There are four primary fuels which can be used in the human body: glucose, protein, free fatty acids, and ketones. These fuels are stored in varying proportions in the body. Overall, the primary form of stored fuel is triglyceride, stored in adipose tissue. Glucose and protein make up secondary sources. These fuels are used in varying proportions depending on the metabolic state of the body.
The primary determinant of fuel utilization in humans is carbohydrate availability, which affects hormone levels. Additional factors affecting fuel utilization are the status of liver glycogen (full or empty) as well as the levels of certain enzymes.
Bodily Fuel Stores
The body has three storage depots of fuel which it can tap during periods of caloric deficiency: protein, which can be converted to glucose in the liver and used for energy ; carbohydrate, which is stored primarily as glycogen in the muscle and liver ; and fat , which is stored primarily as body fat. A fourth potential fuel is ketones. Under normal dietary conditions, ketones play a non-existent role in energy production. In fasting or a ketogenic diet, ketones play a larger role in energy production, especially in the brain.
The main point is that carbohydrate stores are minimal in comparison to protein and fat, sufficient to sustain roughly one day’s worth of energy. Although stored protein could conceivably fuel the body for far longer than carbohydrate, excessive protein losses will eventually cause death. This leaves adipose tissue as the primary depot for long term energy storage. The average person has enough energy stored as body fat to exist for weeks or energy storage. The average person has enough energy stored as body fat to exist for weeks or months without food intake and obese individuals have been fasted for periods of up to one year.
Relationships in fuel use
There are least 4 distinct fuels which the body can use: glucose, protein, free fatty acids (FFA), and ketones. However when we look at the relationships between these four fuels, we see that only glucose and FFA need to be considered.
The difference in the proportion of each fuel used will depend on the metabolic state of the body (i.e. aerobic exercise, weight training, normal diet, ketogenic diet/fasting). Exercise metabolism is addressed elsewhere in this blog and we are only concerned here with the effects of dietary changes on fuel utilization.
In general, tissues of the body will use a given fuel in proportion to its concentration in the bloodstream. So if a given fuel (i.e. glucose) increases in the bloodstream, the body will utilize that fuel in preference to others. By the same token, if the concentrations of a given fuel decrease in the bloodstream, the body will use less of that fuel. By decreasing carbohydrate availability, the ketogenic diet shifts the body to using fat as its primary fuel.
Glucose and protein use
When present in sufficient quantities, glucose is the preferred fuel for most tissues in the body. The major exception to this is the heart, which uses a mix of glucose, FFA and ketones.
The major source of glucose in the body is from dietary carbohydrate. However, other substances can be converted to glucose in the liver and kidney through a process called gluconeogenesis (‘gluco’ = glucose, ‘neo’ = new, ‘genesis’ = the making). This includes certain amino acids, especially alanine and glutamine.
With normal glucose availability, there is little gluconeogenesis from the body’s protein stores. This has led many to state that carbohydrate has a ‘protein sparing’ effect in that it prevents the breakdown of protein to make glucose. While it is true that a high carbohydrate intake can be protein sparing, it is often ignored that this same high carbohydrate also decreases the use of fat for fuel. Thus in addition to being ‘protein sparing’, carbohydrate is also ‘fat sparing’.
If glucose requirements are high but glucose availability is low, as in the initial days of fasting, the body will break down its own protein stores to produce glucose. This is probably the origin of the concept that low carbohydrate diets are muscle wasting. An adequate protein intake during the first weeks of a ketogenic diet will prevent muscle loss by supplying the amino acids for gluconeogenesis that would otherwise come from body proteins.
By extension, under conditions of low glucose availability, if glucose requirements go down due to increases in alternative fuels such as FFA and ketones, the need for gluconeogenesis from protein will also decrease. The circumstances under which this occurs are discussed below.
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.
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.
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.
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. In all likelihood, ketones exist primarily to provide a fat-derived fuel for the brain during periods when carbohydrates are unavailable.
As with glucose and FFA, the utilization of ketones is related to their availability.
Under normal dietary conditions, ketone concentrations are so low that ketones provide a negligible amount of energy to the tissues of the body. If ketone concentrations increase, most tissues in the body will begin to derive some portion of their energy requirements from ketones. Some research also suggests that ketones are the preferred fuel of many tissues.
One exception is the liver which does not use ketones for fuel, relying instead on FFA.
By the third day of ketosis, all of the non-protein fuel is derived from the oxidation of FFA and ketones. As ketosis develops, most tissues which can use ketones for fuel will stop using them to a significant degree by the third week. 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. After three weeks, most tissues will meet their energy requirements almost exclusively through the breakdown of FFA. 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 21
significantly to fat gain in humans. As long as muscle and liver glycogen stores are not completely filled, the body is able to store or burn off excess dietary carbohydrates. Of course this process occurs at the expense of limiting fat burning, meaning that any dietary fat which is ingested with a high carbohydrate intake is stored as fat.
Under certain circumstances, excess dietary carbohydrate can go through DNL, and be stored in fat cells although the contribution to fat gain is thought to be minimal. Those circumstances occur when muscle and liver glycogen levels are filled and there is an excess of carbohydrate being consumed.
The most likely scenario in which this would occur would be one in which an individual was inactive and consuming an excess of carbohydrates/calories in their diet. As well, the combination of inactivity with a very high carbohydrate AND high fat diet is much worse in terms of fat gain. With chronically overfilled glycogen stores and a high carbohydrate intake, fat utilization is almost completely blocked and any dietary fat consumed is stored.
This has led some authors to suggest an absolute minimization of dietary fat for weight loss. The premise is that, since incoming carbohydrate will block fat burning by the body, less fat must be eaten to avoid storage. The ketogenic diet approaches this problem from the opposite direction. By reducing carbohydrate intake to minimum levels, fat utilization by the body is maximized.
From the above discussion, we can represent the body’s overall use of fuel as: Total energy requirements = glucose + FFA
Therefore if energy requirements stay the same, a decrease in the use of glucose will increase the use of FFA for fuel. By corollary, an increase in the body’s ability to use FFA for fuel will decrease the need for glucose by the body. This relationship between glucose and FFA was termed the glucose-FFA Cycle by Randle almost 30 years ago.
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