Question

Explain how the body and brain meet their energy requirements during times of fasting and starvation. Specifically how do the products of gluconeogenesis, glycogenolysis, glycolysis, ketogenesis, and fatty acids meet these needs?

Answer 1

THE STARVATION STATE

Starvation metabolism is not just extended fasting metabolism. Fasting metabolism anticipates the next meal and is able to shift quickly back to the well-fed state. Starvation metabolism, on the other hand, cannot anticipate the next meal. Thus, instead of breaking down protein to maintain blood glucose, metabolism shifts to conserve blood glucose and to spare protein from continual degradation .

After 3 to 5 days of fasting, increasing reliance on fatty acids and ketone bodies for fuel enables the body to maintain blood glucose at 60–65 mg/dL (normal 70–100 mg/dL) and to spare muscle protein for prolonged periods without food.

Liver Metabolism in the Starvation State

Ketosis resulting from increased hepatic production of ketone bodies is the hallmark of starvation. In the absence of insulin, mobilization of FFA from adipose tissue continues to increase. Because the only site for regulation of fat oxidation is at the level of adipose tissue, oxidation of fatty acids in the liver continues unabated. Accumulating acetyl-CoA is shunted through ketogenesis to produce the ketone bodies acetoacetate and ?-hydroxybutyrate. These substrates, which are water-soluble forms of fat, are metabolized to acetyl-CoA and used for energy production by many tissues (e.g., muscle, brain, kidney) but not by red blood cells or the liver. Acetone, a ketone formed spontaneously by decomposition of acetoacetate, gives a fruity odor to the breath.

Gluconeogenesis slows down as the supply of amino acid carbon skeletons from muscle protein catabolism decreases. However, glycerol released by lipolysis in adipose tissue supports a low level of gluconeogenesis in liver, which is the only tissue that contains glycerol kinase (glycerol ? glycerol 3-phosphate ??? glucose).

Adipose Tissue Metabolism in the Starvation State

The combined effects of the absence of insulin and elevated epinephrine concentrations due to the stress of starvationactivate hormone-sensitive lipase, the only site for hormonal regulation of fatty acid oxidation. The mobilized free fatty acids serve not only as a source of ketone body formation in the liver but also as a fuel for most other tissues, such as muscle and heart (but not red blood cells). Glycerol released from lipase activity is the only significant adipose source of carbons for gluconeogenesis.

Muscle Metabolism in the Starvation State

Degradation of muscle protein is decreased in starvation, with most of its energy supplied by FFA and ketone bodies. As starvation persists, muscle relies increasingly on free fatty acids, sparing glucose and ketone bodies for use by the brain.

Brain Metabolism in the Starvation State

Increasing ketone body use by the brain spares blood glucose for use by red blood cells, which rely solely on glucose for energy production. Decreasing glucose use by the brain reduces the need for hepatic gluconeogenesis from muscle and thus indirectly spares muscle protein.

The postabsorptive state, or the fasting state, occurs when the food has been digested, absorbed, and stored. You commonly fast overnight, but skipping meals during the day puts your body in the postabsorptive state as well. During this state, the body must rely initially on stored glycogen. Glucose levels in the blood begin to drop as it is absorbed and used by the cells. In response to the decrease in glucose, insulin levels also drop. Glycogen and triglyceride storage slows. However, due to the demands of the tissues and organs, blood glucose levels must be maintained in the normal range of 80–120 mg/dL. In response to a drop in blood glucose concentration, the hormone glucagon is released from the alpha cells of the pancreas. Glucagon acts upon the liver cells, where it inhibits the synthesis of glycogen and stimulates the breakdown of stored glycogen back into glucose. This glucose is released from the liver to be used by the peripheral tissues and the brain. As a result, blood glucose levels begin to rise. Gluconeogenesis will also begin in the liver to replace the glucose that has been used by the peripheral tissues.

After ingestion of food, fats and proteins are processed as described previously; however, the glucose processing changes a bit. The peripheral tissues preferentially absorb glucose. The liver, which normally absorbs and processes glucose, will not do so after a prolonged fast. The gluconeogenesis that has been ongoing in the liver will continue after fasting to replace the glycogen stores that were depleted in the liver. After these stores have been replenished, excess glucose that is absorbed by the liver will be converted into triglycerides and fatty acids for long-term storage.

Starvation

When the body is deprived of nourishment for an extended period of time, it goes into “survival mode.” The first priority for survival is to provide enough glucose or fuel for the brain. The second priority is the conservation of amino acids for proteins. Therefore, the body uses ketones to satisfy the energy needs of the brain and other glucose-dependent organs, and to maintain proteins in the cells. Because glucose levels are very low during starvation, glycolysis will shut off in cells that can use alternative fuels. For example, muscles will switch from using glucose to fatty acids as fuel. As previously explained, fatty acids can be converted into acetyl CoA and processed through the Krebs cycle to make ATP. Pyruvate, lactate, and alanine from muscle cells are not converted into acetyl CoA and used in the Krebs cycle, but are exported to the liver to be used in the synthesis of glucose. As starvation continues, and more glucose is needed, glycerol from fatty acids can be liberated and used as a source for gluconeogenesis.

After several days of starvation, ketone bodies become the major source of fuel for the heart and other organs. As starvation continues, fatty acids and triglyceride stores are used to create ketones for the body. This prevents the continued breakdown of proteins that serve as carbon sources for gluconeogenesis. Once these stores are fully depleted, proteins from muscles are released and broken down for glucose synthesis. Overall survival is dependent on the amount of fat and protein stored in the body.