang
    Departments of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
    Adv Exp Med Biol 765:365-70. 2013
  2. pmc Ketosis proportionately spares glucose utilization in brain
    Yifan Zhang
    Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 4954, USA
    J Cereb Blood Flow Metab 33:1307-11. 2013
  3. pmc Ketones suppress brain glucose consumption
    Joseph C Lamanna
    Department of Anatomy, Case Western Reserve University, Cleveland, Ohio 44106, USA
    Adv Exp Med Biol 645:301-6. 2009
  4. pmc Diet-induced ketosis improves cognitive performance in aged rats
    Kui Xu
    Department of Anatomy, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
    Adv Exp Med Biol 662:71-5. 2010

Detail Information

Publications6

  1. ncbi Contribution of brain glucose and ketone bodies to oxidative metabolism
    Yifan Zhang
    Departments of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
    Adv Exp Med Biol 765:365-70. 2013
    ....
  2. pmc Ketosis proportionately spares glucose utilization in brain
    Yifan Zhang
    Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 4954, USA
    J Cereb Blood Flow Metab 33:1307-11. 2013
    ..3 to 6.3 mmol/L). Together with our meta-analysis, these data revealed that the degree and duration of ketosis has a major role in determining the corresponding change in CMRglc with ketosis. ..
  3. pmc Ketones suppress brain glucose consumption
    Joseph C Lamanna
    Department of Anatomy, Case Western Reserve University, Cleveland, Ohio 44106, USA
    Adv Exp Med Biol 645:301-6. 2009
    ..3) and in the frontal cortex (CMRGlu = -3.93*[BHB] + 42.7, r2 = 0.5). These data indicate that, under conditions of ketosis, glucose consumption is decreased in the cortex and cerebellum by about 10% per each mM of plasma ketone bodies...
  4. pmc Diet-induced ketosis improves cognitive performance in aged rats
    Kui Xu
    Department of Anatomy, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106, USA
    Adv Exp Med Biol 662:71-5. 2010
    ..Capillary density and HIF-1alpha levels were elevated in the aged ketotic group independent of hypoxic challenge. These data suggest that diet-induced ketosis may be beneficial in the treatment of neurodegenerative conditions...