A 70-kg human can store at most the equivalent of 6700 kJ of energy as glycogen. This source of blood glucose will be exhausted just a few hours after a meal. Because it is critical for brain function that blood glucose levels be maintained near 4.4 mM, the organism adapts metabolically during starvation to increase the use of fuels other than carbohydrate.

About 565,000 kJ is stored in the body as triacylglycerol, largely in adipose tissue, and 100,000 kJ as mobilizable proteins, largely in muscle. These stores provide sufficient energy to permit survival for up to several months, but the compounds must be modified to be of use.

Triacylglycerol mobilization generates energy largely as acetyl-CoA, whose further oxidation in the citric acid cycle requires oxaloacetate. Oxaloacetate and other citric acid cycle intermediates are used in other metabolic reactions and must be replenished via anaplerotic pathways. The most important of these processes is the pyruvate carboxylase reaction, with most of the pyruvate coming from carbohydrate catabolism. During carbohydrate limitation, citric acid cycle intermediates can be provided from glycerol released from fat digestion, but glycerol is not produced in amounts adequate to maintain levels of citric acid cycle intermediates. Alternatively, these intermediates can be produced from protein catabolism and transamination. Consequently, proteolysis is accelerated during the first few days of starvation, because amino acids for protein synthesis are not present in sufficient amounts to counterbalance protein breakdown, which continues at normal rates. A major fate of the released amino acids is gluconeogenesis. During this time, the liver and muscle are shifting to fatty acids as the dominant fuels for their own use.

Because fat breakdown has been activated, both acetyl-CoA and reduced electron carriers accumulate in the liver to the point that the acetyl-CoA cannot all be oxidized (see here). Ketone bodies then begin to accumulate. Accumulation of acetoacetate and -hydroxybutyrate favors reactions that catabolize these ketone bodies. Thus, the brain adapts to reduced glucose levels by increasing the use of ketone bodies as alternative energy substrates. This trend continues for the duration of starvation. The metabolic changes accompanying starvation compromise the organism's abilities to respond to further stresses, such as extreme cold or infection. However, the adaptations do allow life to continue for many weeks without food intake, the total period being determined largely by the size of the fat deposits.