Ketogenesis

What is ketogenesis?

  
In physiological conditions, the human body derives its energy from the aerobic oxidation of liver glycogen (a polymer of glucose) in the Krebs Cycle. The reserve of glycogen in the liver ensures energy supply for one day. Once hepatic glucose stores are depleted, the body has to find another 'fuel' to produce energy. Skeletal muscles and all other parts of the human body, the nervous system excluded, extract energy from acetyl-CoA, which is the result of Beta oxidation of fatty acids. The brain, instead, can only derive energy from glucose.

In order to provide energy to the brain, the liver uses the process of gluconeogenesis. It consists in the formation 'ex novo' of glucose molecules that the brain can use as energy source. The process of gluconeogenesis starts from the 'oxaloacetate' molecule.

Oxaloacetate is obtained by changing the carbon backbone of many amino acids (in red in the figure) through enzymatic reactions that are part of the Krebs cycle

This process, in the liver causes:

- Endogenous biosynthesis of glucose, using carbon skeletons of ‘glucogenic’amino acids as glucose precursors' (The structure of glucogenic aminoacids can be converted, through enzymatic reactions, into oxaloacetate, and consequently into glucose).

- Surplus of Acetyl CoA, which is the second reagent of the first stage of Krebs cycle.

 
At this purpose, to be able to reach extrahepatic tissues, it must be converted into blood solubile molecules. These molecules are the so called ketone bodies. Liver enzymes convert two molecules of Acetyl CoA into acetoacetate. Later, from this reaction, two more ketone bodies, acetone and D-beta hydroxybutyrate, will be formed.

Ketone bodies are highly energetic compounds that, circulating in the blood, reach extra hepatic tissues (skeletal muscle, myocardium, renal cortex, etc). In the extra hepatic tissues ketone bodies will be re-converted into acetyl CoA, which will be able to enter the Krebs Cycle.

In fact, only the liver has the gluconeogenesis enzyme. Consequently, in other districts, oxaloacetate is available to react with acetyl-CoA in the Krebs cycle, being able to produce energy.

With the production of Ketone Bodies, the body can:

- Preserve brain function, by providing, through the process of gluconeogenesis , an adequate supply of glucose

- Provide Acetyl-CoA,derived from β oxidation of fatty acids, to other tissues, in order to ensure an adequate energy supply.


The ketogenic diet, uses in a controlled manner, the formation of ketone bodies in our body, when subjected to a fasting regimen. Slimming action, focused exclusively on the loss of fat body mass, is obtained by a continuous perfusion (90 ml per hour) of glucogenic aminoacids dissolved into two liters of mineral water per day.

This ensures the availability of carbon skeletons, from which to obtain oxaloacetate (and therefore glucose to the brain), without affecting the body's muscle mass. In the meanwhile, for energy purposes, through ketone bodies the body is going to promote the β-oxidation of fatty acids, in order to supply all tissues with acetyl-CoA. Ketone bodies are then expelled through urine.

During treatment the patient, must at a daily basus check the presence of ketone bodies in the urine. This test can be easily done at home. A positive sign of ketogenesis testifies a proper functioning of the therapy. Continuative stress on the kidneys to filter the ketone bodies and nitrogen compounds derived from protein transamination for the production of oxaloacetate, is limiting the duration of ketogenic diet to no more than 10 consecutive days.

After a period of two weeks of balanced food regimen, and consequent return to normal values of plasma ketone bodies the patient can start a next cycle of the ketogenic diet.

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