We all experience a daily cycle of feasting and fasting that occurs after we consume our last meal of the day, fast while we sleep, and then break our fast with our first meal the following day. This daily cycle of feasting and fasting requires pathways of energy metabolism to be carefully coordinated. Excess energy provided by meals (feasting) beyond our immediate needs must be stored (anabolism) so that those stores can subsequently be mobilized (catabolism) to supply energy when fasting. Because pathways of energy storage and mobilization work in opposition to each other they must be regulated in opposite directions. This regulation is achieved largely by hormones that control the activities of key enzymes in metabolic pathways to coordinate the metabolic adaptions that accompany periods of feasting and fasting.

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Insulin, glucagon, and epinephrine are the key hormones involved in the short-term regulation of the metabolic adaptations that occur with feasting and fasting. Insulin is released when meals containing carbohydrates and protein are consumed, and it is the key hormone that stimulates fuel storage. Glucagon and epinephrine are released as blood glucose concentrations drop during a fast, and they are the key hormones that stimulate fuel mobilization.

Insulin stimulates glycogen synthesis in the liver and muscle, and fat synthesis in the liver. It also inhibits the breakdown of glycogen, fat, and proteins. The primary site of glucagon action is the liver, where it increases glucose production by stimulating glycogen breakdown and glucose synthesis from noncarbohydrate sources (gluconeogenesis). Although epinephrine is often associated with the fight-or-flight response, which requires the mobilization of fuels to supply energy to contracting muscles, it also has an important role in regulating energy metabolism during a fast. Like glucagon, epinephrine stimulates glucose production in the liver. It is also the primary hormone that stimulates the release of fatty acids from triglycerides stored in adipose tissue.

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Insulin stimulates the storage of glucose as glycogen in the liver (and skeletal muscle if it has been depleted by exercise) after meals containing carbohydrates, proteins, and fats. Once glycogen stores are replenished the remaining glucose tends to be oxidized to meet the body’s immediate energy needs. Insulin also stimulates the storage of fatty acids as triglycerides in adipose tissue. Generally, little glucose is used to synthesize fat, as it is more efficient to store ingested fat as triglycerides than it is to convert glucose into fatty acids. However, when carbohydrates are consumed in large excess, insulin stimulates both liver and adipose tissue to convert acetyl-CoA generated from glucose oxidation to be used to synthesize fatty acids and then store them in adipose tissue as triglycerides. The process of fatty acid synthesis is called lipogenesis.

Overnight Fast The principle goals of the metabolic adaptations that occur during an overnight fast are to mobilize fatty acids from triglycerides stored in adipose tissue and to maintain blood glucose concentrations. Although fatty acids can supply all the necessary energy for most tissues, the brain, red blood cells, and a few other tissues must have a steady supply of glucose to function.

As the time following the last evening meal lengthens blood glucose begins to decrease, causing insulin levels to fall and glucagon and epinephrine levels to rise. Glucagon and epinephrine stimulate the liver to breakdown glucagon to glucose and release it into blood. While these hormones also stimulate the liver to synthesize glucose (gluconeogenesis) from noncarbohydrate sources such as amino acids, this does not occur at high rates until liver glycogen has been significantly depleted.

Epinephrine also activates two lipases in adipose tissue that release fatty acids (lipolysis) from triglycerides stored there. Fatty acids supply the vast majority of energy for most tissues throughout the body while fasting.

Extended fast—starvation As the fast continues liver glycogen is depleted after approximately 24 hours and all glucose must be supplied by gluconeogenesis in the liver, which uses primarily the carbon skeletons from amino acids to synthesize glucose. This results in a rapid loss of skeletal muscle mass and high rates of urea production to dispose of the amino groups that have been stripped from these amino acids.

If a fast is extended and the individual moves into a state of starvation, additional adaptions occur to prolong the life. Key among these is the preservation of body proteins.

During a fast, the brain is by far the largest consumer of glucose in the body because it cannot obtain an appreciable amount of energy from fat; and the brain may account for as much as 20% of all energy used by the body. If an alternative source of energy for the brain were not available, survival time would be cut dramatically due to the rapid loss of body proteins to supply the amino acids from which to synthesize glucose.

Thankfully, the brain can also derive a significant portion of its energy needs from ketone bodies produced from fatty acids. Once the period of starvation reaches approximately 10 days, ketone bodies supply about two-thirds of the brain’s total energy needs. This adaptation allows protein breakdown to slow as fewer amino acids are used for gluconeogenesis, and this significantly prolongs survival time during starvation.