Energy Substrates

The brain uses glucose as its primary energy substrate. Glucose is not lipid-soluble, and thus requires a BBB transporter. The glucose transporter has a maximal transport capacity for glucose of 1.4 mmol per min per gram brain, or about 1200 g day-1 for the entire brain (a human brain weighs 1400 g). The human brain consumes 15-20% of the body's oxygen; brain glucose utilization is therefore about 100gday-1. The BBB transporter thus has a maximal capacity for transporting glucose well in excess of that demanded daily by the brain.

Inside the brain, glucose is rapidly taken up into neurons by a cellular glucose transporter. Within the neuron, glucose enters the glycolytic pathway. The initial enzyme, hexokinase, has a very high affinity for glucose, and is fully saturated at normal brain glucose concentrations. Hence, overall, each step in the glucose pipeline from blood to brain neurons is designed to maximize glucose supply for neuronal energy production. It only fails when the blood glucose supply is abruptly curtailed, such as when a diabetic patient injects too much insulin and blood glucose levels rapidly fall (the transporter cannot compensate for such abrupt drops in blood glucose). The effect is dramatic: confusion, delirium, seizures, coma, and finally death occur as blood glucose drops to very low levels. Such effects are most rapidly reversed by the infusion of glucose, suggesting that no other compound in blood readily substitutes for glucose as the brain's primary energy substrate.

Normally, the body carefully maintains blood glucose concentrations. During starvation, however, blood glucose falls enough to cause the brain to recruit an additional energy source, i.e., ketone bodies. Ketone bodies are liver-produced by-products of the breakdown of stored fat (fatty acids), and provide an extended supply of energy when the input of food-derived energy is low. The brain uses ketone bodies whenever their blood levels rise; blood ketone body concentrations rise in starvation. The BBB ketone body transporter (ketone bodies are not lipid soluble) is induced in starvation, enhancing the flow of ketone bodies into brain. During prolonged starvation, more than half of the energy used by the brain is derived from ketone bodies. Continued use of some glucose appears obligatory, however, and is supplied via liver gluconeogenesis.

The chronic ingestion of high-fat diets also elevates blood ketone body concentrations, promoting their use by the brain for energy production. However, extremely high levels of fat must be consumed, and such diets are unpalatable. Hence, diet is not thought normally to influence cerebral energy production via dietary fat manipulation of ketone body supply to brain. Very high-fat diets are occasionally used clinically to treat intractable seizures. Though the beneficial effect is linked to levels of circulating ketone bodies, the mechanism is presently unknown.

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