brain (see chapter 5 for more detail) (6). While many tissues of the body (especially muscle) use
a large amount of ketones for fuel during the first few weeks of a ketogenic diet, most of these
same tissues will decrease their use of ketones as the length of time in ketosis increases (4). At
this time, these tissues rely primarily on the breakdown of free fatty acids (FFA). In practical
terms, after three weeks of a ketogenic diet, the use of ketones by tissues other than the brain is
negligible and can be ignored.
A potential effect of ketones (discussed further in chapter 5) is to inhibit protein
breakdown during starvation through several possible mechanisms, discussed in detail in the next
chapter. The only other known function of ketones is as a precursor for lipid synthesis in the
brain of neonates (4).
Section 2: Ketogenesis and the two site model
The formation of ketone bodies, called ketogenesis, is at the heart of the ketogenic diet and
the processes involved need to be understood. As described in the previous chapter, the primary
regulators of ketone body formation are the hormones insulin and glucagon. The shift that occurs
in these two hormones, a decrease in insulin and an increase in glucagon is one of the major
regulating steps regulating ketogenesis.
A great amount of research has been performed to determine exactly what is involved in
ketogenesis. All the research has led to a model involving two sites: the fat cell and the liver. In
addition, the enzyme mitochondrial HMG CoA reductase (MHS) has been suggested as a third
site of regulation (4,8). For our purposes, MHS and its effects are unimportant so we will focus
only on the first two sites of regulation: the fat cell and the liver.
The fat cell
As discussed in the previous chapter, the breakdown of fat in fat cells, is determined
primarily by the hormones insulin and the catecholamines. When insulin is high, free fatty acid
mobilization is inhibited and fat storage is stimulated through the enzyme lipoprotein lipase
(LPL). When insulin decreases, free fatty acids (FFA) are mobilized both due to the absence of
insulin as well as the presence of lipolytic (fat mobilizing) hormones such as the catecholamines
(9,10). Glucagon, cortisol and growth hormone play additional but minor roles.
Insulin has a much stronger anti-lipolytic effect than the catecholamines have a lipolytic
effect. If insulin is high, even though catecholamines are high as well, lipolysis is blocked. It is
generally rare to have high levels of both insulin and catecholamines in the body. This is because
the stimuli to raise catecholamine levels, such as exercise, tend to lower insulin and vice versa.
Breakdown and transport of Triglyceride (11)
When the proper signal reaches the fat cell, stored triglyceride (TG) is broken down into
glycerol and three free fatty acid (FFA) chains. FFA travels through the bloodstream, bound to a