Ketone bodies as the brain's fuel in prolonged fasting
In prolonged fasting, the brain increasingly uses ketone bodies, fuel molecules made by the liver mainly from fatty acids.
Remember
Once liver glycogen is used up in prolonged fasting, the brain increasingly turns to ketone bodies, which the liver makes mainly from fatty acids, since the brain itself cannot use fatty acids.
Glucose from the gut fuels the body in the first hours after a meal. Once about 8 hours have passed, the glycogen stores (stored glucose) begin to run out, and the liver starts making glucose from other sources through gluconeogenesis. After several days without food the glycogen has gone, and the body is relying on fat.
The brain and red blood cells cannot use fatty acids, but most tissues do. So the liver makes ketone bodies, mainly from fatty acids, as a fuel the brain can use when glucose is scarce. Ketone bodies are water-soluble (they dissolve in the blood) and can cross the blood-brain barrier (the tightly sealed lining of the brain's blood vessels), so neurones can use them for energy.
The signal for the switch is a hormone pattern: very low insulin and high glucagon. It puts the liver into fasting mode, and the liver converts fatty acids into ketone bodies. The brain still needs some glucose, which comes from gluconeogenesis.
Using ketone bodies reduces the brain's need for glucose. Because the brain depends less on glucose, the liver needs to make less new glucose, so muscle protein is spared. The sequence is glycogen first, then gluconeogenesis, then ketones.
Key facts
- Brain fuel
- the brain increasingly uses ketone bodies as liver glycogen runs out during fasting.
- Source
- the liver makes ketone bodies mainly from fatty acids, and a smaller share comes from amino acids that can be converted into ketones, such as leucine.
- Fatty acids
- the brain cannot use them directly, so the liver has to convert them into ketone bodies first.
- Red blood cells
- mature red cells have no mitochondria, so they cannot burn fatty acids and depend entirely on glycolysis.
- Timing
- glycogen begins to run out after about 8 hours of fasting, and after several days no glycogen is left.
- Hormone signal
- very low insulin and high glucagon switch the liver into fasting mode.
- Benefit
- the brain needs less glucose, so the liver makes less new glucose and muscle protein is spared.
Exam traps
- Fatty acids released from adipose tissue (fat) do not fuel the brain directly, because the brain cannot use fatty acids. The liver converts them into ketone bodies, which the brain can use.
- Glucose from liver glycogen does not keep the brain going in prolonged starvation, because liver glycogen begins to run out after about 8 hours and has gone by several days. It is the brain's fuel in the early hours of a fast.
- Neurones do not burn amino acids directly as a main fuel. Amino acids from muscle breakdown go to the liver to make glucose, and protein is spared in prolonged starvation.
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