After the exhaustion of the glycogen reserve, and for the next 2–3 days, fatty acids are the principal metabolic fuel. At first, the brain continues to use glucose, because if a non-brain tissue is using fatty acids as its metabolic fuel, the use of glucose in the same tissue is switched off.  Thus, when fatty acids are being broken down for energy, all of the remaining glucose is made available for use by the brain.
After 2 or 3 days of fasting, the liver begins to synthesize ketone bodies from precursors obtained from fatty acid breakdown. The brain uses these ketone bodies as fuel, thus cutting its requirement for glucose. After fasting for 3 days, the brain gets 30% of its energy from ketone bodies. After 4 days, this goes up to 75%.
Thus, the production of ketone bodies cuts the brain's glucose requirement from 80 g per day to about 30 g per day. Of the remaining 30 g requirement, 20 g per day can be produced by the liver from glycerol (itself a product of fat breakdown). This still leaves a deficit of about 10 g of glucose per day that must come from some other source. This deficit is supplied via gluconeogenesis from amino acids from proteolysis of body proteins.
After several days of fasting, all cells in the body begin to break down protein. This releases amino acids into the bloodstream, which can be converted into glucose by the liver. Since much of the human body's muscle mass is protein, this phenomenon is responsible for the wasting away of muscle mass seen in starvation.
However, the body can selectively decide which cells break down protein and which do not. About 2–3 g of protein must be broken down to synthesize 1 g of glucose; about 20–30 g of protein is broken down each day to make 10 g of glucose to keep the brain alive. However, to conserve protein, this number may decrease the longer the fasting.
Starvation ensues when the fat reserves are completely exhausted and protein is the only fuel source available to the body. Thus, after periods of starvation, the loss of body protein affects the function of important organs, and death results, even if there are still fat reserves left unused. (In a leaner person, the fat reserves are depleted earlier, the protein depletion occurs sooner, and therefore death occurs sooner.)
The ultimate cause of death is, in general, cardiac arrhythmia or cardiac arrest brought on by tissue degradation and electrolyte imbalances.
In the very obese, it has been shown that proteins can be depleted first. Accordingly, death from starvation is predicted to occur before fat reserves are used up.