Ketone bodies are normally utilised in the body when there is deficiency of glucose to fulfil the energy needs. Especially in the case of brain. What if the brain had a choice between both the cases. Which source will be used by the brain?
Note: Following is the case study of two papers: Ketones suppress brain glucose consumption[1] and Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia[2]You must be aware that when you starve, your body generates energy on its own. But how? How you are able to work, learn or understand things when you are not taking calories.
When the person starves. The energy metabolism shifts from glucose metabolism to ketone bodies oxidation. When the ketone bodies are infused into the bloodstream of normal people, the global cerebral blood flow (CBF), global carbohydrate metabolism, global cerebral oxygen metabolism are determined.
If ketone bodies are infused or administered in the patient’s bloodstream, the condition is termed hyperketonemia, due to which there is a reduction of utilization of glucose in the body. But the fact that you can see after the reduced glucose utilization in the body is that there is no alteration in carbohydrate uptake and oxygen metabolism in the brain. This is due to the fact that the brain uses ketone bodies infused in the body for various brain activities. The body in this case still takes carbohydrates from food and does not utilize them for glucose production and utilization as energy. Hence the metabolic activity of the brain is not affected. So, if your body is having ketone bodies your brain will utilize ketone bodies for brain activities first rather than glucose.
Glucose is utilized by the body to generate Adenosine triphosphate that is the energy to carry out the specific tasks you perform including brain-like learning, memory, thinking etc. But as you starve ketone utilization starts in the body followed by lipolysis, that is the fat breakdown, which is stored in the adipose tissue in order to generate energy for performing various body activities. And as a result, glucose utilization and metabolism decreases.
Procedure
What happens when you are having enough of the glucose in the body. Whether the body uses ketone bodies or glucose as a result of having an equal amount of ketone bodies and glucose in the body?
Four subjects - 2 males and 2 females were asked to participate in a 2 days small study with a time interval of 1-2 weeks. The subjects were asked to take light breakfast in the morning and were divided into two groups - control and hyperketonemia. that is, one group of subjects were normal and the others were already having hyperketonemia that is more ketone bodies in the blood. After dividing the subjects into two groups. Catheter insertion was done and subjects were allowed to rest in the supine position for one hour in the darkroom. After one hour of rest, Beta Hydroxy Butyrate (BHB) was infused in both the groups that were continued throughout the study. The figure below has illustrated the study in brief.
Results
After performing this particular study in 4 subjects the results that were obtained were as follows:
Effect on arterial concentration, arteriovenous differences and cerebral metabolic rates for the brain before, during and after hyperketonemia
After ketone bodies infusion there was 7 folds increase in blood concentration of BHB.
Acetoacetate increase from 0.02-0.24. That is increase was seen as there was conversion to acetoacetate in tissue.
Glucose, lactate, and pyruvate were constant in hyperketonemia.
Global cerebral blood flow increased by 39%.
Increase in BHB and acetoacetate metabolic rate.
Global glucose metabolism decreases by 33%.
Oxygen metabolic rate was constant.
Net pyruvate and lactate efflux had no change.
Effect on cerebral blood flow, Paco2, pH, and HCO3- after ketone bodies infusion
Cerebral blood flow increased after BHB infusion.
Arterial Co2 tension (Paco2) and pH were not having any significant changes after the infusion.
Carbonate ion (HCO3) levels were kind of increased due to infusion.
Effect on oxygen-to-glucose molar ratio and O2 equivalents of glucose and ketone bodies after producing hyperketonemia
Oxygen to glucose molar ratio increased from 5.57 to 7.91 hence indicating increased oxidation of non-glucose compounds.
Oxygen equivalents of glucose decreased while of ketones increased as in control condition 97% oxygen is used for glucose metabolism while in presence of ketones 74% oxygen use by glucose while 26 % shift to ketone bodies.
Changes seen in PCO2, pH, arteriovenous differences in glucose and oxygen seen after the infusion of ketone bodies is illustrated in the graph
CBF [a-v Glu] and CBF [a-v O2] had comparable decrease till 60 minutes of infusion that is stable at different relative values.
After 60 minutes CBF [a-v Glu] decrease was more pronounced but CBF [a-v Glu] didn’t decreased much.
Regional differences in glucose metabolism seen in various parts of the brain after ketone bodies infusion
From the above data, the highest increase is seen in gyrus cingulus and mesencephalon while negligible changes in cortical and subcortical regions.
Discussion
BHB metabolism: 5 times↑
Glucose metabolism: 33% decrease
Regional pattern rCMRGlu: small change
Altered carbohydrate metabolism
BHB infusion: 7 times increase in BHB blood levels.
Cerebral metabolic rate of BHB (CMRBHB) 5-fold increase.
If a patient is having prolonged hypoglycemia ketone bodies blood levels increases due to ketone oxidation.
This proves that when you have ketone bodies in your bodies, glucose utilization decreases, hence the cerebral metabolic rate of glucose decreases. While ketone bodies utilization increases, hence the cerebral metabolic rate of Beta Hydroxy Butyrate (BHB) increases. But there is no alteration in brain activities due to the unaltered cerebral metabolic rate of oxygen.
Causes
As we talk about the causes of decreased glucose use and increased ketone body use by the brain, we can conclude that there are metabolic changes due to hyperketonemia like:
Inhibition of hexokinase and phosphofructokinase inhibits the glucose breakdown hence its utilization by the body and hence ketone bodies utilization is increased.
When ketone bodies levels increase in the body like Beta Hydroxy Butyrate (BHB). There is a decrease in adenosine monophosphate (ADP) production leading to an increase in citrate levels in tricarboxylic acid (TCA) cycle and this citrate inhibits the glycolysis that is glucose breakdown to produce energy.
Hyperketonemia is also responsible for the efflux of lactate from the body cells and inhibits pyruvate oxidation and ultimately inhibits the glycolysis and glucose utilization in the body.
In this study, there was no observed difference in lactate and pyruvate efflux hence it was clear that glycolysis inhibition is not due to lactate or pyruvate oxidation.
Regional glucose metabolism analysis
It was clear that the mesencephalon and cortex ratio increased by 8% after ketone bodies infusion. This indicates that a small decrease in glucose metabolism than the rest parts of the brain that is ketone oxidation was less in these two areas.
Cerebral metabolic rates that are CMRBHB ↑ and CMRGlu hence CMRoverall remains unchanged leading to an increase in CBF. This can be due to the direct action of BHB on cerebrovascular smooth muscle.
Cerebral metabolic rate of glucose is inversely proportional to cerebral blood flow (CMRGlu α 1/ CBF).
Here the CBF increase is associated with glycolysis inhibition and not decreased glucose supply to brain as glucose supply is ample.
Reasons for the increase in cerebral metabolic rate of beta hydroxy butyrate and cerebral blood flow
↓Glycolytic flux that movement between fructose-6-phosphate and fructose-1,6-bisphosphate.
Glycolysis blockage i.e., glucose breakdown to pyruvate and other oxidized substrates.
Glucopenia i.e., glucose shortage
Decreased carbohydrate metabolism
↓glycolysis and ↑CBF coupling here is independent of the energy state of the brain as total cerebral oxidation metabolism and energy didn’t change in hyperketonemia.
What are adipose tissues?
White adipose tissue (WAT): Stores energy
Brown adipose tissue (BAT): Thermoregulation hence uses an excess of energy to generate heat.
BAT is named so due to the presence of mitochondria which is a site of oxidation of nutrients (Glucose and lipids).
BAT pulls glucose as insulin leads to glycolysis and generates energy that is required by cells or tissue.
But when the body contains ketone bodies leading to ketone body oxidation mitochondrial uncoupling occurs in presence of UCP-1. This leads to the generation of a large amount of energy which is wasted as heat. This leads to a decrease in insulin and glucose levels.
What happens in your body in case of increased insulin levels and decreased ketone bodies (Insulin ↑ and ketone↓)?
Insulin stimulates adipocytes to increase the influx of energy and decrease efflux of energy hence responsible for energy storage and increases WAT mass.
Insulin decrease BAT mitochondrial uncoupling hence more storage of energy.
Insulin decreases metabolic rate
Insulin converts BAT to WAT that is more storage and less use.
This is because the glucose levels are more in the body hence more insulin is secreted.
What happens in your body in case of decreased ketone bodies levels and increased ketone bodies levels (Insulin↓ and ketone↑)?
High ketone diet maintains energy and keeps insulin levels down as glucose is not utilized to generate energy.
It leads to mitochondrial uncoupling in the presence of UCP-1 hence an increase in respiration and energy generation.
Converts WAT to BAT hence more energy is produced which is used to generate heat and storage decreases.
This is because glucose utilization decreases and ketone bodies use increases, hence less insulin is required.
Conclusion
Ketone bodies produce more energy compared to glucose hence brain uptake ketones easily as brain activities require higher energy like neurotransmission. Ketone bodies decrease the glycolytic rates at various levels like citrate, phosphofructokinase and/or hexokinase. Ketones are a carbon source for glutamate and thus help to balance glutamate/glutamine homeostasis through stabilization of energy metabolism in astrocytes.
It is concluded that even if the person is normoglycemic. Brain uptake ketone bodies based on ketone availability and not glucose availability or deficiency. This shows that even if the person is having normal glucose and ketone levels the brain will utilize ketone bodies for energy generation and due to this glucose metabolism in the body decreases.
It can also be concluded that if the person's body is utilizing ketone bodies instead of glucose for producing energy. There would be less fat storage and more utilization. It is on the same hand beneficial for the brain. As brain needs high energy for activities. As more energy will be utilized this concludes that storage would decrease, leading to WAT conversion to BAT.
Hence if your body is having equal levels of glucose and ketone bodies. We can infer that the brain will utilize ketone bodies to generate energy.
References
Hasselbalch SG, Madsen PL, Hageman LP, Olsen KS, Justesen N, Holm S, Paulson OB, Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia, 0193-1849/96 $5.00 Copyright o 1996 the American Physiological Society Page No. 746-751. https://tahomaclinic.com/Private/Articles4/Depression/Hasselbalch%201996%20-%20cerebral%20blood%20flow%20and%20carbohydrate%20metabolism%20during%20acute%20hyperketonemia.pdf
LaManna, J. C., Salem, N., Puchowicz, M., Erokwu, B., Koppaka, S., Flask, C., & Lee, Z. (2009). Ketones suppress brain glucose consumption. Advances in experimental medicine and biology, 645, 301–306. DOI: doi.org/10.1007/978-0-387-85998-9_45. https://pubmed.ncbi.nlm.nih.gov/19227486/
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