Beta-hydroxybutyrate or BHB, other than being an intimidating tongue twister, is a molecule that often features in ketosis discussions. You may have come across the word a lot in discussions of the ketogenic diet and may be left overwhelmed with the abundance of jargon. Don’t worry though if you’re not quite sure about it! This article will demystify what it actually is, the science behind what it does, where it comes from and why it is important to you for the purposes of optimizing your keto goals and knowledge. You’ll then be able to make more informed choices to suit your requirements.
Let’s start with the technical description. BHB or beta-hydroxybutyrate is also known as Beta-hydroxybutyric acid or 3-hydroxybutyrate. It is an organic compound with formula C4H8O3.1 BHB has a property called 'chirality,' or 'optical isomerism.' What's this, I hear you ask? It means that there are mirror images of BHB that exsist in nature. Think of your left and right hand. Both have four fingers and a thumb, but they are can't be overlayed onto one another. There are left and right handed forms of BHB, called D- and L- BHB. Our body makes D-BHB and uses it for energy. We don't normally make L-BHB, and if you consume this form, it does not get removed from the blood quickly. 2 Research suggests L-BHB might be directed into cholesterol synthesis in the body. 3
With regards to ketones in metabolism, BHB is considered one of the three ketone bodies. However, if we’re being finicky, this isn’t really true. Chemically speaking, it does not have the chemical bonds needed to match the definition of a ketone. This would be when you have carbonyl carbons that are bonded to two other carbon atoms, for those of you interested.
Technicalities aside then, BHB is considered one of the three ketone bodies since it behaves like a ketone in the body, and so we’ll go along with this for the purposes of our discussion. D-BHB levels increase in the brain, heart, muscle, liver and other tissues when restricting calories, fasting, following a ketogenic diet or even through exercise.4
Before diving further into an exploration of BHB, let us first clarify our basic keto knowledge with a quick recap. Normally, we eat carbohydrates that are converted into glucose in the blood. This glucose is used as the brain’s primary source of fuel. However, when restricting carbohydrate intake when following a ketogenic diet, the brain must use an alternative source of fuel as blood glucose levels are low. The body then adapts to turning fatty acids into ketones, and it is these ketones that can be used as the major source of fuel for the brain (up to 60%).5
“Ketogenic” fatty acid metabolism produces 3 different types of ketones:
The first one, acetone, is the least abundant as it is produced in much smaller amounts, and primarily ends up being exhaled through the lungs rather than being used as fuel.6 Acetoacetate is part of the metabolic pathway whereby humans make and use ketones but tends to be found in the blood at lower levels than D-BHB. D-BHB is the predominant blood borne ketone body.
Now we’ve understood this…let’s dive into where D-BHB comes from!
D-BHB is found in nature; in fact, your own body makes it (i.e, endogenous D-BHB). As we’ve established, when the body does not have enough carbohydrates to use as fuels, it turns fatty acids into ketones in a process known as ketogenesis. The first of the ketones that are made in the fasting state is Acetoacetate (AcAc). This forms as a result of the breakdown of fatty acids through to produce acetyl CoA, which then undergoes a chain of reactions to eventually form AcAc. In the liver, the BHB-dehydrogenase enzyme reduces AcAc to form D-BHB. This D-BHB then goes on to be used as fuel for the body and is the primary circulating ketone body.
Thus, it makes sense that being in ketosis raises D-BHB levels. In fact, the liver is regularly producing ketones to some small extent; typically after an overnight fast blood BHB might be 0.1 - 0.3 mM. The best way to raise production of endogenous D-BHB to reach a state of nutritional ketosis over 0.5 mM of D-BHB, is through restricting carbohydrates, fasting or by following a ketogenic diet.
Waiting for the body to naturally produce ketones can be difficult and unpleasant. To get around the need for fasting or a ketogenic diet, exogenous BHB can be consumed through the form of exogenous ketones that are a kind of BHB supplement. While BHB is found at trace amounts in many foods including eggs and milk, this would not usually raise blood ketone levels. In order to eat BHB in sufficient amounts to raise ketones, you can use ketone salts and ketone esters. Medium chain triglycerides (MCT) do not contain BHB itself, but MCT consumption can raise D-BHB slightly.
BHB salts are a compound consisting of a mineral ion such as sodium (Na+), potassium (K+), and the ketone body betahydroxybutyrate. In the supplement, the compound is held together by ionic bonds, but when consumed, the salt dissociates into free Na+, K+, and BHB. Thus, BHB blood concentrations are raised. Levels typically reach 0.5 - 1 mM.2 Many BHB salts contain a high amount of L-BHB, which doesn't get burned as easily as D-BHB. This is because it is tricky to seperate D- and L- BHB in the lab. Why is BHB combined with sodium and potassium? Mainly because BHB has to be bound to something and these salts are easy and cheap to make. One advantage of using the salt form of BHB when on the ketogenic diet is that consumption replenishes electrolytes lost in the urine: being on the diet can have a diuretic effect.
Ketone esters are ketone drinks, where the raw ketone (here, BHB) is bound to a ketone precursor using an ester bond. HVMN Ketone is the world’s first commercially available ketone ester drink. It contains D-BHB bound to precursor called butanediol. There is no extra mineral load in ketone esters. The uptake of BHB from ketone ester drinks tends to be faster, and levels reach 3-5 mM, several time higher than after ketone salt drinks.2
Other than salts and esters, blood D-BHB can be elevated indirectly by taking MCT (medium chain triglyceride) oils. Medium chain triglycerides are fats that must be broken down to produce D-BHB before being used for energy, so energy from MCT oil powder is obtained more slowly than from than ketone salts. Moreover, these are calorically dense so not an ideal solution for those wishing to keep calories low in order to burn fat.
But why bother supplementing with BHB? This is because supplements have been shown (with a mixture of anecdotal and scientific evidence) to provide several health benefits including:
For athletes, in particular, using exogenous ketone bodies from HVMN Ketone allows them to reap the benefits of having ketones as an extra energy without being in nutritional ketosis and depleting their glycogen levels.
So now we’ve established what it is and where it comes from, what does it actually do?
Firstly, we’ve established that D-BHB can produce energy. This happens through a process known as ketolysis. Ketones are broken down using aerobic respiration inside the mitochondria. Ketolysis happens throughout all tissues in the body except the liver (as it does not contain one of the key enzymes for ketone oxidation).
The D-BHB, when it has entered the mitochondria of the cell, is converted to acetoacetate, after which it undergoes a reaction where CoA is added. This results in acetoacetyl-CoA. This is then cleaved to form acetone and acetyl-CoA. The acetyl-CoA progresses into the Krebs cycle and results in the production of ATP, the energy needed for the cells!9 There you go, D-BHB → energy!
D-BHB can cross the blood-brain barrier, meaning it can cross from the peripheral circulation to the central nervous system.4 This means, besides providing energy, D-BHB has several other functions inside the brain.
D-BHB can trigger the release of chemicals called neurotrophins, which support brain health. One of these is called BDNF, raising D-BHB can increase the levels of this neurotrophins in the brain area called the hippocampus.10 BDNF, brain-derived neurotrophic factor, is a protein in the brain that associates with cognitive enhancement, alleviation of depression and reduction of anxiety. Moreover, D-BHB increases the signaling in TrkB, which is the receptor for BDNF (Sleiman2016)!
D-BHB can also help to reduce inflammation in the brain. A study conducted in 2017 that observed rats found that D-BHB was associated with the reduction of stress-induced neuro-inflammation.11
The combination of energy provision, neurotrophins and anti-inflammatory actions mean that D-BHB is a promising substrate that could help with various neurological conditions. For example, in a study conducted on 20 subjects with Alzheimer’s disease or demonstration of a mild cognitive deficit, increased body D-BHB levels were found to be associated with greater cognitive performance through better performance in memory recall tests.12 Similarly, HVMN Ketone helped to reverse symptoms of Alzheimer's Disease in one clinical case study.13 More research in humans is needed, but the various hypothesis are backed up by strong animal data.
The three ketones are measurable as follows:
D-BHB is the most abundant of the ketones and is widely used to measure ketone levels since it is present at far higher levels than Acetone and Acetoacetate. Moreover, the laboratory reactions required to measure it are easier to conduct. Also, as D-BHB is mostly outside the cell, it can be measured in the blood as it is being carried to your cells. For this reason, it is considered the most accurate and convenient measure of the ketogenic state.
Blood D-BHB can be measured using a blood glucose monitor, which also has the capability to measure blood ketone levels. The test can be done at home, much like the way those with diabetes check their blood sugar. With a simple finger prick, a small droplet of blood can be placed on a testing stick, and then popped into a monitor to reveal D-BHB blood levels. The monitor can't measure L-BHB. Measuring D-BHB in blood is considered more accurate than measuring acetoacetate in urine. This is because urine ketone measurements are affected by several factors including dilution and hydration.
If you’re falling in the 0.5-3 mM range after a reading from a blood test, this means you’ve entered nutritional ketosis.
Another reason you should be interested in BHB is that it is the most common ketone body in commercially available ketone supplements. This is because of its stability and abundance, making it easier to put into a product form. HVMN Ketone contains 98.24% D-BHB and D-BHB precursor.
Taking an exogenous supplement, like HVMN Ketone, has the benefit of providing an energy source and putting you into ketosis a lot faster than simply following a low-carb diet. It also allows you to bypass the period of adaptation, the keto flu, and the symptoms that come with it. The symptoms may include dehydration, cravings, nausea, vomiting, and constipation among others. Taking exogenous BHB can reduce these symptoms. As a note of caution, BHB supplementation as ketone salts and MCTs has been known to cause some gastrointestinal distress initially, so we advise easing into it and increasing the intake slowly.
A final important thing to note is that taking ketone supplements won’t trigger production of ketones in the body. So you ARE NOT in a ketogenic state after taking exogenous ketones. However, exogenous ketones DO put you in the state of ‘ketosis’ (having raised levels of blood ketones) and this may allow you to reap some of the benefits of D-BHB without fasting or following a ketogenic diet.
So there you have it. Now, equipped with more knowledge about BHB and the processes going on inside your own body, you’ll be better able to make sound decisions to optimize your keto goals. Good luck!
Webber, R.J., and Edmond, J. (1977). Utilization of L(+)-3-Hydroxybutyrate, D(-)-3-Hydroxybutyrate, Acetoacetate, and Glucose for Respiration and Lipid-Synthesis in 18-Day-Old Rat. J Biol Chem 252, 5222-5226.
Sleiman SF, Henry J, Al-Haddad R, et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elmquist JK, ed. eLife. 2016;5:e15092. doi:10.7554/eLife.15092.
Yue Qiao, Zhaohua Gao, Yong Liu, et al., “Breath Ketone Testing: A New Biomarker for Diagnosis and Therapeutic Monitoring of Diabetic Ketosis,” BioMed Research International, vol. 2014, Article ID 869186, 5 pages, 2014. doi:10.1155/2014/869186
Murray, A.J., Knight, N.S., Cole, M.A., Cochlin, L.E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M.K., Atherton, H.J., Schroeder, M.A., et al. (2016). Novel ketone diet enhances physical and cognitive performance. FASEB J.
Cox, P.J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., Murray, Andrew J., Stubbs, B., West, J., McLure, Stewart W., et al. (2016). Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes. Cell Metabolism 24, 1-13.
Yamanashi, T., Iwata, M., Kamiya, N., Tsunetomi, K., Kajitani, N., Wada, N., Iitsuka, T., Yamauchi, T., Miura, A., Pu, S., et al. (2017). Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses. Sci. Rep. 7, 7677.
Reger, M.A., Henderson, S.T., Hale, C., Cholerton, B., Baker, L.D., Watson, G.S., Hyde, K., Chapman, D., and Craft, S. (2003). Effects of beta-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol. Aging 25, 311-314.
Newport, M.T., VanItallie, T.B., Kashiwaya, Y., King, M.T., and Veech, R.L. (2015). A new way to produce hyperketonemia: use of ketone ester in a case of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 11, 99-103.
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