By Cliff Harvey
There is a lot of confusion about the term nutritional ketosis amongst people. It is important to understand when and why nutritional ketosis occurs, and the basis of a ketogenic diet.
So what exactly is ketosis?
Ketosis refers to the production of ketone bodies for use as an alternative fuel in times of fasting or drastic carbohydrate restriction. A restriction of carbohydrate, either by fasting or by restricting dietary carbohydrate results in reduced insulin levels, thereby reducing lipogenesis and fat accumulation. When glycogen reserves become insufficient to supply glucose necessary for normal fat oxidation (via the provision of oxaloacetate in the Krebs cycle) and for the supply of glucose to the Central Nervous System (CNS), an alternative fuel source is needed.
Can the CNS use fat as a fuel?
It is commonly suggested that the CNS typically cannot utilise fat for fuel, as the common dietary lipids (long chain fatty acids) are almost always bound to albumin and are unable to cross the blood-brain barrier, although this contention has been drawn into question, for example due to the easy desorption of FAs from albumin (1) and there may be other more subtle reasons as to why neurons, astrocytes and ganglia may be more adapted to using glucose for fuel. Namely that ß-oxidation of fatty acids (FAs) demands more oxygen than the oxidation of glucose, thereby increasing the risk of hypoxia of neurons, ß-oxidation of FAs generates superoxide, causing increased oxidative stress for neurons, and that the rate of ATP generation from fatty acids (as compared to glucose) is slower, and so in times of rapid neuronal firing there may be reduced fuel provision if FAs are the primary energy providing substrate for the brain (2). This suggests an evolutionary-adaptive advantage to lowering of fatty oxidative capacity of brain cell mitochondria to avoid these challenges and thus favours glucose oxidation in the brain.
Some dietary fats (such as short and medium chain triglycerides) are able to easily cross the blood-brain barrier (as they are not bound to albumin) and be used extensively by neurons, but their availability is scarce in the typical diet and so the CNS relies primarily on glucose for fuel.
Alternative fatty acid derived fuels ‘ketones’; acetoacetate and ß-hydroxybutyric acid (BOHB) and acetone, do not promote the same raft of problems associated with LCFA metabolism in the brain (2).
How are ketone bodies produced?
Ketone bodies are produced through a process called ‘ketogenesis’ in the liver to accommodate fuel demands during times of carbohydrate scarcity.
Acetoacetate is the primary ketone body, with BOHB providing the primary circulating ketone. Technically BOHB is not a ketone body (as the ketone moiety has been reduced to a hydroxyl group) however it functions as a primary fuel in the process of ketosis. Some acetoacetate is produced under normal dietary conditions (which include moderate to high levels of carbohydrate) but this small amount is metabolised readily and rapidly by skeletal and heart tissue, resulting in only minimal levels of circulating ketones. It has been clinically observed that higher fat, moderated carbohydrate diets (such as ‘Paleo’ and ‘Primal’ diets), not necessarily of a LCKD nature may result in consistently higher levels of circulating BOHB than would be seen in standard western-style (higher-carbohydrate) diets, yet still under the threshold of what is considered a functional or nutritional ketosis. A dearth of evidence in this area of broad metabolic adaptation to varying macronutrients (especially over a longer term of ingestion) requires further research and elucidation.
When acetoacetate is produced in large amounts it is able to accumulate and be converted into the other ketone bodies (acetone and BOHB) leading to the presence of ketones in the blood and urine (ketonaemia and ketonuria respectively) and in the breath.
Ketones are utilised by tissue as a source of energy. BOHB results in two molecules of acetyl CoA which enter the Krebs cycle. In ketosis blood glucose levels stay within normal physiological limits due to the creation of glucose from glucogenic amino acids and via the liberation of glycerol during fatty oxidation. In silico models further suggest a plausible conversion of fatty acids to glucose (3), more likely to occur in periods of carbohydrate restriction.
All these factors of ketone, fatty-acid and glucose regulation are crucially important as certain cell types—in particular red blood cells (RBCs), lacking mitochondria, are only able to use glucose as a fuel source and thus the preservation of stable glucose levels is critical for survival.
What is a ketogenic diet?
A ketogenic diet is a form of LCHF diet that is very low in carbohydrate, low to moderate in protein and high in fat. It is often termed a ‘very low carbohydrate ketogenic diet’ (VLCKD). VLCKDs are characterised by the expression of ketone bodies in the blood, breath and urine. This expression of ketones is a ‘functional’ nutritional ketosis as described above.
VLCKDs have been used to successfully treat childhood epilepsy since the 1920s with systematic reviews concluding efficacy for reduction of seizure frequency and severity (4; 5; 6) along with one meta-analysis (7) (authors noting a relative scarcity of high-quality randomised controlled trials) and a more recent randomised controlled trial (8). Carbohydrate dose appears to be inversely proportionate to seizure activity in ketogenic diets, with higher carbohydrate allowances (20g vs 10g per day) more tolerable (9; 10).
Much of the research elucidating the inducement of ketosis has come from the area of hospital epilepsy treatment and subsequent research.
Macronutrient ratios of differing amounts have been shown to affect the ability of the body to reach a state nutritional ketosis.
A ‘ketogenic ratio’ of 4 parts fat to 1 part protein and carbohydrate (a ‘4:1 protocol’) has been suggested as the best way to induce ketosis. This protocol forms the basis of the Johns Hopkins protocol (11) and is used by many medical practitioners and the research hospital of the same name in their treatment of childhood epilepsy. This ratio equates to approximately 80% of calories in the diet from fat. However evidence suggests that relatively lower fat diets (with approximately 60%-75% of calories from fat) can induce ketosis effectively if a significantly high proportion of Medium Chain Triglycerides (MCTs) are included (12) and that these ‘MCT diets’ are also effective in the treatment of epilepsy and seizures (13).
Huttenlocher (14) demonstrated that an MCT modified ketogenic diet with 60% of calories coming from MCTs, and exhibiting a 3 fold increase in carbohydrate (18% vs 6%) and a ~50% (7% vs 10%) increase in protein over a more standard (in this case 3:1) ketogenic diet could induce a functional ketosis for epilepsy treatment (with little clinically significant difference in BOHB levels). A fast has traditionally been used to initiate ketosis. Bergqvist and colleagues demonstrated that fasting for 24 hours followed by a 4:1 approach achieves a rapid induction of a functional, nutritional ketosis in epileptic patients within two days, with a further day required (mean serum BOHB across participants) for a gradual, non-fasted entry into ketosis (with a progressive daily increase in non-lipid to lipid ratio of: 1:1, 2:1, 3:1, 4:1), however there was no significant difference in efficacy or clinical outcomes between the two approaches (15).
1. Hamilton, J. A. (1998). Fatty acid transport: difficult or easy? Journal of Lipid Research, 39(3), 467-481.
2. Schonfeld, P., & Reiser, G. (2013). Why does brain metabolism not favor burning of fatty acids to provide energy[quest] - Reflections on disadvantages of the use of free fatty acids as fuel for brain. J Cereb Blood Flow Metab, 33(10), 1493-1499. doi: 10.1038/jcbfm.2013.128
3. Kaleta, C., de Figueiredo, L. F., Werner, S., Guthke, R., Ristow, M., & Schuster, S. (2011). In Silico Evidence for Gluconeogenesis from Fatty Acids in Humans. PLoS Computational Biology, 7(7), e1002116. doi: 10.1371/journal.pcbi.1002116
4. Keene, D. L. (2006). A Systematic Review of the Use of the Ketogenic Diet in Childhood Epilepsy. Pediatric Neurology, 35(1), 1-5. doi: http://dx.doi.org/10.1016/j.pediatrneurol.2006.01.005
5. Lefevre, F., & Aronson, N. (2000). Ketogenic Diet for the Treatment of Refractory Epilepsy in Children: A Systematic Review of Efficacy. Pediatrics, 105(4), e46.
6. Levy, R. G., Cooper, P. N., Giri, P., & Pulman, J. (2012). Ketogenic diet and other dietary treatments for epilepsy. The Cochrane Library.
7. Henderson, C. B., Filloux, F. M., Alder, S. C., Lyon, J. L., & Caplin, D. A. (2006). Efficacy of the Ketogenic Diet as a Treatment Option for Epilepsy: Meta-analysis. Journal of Child Neurology, 21(3), 193-198. doi: 10.2310/7010.2006.00044
8. Neal, E. G., Chaffe, H., Schwartz, R. H., Lawson, M. S., Edwards, N., Fitzsimmons, G., . . . Cross, J. H. (2008). The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. The Lancet Neurology, 7(6), 500-506. doi: http://dx.doi.org/10.1016/S1474-4422(08)70092-9
9. Kossoff, E. H., Rowley, H., Sinha, S. R., & Vining, E. P. (2008). A prospective study of the modified Atkins diet for intractable epilepsy in adults. Epilepsia, 49(2), 316-319.
10. Kossoff, E. H., Turner, Z., Bluml, R. M., Pyzik, P. L., & Vining, E. P. (2007). A randomized, crossover comparison of daily carbohydrate limits using the modified Atkins diet. Epilepsy & Behavior, 10(3), 432-436.
11. Freeman, J. M. (2007). The ketogenic diet: a treatment for children and others with epilepsy: Demos medical publishing.
12. Huttenlocher, P., Wilbourn, A., & Signore, J. (1971). Medium‐chain triglycerides as a therapy for intractable childhood epilepsy. Neurology, 21(11), 1097-1097.
13. Trauner, D. A. (1985). Medium‐chain triglyceride (MCT) diet in intractable seizure disorders. Neurology, 35(2), 237. doi: 10.1212/wnl.35.2.237
14. Huttenlocher, P. R. (1976). Ketonemia and Seizures: Metabolic and Anticonvulsant Effects of Two Ketogenic Diets in Childhood Epilepsy. Pediatr Res, 10(5), 536-540.
15. Bergqvist, A. G. C., Schall, J. I., Gallagher, P. R., Cnaan, A., & Stallings, V. A. (2005). Fasting versus Gradual Initiation of the Ketogenic Diet: A Prospective, Randomized Clinical Trial of Efficacy. Epilepsia, 46(11), 1810-1819. doi: 10.1111/j.1528-1167.2005.00282.x