Since protein breakdown is intimately related to glucose requirements and availability, we
can effectively consider these two fuels together. Arguably the major adaptation to the ketogenic
diet is a decrease in glucose use by the body, which exerts a protein sparing effect (2). This is
discussed in greater detail in chapter 5.
Free Fatty Acids (FFA) and ketones
Most tissues of the body can use FFA for fuel if it is available. This includes skeletal
muscle, the heart, and most organs. However, there are other tissues such as the brain, red
blood cells, the renal medulla, bone marrow and Type II muscle fibers which cannot use FFA and
require glucose (2).
The fact that the brain is incapable of using FFA for fuel has led to one of the biggest
misconceptions about human physiology: that the brain can only use glucose for fuel. While it is
true that the brain normally runs on glucose, the brain will readily use ketones for fuel if they are
available (4-6).
Arguably the most important tissue in terms of ketone utilization is the brain which can
derive up to 75% of its total energy requirements from ketones after adaptation (4-6). In all
likelihood, ketones exist primarily to provide a fat-derived fuel for the brain during periods when
carbohydrates are unavailable (2,7).
As with glucose and FFA, the utilization of ketones is related to their availability (7).
Under normal dietary conditions, ketone concentrations are so low that ketones provide a
negligible amount of energy to the tissues of the body (5,8). If ketone concentrations increase,
most tissues in the body will begin to derive some portion of their energy requirements from
ketones (9). Some research also suggests that ketones are the preferred fuel of many tissues (9).
One exception is the liver which does not use ketones for fuel, relying instead on FFA (7,10,11).
By the third day of ketosis, all of the non-protein fuel is derived from the oxidation of FFA
and ketones (12,13). As ketosis develops, most tissues which can use ketones for fuel will stop
using them to a significant degree by the third week (7,9). This decrease in ketone utilization
occurs due to a down regulation of the enzymes responsible for ketone use and occurs in all
tissues except the brain (7). After three weeks, most tissues will meet their energy requirements
almost exclusively through the breakdown of FFA (9). This is thought to be an adaptation to
ensure adequate ketone levels for the brain.
Except in the case of Type I diabetes, ketones will only be present in the bloodstream
under conditions where FFA use by the body has increased. For all practical purposes we can
assume that a large increase in FFA use is accompanied by an increase in ketone utilization and
these two fuels can be considered together.
Relationships between carbohydrates and fat
Excess dietary carbohydrates can be converted to fat in the liver through a process called
de novo lipognesis (DNL). However short term studies show that DNL does not contribute