Ketones are chemical compounds that contain two constituents bonded to a carbon atom that is also double bonded to an oxygen atom. In human metabolism the ketones are the keto acids (also referred to as ketone bodies) identified as beta-hydroxybutyrate and acetoacetate. These ketones are produced in the liver from any nutrient (fat, carbohydrate, and amino acid) that, when oxidized, yields acetyl-CoA (acetyl-coenzyme A). Acetyl-CoA is converted to the ketones in the liver and the ketones are delivered to the blood, taken up by non-hepatic tissues, metabolized back to acetyl-CoA and then oxidized in the TCA cycle yielding the energy needed for ATP synthesis. The process of ketone synthesis is referred to as ketosis.
The pathway for the hepatic synthesis of ketones and the extra-hepatic tissue utilization of the ketones is outlined in detail in the Fatty Acid Oxidation page of my website:
Ketosis is the the normal metabolic response to an energy deficit or a metabolic crisis. The typical metabolic process of ketone synthesis occurs continuously under normal metabolism but increases dramatically during periods of fasting and starvation. Indeed, the process of ketosis is critical for long-term survival during periods of starvation. The normal production of ketones during fasting, and in periods of starvation, is essential to provide an oxidizable carbon source for use by the brain while simultaneously conserving precious glucose (produced by the gluconeogenic pathway) reserves for use by red blood cells which can survive only by the oxidaiton of glucose. The consumption of a diet high in fatty acids, such as the Atkins diet (often called the ketogenic diet), can lead to increased ketone production even without an energy deficit. However, in certain disease state, particularly in type 1 diabetes, the aberrant overproduction of ketones results in potentially severe metabolic acidosis referred to as diabetic ketoacidosis, DKA. The pathology of DKA is associated with the potential for life-threatening complications in blood electrolyte balance (particularly potassium) which can easily precipitate cardiac failure and death.
There is significant research demonstrating why and how we make and utilize ketones during periods of fasting, and the metabolic benefits of these pathway to survival. However, little research has looked at the potential benefits, if any, of the dietary consumption of ketones, independent of a caloric or carbohydrate deficit. Essentially all tissues, except the liver, can utilize ketones as an energy source. In addition, ketones regulate the mobilization and utilization of other fuel substance. A recent publication in the journal Cell Metabolism demonstrates a unique and potentially physiological significance associated with dietary ketone intake, that being enhanced endurance performance in athletes. The premise behind this study was the understanding that the metabolic demands of long-term performance exercise closely mimic the metabolic conditions that are precipitated by starvation.
Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes
One can achieve ketosis by direct consumption of beta-hydroxybutyrate but due to the necessity of consuming this compound in the acid form or as a salt, it can lead to significant acidification and increasing salt loads. The studies undertaken in this paper utilized an esterified form of ketone, ethyl (R)-3-hydroxybutyrate. The resultant ketone is identified as (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. When this ketone is ingested intestinal esterases cleave the compound into its constituent parts, beta-hydroxybutyrate and (R)-1,3-butanediol. Both of these compounds were shown to be efficiently absorbed and delivered to the portal circulation delivering them to the liver. Within the liver the butanediol is metabolized to beta-hydroxybutyrate. When released from the liver to the blood the beta-hydroxybutyrate can taken up by other tissues and oxidized for energy.
During exercise, especially as the intensity increases, there is an increased demand for, and reliance on, glucose oxidation within skeletal muscle. This condition can result in restricted utilization of glucose by the brain and red blood cells. Therefore, the authors reasoned that the metabolic rearrangements induced by ketosis may represent a means for sustaining physical performance in humans.
Several experiments were carried out in volunteers to examine the fuel selection during exercise when ingesting a drink containing the ketone ester, carbohydrate, or fat. Each individual in the study on each of the "diets" underwent resting and exercise blood ketone analysis.As would be expected those individuals consuming the ketone ester drink showed a rapid rise in blood ketones at rest following an overnight fast. However, the level of blood ketones remained at the elevated level during a 1 hr cycling exercise. Serum lactate levels were similar in all three study groups at rest but were significantly lower in the ketone ester group following exercise. Exercise caused a significant rise in plasma glycerol in the carbohydrate and fat consuming participants but not in the ketone ester participants. Glycerol is normally released from adipose (fat) tissue in response to fasting and exercise induced increases in fatty acid release from triglycerides stored in adipose tissue. Other metabolic parameters, such as blood glucose and insulin levels were as predicted based upon the "diet" consumed. For example glucose ingestion triggers a rapid rise in insulin release and this was seen at greater levels in the participants consuming the carbohydrate "diet".
The ingestion of the ketone ester drink resulted in dramatic alterations in the metabolic profiles of skeletal muscle both at rest and during exercise. Prior to, and following exercise the concentrations of glucose oxidation (glycolysis) products were significantly lower in skeletal muscle in the ketone ester consuming participants compared to those that consumed the fat or carbohydrate drinks. Therefore, consumption of the ketone ester significantly alters muscle glucose utilization during exercise explaining the reduced levels of blood lactate that were observed. In addition, the ingestion of the ketone ester significantly decreased the demand for oxidation of the branched-chain amino acids (BCAA), leucine, isoleucine, and valine. The BCAA are enriched in skeletal muscle proteins due, in part, to their significant energy content that can be utilized during periods of fasting and starvation as well as during strenuous exercise. The sparing of the BCAA during exercise following ketone ester ingestion allows for an increased maintenance of muscle mass.
In the highly trained athletes in this study it was found that the consumption of the ketone ester drink, which alters muscle metabolic profiles, resulted in an approximately 2% increase in exercise performance. Given that skeletal muscle CANNOT obtain energy from acetyl-CoA, ketosis is not advantageous under all physiological conditions such as those conditions that rely almost solely on anaerobic (oxygen free) metabolism. Because anaerobic oxidation of glucose to pyruvate yields ATP it is the only metabolic pathway that can provide muscle the energy it needs during sprinting or short burst high intensity exercise.
The take home from this study is that ingestion of ketones, in conjunction with adequate carbohydrate and fat, alters the normal metabolic processes that take place within skeletal muscle during exercise and that these changes have the potential to increase the level of intensity attainable during endurance physical activity.