To gain a better understanding of ketosis and the ketogenic diet, it is important to take a look at the physiology behind the diet. If you recall from the article What is a Ketogenic Diet? the goal of a ketogenic diet is to induce ketosis by increasing ketone body production. A key step in understanding the diet is to learn what ketosis is, what are ketones and what do they do.
Learning the basics of the various metabolic processes of the body will better your ability to understand ketosis. Under the normal physiological conditions that are common today, glucose is our body’s primary source of energy. Following ingestion, carbohydrates are broken down into glucose and released into the blood stream.
This results in the release of insulin from the pancreas. Insulin not only inhibits fat oxidation but also acts as a key holder for cells by allowing glucose from the blood to be shuttled into cells via glucose transporters (GLUT). The amount of insulin required for this action varies between individuals depending on their insulin sensitivity. Once inside the cell, glucose undergoes glycolysis, a metabolic process that produces pyruvate and energy in the form of adenosine triphosphate (ATP). Once pyruvate is formed as an end product of glycolysis, it is shuttled into the mitochondria, where it is converted to acetyl-CoA by pyruvate dehydrogenase.
Acetyl-CoA then enters the TCA cycle to produce additional energy with the aid of the electron transport chain. Since glucose is so rapidly metabolized for energy production and has a limited storage capacity, other energy substrates, such as fat, get stored as triglycerides due to our body’s virtually infinite fat storage capacity. When a sufficient source of carbohydrates is not available, the body adapts by first utilizing glycogen (stored carbohydrates) and available amino acids, and mobilizing stored fatty acids to burn (fat oxidation) and supply energy. When this process of fat oxidation occurs at a high enough rate, ketones are produced in the liver.
Ketones are organic compounds that are produced by the liver during times of low blood glucose, decreased insulin production, and increased fatty acid oxidation. There are three different molecules that are classified as ketones or ketone bodies: beta-hydroxybutyrate, acetoacetate, and acetone. Acetoacetate (AcAc) and beta-hydroxybutyrate (BHB) are the primary ketone bodies that are utilized by our metabolic systems. Acetone is rapidly exhaled through the lungs and excreted in the urine. However, acetone can also serve as an alkalizing agent to prevent acidosis from occurring. From a molecular perspective BHB is technically not a ketone body due to its lack of carboxylic acid, however, for all intensive purposes we will be referring to it as one due to its behavior.
It is important to note that there are several conditions that can allow for the production of ketones. For a more in-depth look at the different types of ketosis, check out Are There Different Types of Ketosis? At this point, I want to reiterate that the production of ketones occurs following beta-oxidation (the breakdown of fatty acids). Note that the fat required for this process to occur can be obtained from stored body fat (triglycerides) or from ingested dietary fat. That means for the sake of this article we are going to focus primarily on fasting and dietary modification as means for ketone production.
Under conditions of decreased fuel availability, such as fasting, glucagon (the other hormone secreted by the pancreas that suppresses insulin production) activates hormone sensitive lipase (HSL) to initiate a process known as lipolysis (mobilizing stored triglycerides). During lipolysis, triglycerides (stored body fat) are broken down into free fatty acids (FFAs) and glycerol, which are then released into circulation. FFAs are transported through the blood to be utilized for ATP (energy) production by many organs, especially the heart, skeletal muscle, and liver. Glycerol is delivered to the liver and utilized for gluconeogenesis (endogenous production of glucose). As blood glucose continues to decrease, further hormonal responses, such as catecholamine and cortisol, cause additional mobilization of FFAs.
Once fatty acids enter the cell, they are converted to fatty acid acyl-coA and bound to carnitine to allow for entrance into the mitochondria, which is where beta-oxidation can occur. Beta-oxidation of FFAs results in the production of acetyl-CoA which then enters the TCA cycle ultimately resulting in energy production. When acetyl-CoA accumulates in the liver, it can be utilized for the production of ketone bodies. This occurs to an extent after an overnight fast but increases as a fast continues.
When we lower carbohydrate intake and increase our dietary fat consumption, ketones can also be produced. This occurs due to an increased need for fuel resulting from the restriction of carbohydrates. This action forces the body to digest and metabolize fats rather than shuttling them towards storage. This increase in fat oxidation is responsible for the ketones produced in this instance.
This is where the science can get a bit heavy so feel free to skip over this section if you are not interested in biochemistry! Ketones are produced through a process known as ketogenesis, which begins with the beta oxidation of fatty acids. Therefore, for this to occur there must be enough fatty acids available or rather the need for fatty acids to be available. This is the case during times of low blood glucose. When glucose availability is lowered, our body will turn to glycogen (stored carbohydrate) in an attempt to increase blood glucose. The human body has a limited supply of glycogen, meaning that once it has run out it must make an additional attempt to find a source of energy. This is finally where fatty acids come into play. They can be utilized by various tissues or shuttled to the liver for oxidation.
Note that even though this is occurring, the body is still making an attempt to produce glucose through gluconeogenesis for various reasons. One way the body does this is through the use oxaloacetate, an intermediate for the TCA cycle. This leads to the depletion of the TCA cycle in liver rendering it temporarily inactive. If you recall, typically when fatty acids are beta oxidized they enter the TCA cycle, however, under these conditions this cannot occur. This results in a build-up of acetyl-CoA in the liver, which can be used for ketogenesis. The process is as follows: Two acetyl-CoA molecules are condensed to form acetoacetyl-CoA. Acetoacetyl-CoA is then joined by an additional acetyl-CoA, resulting in the formation of HMG-CoA. HMG-CoA is then cleaved, resulting in AcAc and acetyl-CoA. AcAc can either exit the liver or be converted to BHB.
Due to the fact that the liver does not possess the appropriate enzymes (specifically SCOT) to utilize ketones, ketones in the liver are shuttled into the bloodstream to be delivered to peripheral tissues known as extrahepatic (outside the liver) tissues. Increased concentration of ketones in the blood (0.5-10.0 mmol) leads to a metabolic state known as ketosis.
Ketosis is a metabolic state in which blood ketone concentration is elevated to 0.5 mmol or greater compared to basal levels of 0 or 0.1 mmol. This state is commonly accompanied by lower blood glucose, low insulin, and increased fat oxidation; these factors all play a major role in the amount of ketones produced. Previously we mentioned that this state can occur to varying degrees via fasting or dietary modification. In addition, it can also occur from ingesting ketone supplements and various disease conditions. Learn more about the different types of ketosis in Are There Different Types of Ketosis?
The process by which ketones are used for energy is referred to as ketolysis (breakdown of ketones), and this occurs in the mitochondria of organs outside of the liver. Ketones, once they reach target organs, are transported into the cells of those organs via monocarboxylate transporters or MCTs (not to be confused with medium-chain triglycerides). MCTs serve as the ketones version of the GLUT transporters needed for glucose transport. Once inside the cell, ketones can be metabolized by various enzymes resulting in energy production. If BHB enters the cell, then it has to be converted back to acetoacetate before it can be further metabolized to yield energy. The heart, kidneys, central nervous system, and skeletal muscle have the highest activity of these enzymes, making them primary locations for ketone metabolism (2).
The ability to effectively utilize ketones is referred to as “keto-adaptation,” which is a topic of controversy. This adaptation period may be due to the necessity to up regulate the appropriate transporters and enzymes needed for ketone metabolism. However, research has demonstrated that certain tissues, like muscle, will utilize FFAs for energy, thus sparing ketones for the brain, since it is unable to utilize free fatty acids (3).
On the other hand, MCT transporters in the brain are able to rapidly adapt to increased ketone uptake. In fact, brain utilization of ketones is proportional to ketone production up until about 12 mmol (4). Brain glucose metabolism decreases as ketone concentration increases, which gives us reason to believe that ketones are our brain’s preferred fuel source (5).
The whole process from ketogenesis to ketolysis is summarized in the image below.
As can be seen from the explanation of ketone metabolism, the process of ketone production and utilization is rather complicated compared to glucose metabolism, hence why it is often questioned why we still possess this unique physiological feature. It is thought that we have retained this ability to produce and transition to an alternative fuel source because it is essential to our survival, especially during conditions of starvation. Since ketone bodies are water-soluble, they are not only easier to transport but also easier to metabolize, which is crucial during times of starvation or decreased fuel availability. The water solubility of ketones allows them to be utilized by the brain during these conditions, which is essential for survival.
Being in a state of ketosis can also provide an array of health benefits. Aside from the obvious benefit of lowering and maintaining blood glucose levels, improved blood lipid profiles, decreased inflammation, and improved cognition are other typical consequences of being in ketosis. The state of ketosis has been demonstrated not only to be beneficial for weight loss (6,7,8), but also may have implications for sports performance, epilepsy, Parkinson’s, Alzheimer’s, cardiovascular disease, various metabolic disorders, and even cancer (9)!