Table of contents
What are ketone bodies and how are they produced?
What are the main types of ketone bodies?
How do ketone bodies produce energy?
What are the supposed health benefits of ketone bodies?
How to measure ketone bodies in the body?
What level of ketone bodies should be maintained?
Can you supplement with ketone bodies?
Final thoughts
The keto diet focuses on eliminating carbohydrates, in order for the body to enter a state called ketosis.
As mentioned in our previous article, ketosis is a metabolic state in which there are elevated levels of circulating ketone bodies.
But what are ketone bodies and why are they relevant to the keto diet?
What are ketone bodies and how are they produced?
Ketone bodies are a source of energy, produced in the liver
Ketone bodies endogenously produced compounds that supply the body with energy[1].
They are water-soluble molecules which are produced from fatty acids in the liver, in a process called ketogenesis[1][2].
Ketone bodies are energy sources that are produced at low levels, even while not in ketosis. This occurs when insulin levels are low and the level of free fatty acids is relatively high. Low levels of ketone bodies can be produced between meals, during periods of fasting and after prolonged periods of exercise[1][2].
However, when significantly restricting carbohydrates, insulin levels drop to persistent low levels. This stimulates the release of fats stored in adipose tissue, leading to an increase in serum fatty acid levels. At this point, the production of ketone bodies is significantly upregulated[2][3].
These fatty acids are then converted into ketone bodies in the liver. Once synthesised, they become available to other body tissues as a source of energy[1][2].
This process of producing ketone bodies is referred to as ketogenesis[3].
You can learn how ketone bodies are produced in more detail in this article.
Ketone bodies are unique and not to be confused with ketones.
In chemistry, ketones are functional groups that include sugars (called ketoses), steroids and solvents[1][2].
They are characterised by a carbonyl group, in which the carbon atom is covalently bonded to an oxygen atom (C=O)[1].
This differs from an aldehyde as the carbonyl group is in the middle of the molecule, whereas the carbonyl group in aldehydes is at the terminal carbon[1][2].
Ketogenesis can also occur outside of the liver
While the majority of ketogenesis occurs in the liver, there is also emerging evidence that it can occur in other body tissues[4].
A study published in Nature recently found that glial cells are ketogenic, as they can locally synthesise ketone bodies and supply energy to neurons[4].
This study was conducted in the model organism drosophila, but has potential learnings for human production of ketone bodies[4].
What are the main types of ketone bodies?
There are 3 ketone bodies that are produced endogenously in the body; acetoacetate, 3-β-hydroxybutyrate and acetone[2].
Of the 3, only 2 ketone bodies are produced at high levels; acetoacetate and 3-β-hydroxybutyrate[2].
Acetoacetate and 3-β-hydroxybutyrate provide the majority of the energy derived from ketone bodies and are membrane permeable. This means they can cross the blood-brain barrier, and provide energy to the brain[2].
This is important because normally the brain preferentially uses glucose as an energy source. But given that ketone bodies can also fuel the brain, they represent a reasonable alternative to glucose[2].
Acetoacetate
Acetoacetate is synthesised under low carbohydrate conditions and accumulates during fatty acid metabolism. It is one of the primary ketone bodies produced during ketosis[2].
3-β-hydroxybutyrate
3-β-hydroxybutyrate is formed by the reduction of acetoacetate, which takes place in cellular mitochondria[2].
Acetone
Acetone is the least common endogenously produced ketone body, and is generated through decarboxylation of acetoacetate. It is responsible for the sweet smelling breath experienced while in ketosis[2].
How do ketone bodies produce energy?
The process of generating ATP from ketone bodies is called ketolysis[5].
This process takes a number of steps, in which acetoacetate is eventually converted into acetyl-CoA. The produced acetyl-CoA then enters the citric acid cycle, where it is phosphorylated (oxidative phosphorylation) to yield ATP[5].
In contrast to ketogenesis, which occurs primarily in the hepatocytes, ketolysis takes place outside the liver. This is because the liver lacks the key enzyme, succinyl CoA transferase (SCOT)[6].
As a result, the liver cannot utilise ketone bodies[6].
Instead, ketolysis occurs at high levels in the mitochondria of metabolically active tissues; This includes the brain, heart and skeletal muscles[6].
What are the supposed health benefits of ketone bodies?
As mentioned in our articles on the health benefits of keto, and the pros and cons of the keto diet, keto is associated with numerous health benefits.
However, it is not clear to what extent ketone bodies play a role in these health benefits.
Some studies, focussing on β-hydroxybutyrate, have found evidence to support the role of ketone bodies in positive health outcomes[7][8].
Note: most of these studies are pre-clinical and occur in animal models
Anti-inflammatory
β-hydroxybutyrate has been shown to have anti-inflammatory effects in animal models[7][8].
This could be contribute to the overall anti-inflammatory effect of the keto diet[7].
A study conduced in old mice showed that when supplemented with β-hydroxybutyrate, pro-inflammatory signalling was reversed. As a result, the study concluded that β-hydroxybutyrate plays a role in suppressing age-related inflammation[7].
Another animal study found that β-hydroxybutyrate suppressed the NLRP3 inflammasome (which induces inflammation), leading to reductions in inflammatory-mediated diseases[8].
Cognition and memory
As you may have read in our article on cognition and brain function, there is evidence that the keto diet has positive effects on cognition.
A significant component of this improvement seems to be due to the utilisation of ketone bodies.
A study conducted in patients with type II diabetes compared their working memory after supplementation with β-hydroxybutyrate or a placebo[9].
The results showed a significant improvement in working memory, corresponding to a 17% improvement in those supplemented with β-hydroxybutyrate, compared to placebo[9].
Another study showed cognitive improvement in Alzheimer’s patients, after supplementation with the ketone body β-hydroxybutyrate[10].
In this study, patients were either given placebo or an oral dose of medium chain triglycerides (MCTs). The supplemented MCTs were quickly broken down to ketone bodies, leading to elevated β-hydroxybutyrate levels[10].
Cognitive scores (measured by Alzheimer’s Disease Assessment Scale-Cognitive Subscale) significantly improved in the MCTs group, compared to placebo. Interestingly, higher ketone levels were associated with greater improvements in cognition[10].
This suggests that the ketone body β-hydroxybutyrate plays a significant role in cognitive improvement.
Epilepsy
The ketogenic diet is currently utilised as a treatment for epilepsy.
This is used especially in patients (and often in children) who have been unable to manage their symptoms through conventional drugs[11].
There is some evidence to suggest that ketone bodies are responsible for the decrease in frequency and severity of seizures that can be experienced in patients with epilepsy[12].
A study specifically examined the association between levels of β-hydroxybutyrate and seizure control in epileptic children[12].
The study found that having β-hydroxybutyrate levels greater than 4 mmol/L was significantly more likely to result in decreased seizure frequency, than those with lower levels[12].
This demonstrates that ketone bodies, notably β-hydroxybutyrate, have the ability to bring about positive health benefits.
The studies found that specific levels of ketone bodies are often associated with greater health benefits. So how can you measure levels of ketone bodies in your body to ensure optimal results?
How to measure ketone bodies in the body?
Measuring ketone bodies can be a helpful way to monitor whether you are in ketosis and enable you to optimise levels for health benefits.
In addition, diabetic individuals may be more likely to monitor their ketone levels. This is because uncontrolled high levels can lead to a condition called diabetic ketoacidosis (DKA), which can lead to severe health complications[13].
Currently, there are 3 primary ways to measure ketone bodies, which include chemical sensors to measure acetoacetate in urine, β-hydroxybutyrate in blood and acetone in breath.
Urine testing for ketone bodies
Urine ketone body test sticks are a cheap and simple way to measure ketone bodies.
The tests are based on the nitroprusside reaction, which detects acetoacetate[14].
These tests can detect the presence of ketones in urine, but they are not very reliable in terms of quantitative measurements. In addition, urine frequency and time since last urination, can influence the results obtained[14].
Furthermore, traditional urine tests only measure acetoacetate, which does not give a good indication of levels of β-hydroxybutyrate (the most common ketone body in the blood)[14].
These tests are recommended in resource poor environments, and where individuals want a cheap and easy way to monitor whether they are in ketosis.
Blood tests for ketone bodies
Blood testing for ketones is currently the gold standard measurement.
It involves measuring levels of all 3 ketone bodies, but with particular focus on β-hydroxybutyrate. This is because β-hydroxybutyrate is the most common ketone body detectable in the blood[14][15].
Blood tests are currently the most accurate way of measuring ketone levels and can be quantified with a high degree of accuracy and precision[14][15].
Blood testing provides a higher degree of sensitivity and specificity compared to a urine test, but is generally more expensive[15].
It is therefore recommended to use blood tests to monitor diabetic patients.
Breath tests for ketone bodies
Breath detection of ketones is a relatively novel way of measuring ketone levels and relies on detection of acetone.
Studies have shown that breath detection of acetone correlates to blood tests of β-hydroxybutyrate, representing a test with a high degree of specificity and sensitivity[16].
Breaths tests are a popular way to measure ketosis as they are a non-invasive method of reliably detecting ketone levels. In addition, these tests can be used with minimal preparation time and repeat measurements can easily be taken, without the complexity associated with blood tests[16].
Breath tests are however more expensive, which means they are not commonly used outside of clinical settings.
What level of ketone bodies should be maintained?
The optimal blood concentration of ketone bodies for nutritional ketosis is approximately 0.5 to 3 mg/dL[17].
In order to reach this level of ketone production through nutritional ketosis, carbohydrates should generally be limited to <50g net carbs per day[17].
Nutritional ketosis is a healthy state in which your body primarily uses ketone bodies for energy. This is in stark contrast to a diabetic complication known as diabetic ketoacidosis (in which levels of ketone bodies are 5 – 10 times higher than levels maintained during nutritional ketosis)[17].
Maintaining ketone levels of 0.5 to 3 mg/dL is safe and healthy in individuals without underlying health conditions e.g. diabetes.
It is recommended to consult a medical professional before adopting a new diet.
Can you supplement with ketone bodies?
The primary method of producing larger quantities of ketone bodies is through nutritional ketosis[2].
By severely limiting carbohydrate intake, insulin levels drop low enough that fatty acids are primarily converted into ketone bodies in the liver[2].
But can you maintain ketone body levels through supplementation?
In short, yes you can.
Given the health benefits associated with ketone bodies, there has been a large amount of interest in using supplements to mimic the effect of nutritional ketosis.
As mentioned in earlier cited studies, ketone supplements have led to improvements in inflammation, cognition and seizures[7][9][11].
In addition, there is emerging evidence that β-hydroxybutyrate supplementation can lead to improved exercise endurance and improvements in post-exercise recovery. As a result, there is growing interest among athletes who want to optimise their performance[18].
Ketone bodies are commonly supplemented in the form of ketone salts.
This is because ketone bodies in their free acid form are unstable and generally ineffective at producing sustained ketosis[19].
Another popular supplementation method is to use medium chain triglycerides (MCTs). This is because they are quite readily broken down into ketone bodies, inducing a state of ketosis[19].
In both cases, ketosis can be induced without carbohydrate restriction.
More recently, evidence is emerging on the utility of supplementing with ketone salts and MCTs simultaneously. This is because studies in rats have shown that combined supplementation leads to rapid and sustained levels of β-hydroxybutyrate[19].
Final thoughts
Ketone bodies are an alternate form of energy which on the keto diet, replaces glucose as the primary fuel.
As discussed, they have numerous proposed health benefits and can even be taken as a supplement, as a way to reap the benefits without carbohydrate restriction.
Understanding ketone bodies and their impact on health is still an active area of research.
If you would like to learn more about ketosis and ketogenesis, check out this article.
