I have been aware of ketones since my college nutrition class, but I've never had anyone explain them outside of "a product of fat metabolism." Ketones are a nutritional antihero - they are a critical part of our physiology, but they have developed a certain mysteriousness and notoriety. While this makes for an exciting adventure through nutrition books, it hinders the public understanding of nutrition. As such, ketones and ketosis have become red herrings due to poor information. And this is as good of a time as any to discuss what ketones are, and how and why they are produced.
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| Source: Wikipedia |
"Ketones" refers to a family of compounds that contain a particular functional group, or more simply, a specific structural signature. The adjacent images are the three ketones relevant to ketosis in the body and are often referred to as "ketone bodies." And don't worry, I don't take anything away from their molecular structure either. From top to bottom, they are acetone, acetoacetate, and β-hydroxybutyrate (BHB). Fatty acids are metabolized into acetoacetate and BHB to be used for energy, and acetone is a spontaneous byproduct. How ketones become useful gets a bit more complicated.
Understanding ketosis requires a brief detour into food catabolism - the metabolic process that breaks down our food for energy. Carbohydrates, fat, and protein can be used to produce energy. We can either eat them or take them from our body stores (glycogen, body fat, and muscle, respectively). To get energy from these foods, we eventually want them to undergo a metabolic process known as the Tricarboxylic Acid Cycle (TCA cycle, or Kreb's Cycle). Acetyl-CoA is the molecule that enters the TCA cycle to produce the necessary metabolites for aerobic metabolism and subsequent energy production. Through different metabolic processes, carbohydrates, fat, and protein can be converted into acetyl-CoA, and therefore all can converge onto the TCA cycle and eventually produce usable energy.
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| Simplified depiction of aerobic metabolism |
Our bodies preferentially use carbohydrates and fat for energy when carbohydrates are plentiful. When carbohydrate availability becomes sufficiently low, such as during exercise, prolonged fasting or starvation, or during uncontrolled insulin-dependent diabetes, our bodies will use protein to make glucose and shift heavily towards fat metabolism. Muscles will readily metabolize fatty acids for fuel - either from circulating fats or from fat stores within the muscle. The brain, however, cannot directly metabolize fat, but can do so indirectly by using ketones. The ketones are produced exclusively in the liver, where fatty acids are converted to acetyl-CoA then to ketone bodies. These ketone bodies circulate to muscle and the brain, where they are reconverted into acetyl-CoA and further metabolized for fuel (just like our food “substrates” in the figure above). This increase in ketone production, and concomitant elevation in the blood, is ketosis.
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| Ketone production and distribution. Source: FreeDigital Photos. Liver = dreamdesigns, brain=smokedsalmon, arm=ambro |
It is often stated that the brain needs a certain amount of glucose, and therefore we must eat this amount of glucose. However, this is overstated. In the presence of sufficient carbohydrate, the brain will preferentially metabolize glucose; but the brain has no problem using both ketones and glucose produced from protein (the body ensure glucose is produced for the brain). As an analogy, children will preferentially consume soda rather than vegetables, but we don’t simply conclude that children must consume a certain amount of soda. Furthermore, according to Freeman and Kossoff, the newborn brain will "avidly" use ketones for fuel, and the developing fetus uses ketones to form the myelin that surrounds the nerves. And as Brooks, Fahey, and Baldwin explain in the prominent textbook Exercise Physiology: "During dietary starvation, the ability to sustain life depends on the bodies ability to form and utilize ketones." However, we can also enter ketosis while forgoing starvation.
In the succinct words of Freeman and Kossoff, "the ketogenic diet is a high-fat, adequate protein, low-carbohydrate diet designed to produce ketosis through mimicking the metabolic changes of starvation." The "classic" ketogenic diet is comprised of a greater than 3:1 ratio of fat to carbohydrates and protein. This diet has been used to control seizures in epileptic children since the 1920's and is "as effective, perhaps more effective, than current anticonvulsant medications." However, few people, even low carb fanatics, will maintain such a herculean diet since consuming more than adequate protein will halt ketosis, at least transiently.
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Despite it's notoriety as a ketogenic diet, the Atkin's diet is better described as a "transiently ketogenic" diet - to borrow a phrase from Robb Wolf - and ketosis will likely only occur during the "induction phase" of the diet. Since the Atkin's diet relies heavily on meat and vegetables, and less so on cream and eggs, it is comprised of a roughly 1:1 ratio of fat to carbohydrate and protein. Each high-protein meal would likely halt ketosis, but delaying a meal and fasting overnight (sleep) would likely permit ketosis.
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And what about ketosis and diabetes? Diabetic ketoacidosis can occur when an insulin-dependent diabetic is not treated with insulin. Without insulin, most cells cannot use the accumulating blood glucose so the body “thinks” it is starving; the liver than continually produces more and more ketones. The accumulating ketones acidify the blood, which is exasperated by dehydration caused by glucose (and water) excretion into the urine. This is acidosis and will lead to coma and death if not treated with insulin. Of note, ketoacidosis-induced coma can be distinguished from insulin-induced coma by the "fruity" smell of acetone on the breath. Remember that I said acetone is a spontaneous byproduct of ketone production? While I couldn't find consistent numbers for ketone levels in dietary ketosis versus ketoacidosis, ketoacidosis has blood ketones somewhere between 20-30 times higher than non-ketosis levels and between 4 to 10 times higher than dietary/fasting ketosis. Ketosis is physiological and regulated; ketoacidosis is pathological.
So after all this, simply stated, ketones are a product of fat metabolism. But a product that allows our brain, and therefore us, to survive without dietary carbohydrate. Antagonists of low carb diets frequently portray ketosis as a boogeyman, even though there is little reason to think that it is. However, as the blogger HyperLipid has asked, "I think it's an open question about whether placing yourself at the very extremes of physiology is a good or a bad thing. It should certainly assist weight loss, but would it improve health?" At the very least, we can say that ketosis is a normal physiologic process. And if starvation or carbohydrate unavailability was a semi-frequent occurrence in our evolutionary history, than perhaps we can compare ketosis to vigorous exercise – total avoidance is more abnormal than normal.
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