Ketone Bodies - The Basics

Ketone bodies are short chain, four-carbon organic acids, namely beta-hydroxybutyrate (BHB), acetoacetate (AcAc) and acetone. The primary physiological role of ketone bodies is to ensure survival of the brain (can't use fatty acids) during an energy crisis, as they provide 2/3's of the brains energy during prolonged starvation and 30-40% of total body energy demands after a 3-day fast. They also play a role in energy provision in skeletal muscle, as exercise increases the capacity of muscle to extract ketone bodies from the blood and athletic training enhances the capacity of an individual to use them as a fuel source. I will deal with BHB and AcAc because acetone plays a negligible role in energy provision. BHB is technically not a ketone body as the ketone moiety has been replaced with a hydroxyl (OH) group: 

From top to bottom: Acetone, AcAc, BHB

Ketone Body Formation (Ketogenesis)

Ketone bodies are produced in the mitochondria of the liver during situations characterised by low carbohydrate availability e.g. fasting, starvation and ketogenic diets (5% carbohydrate, 10-15% protein, 85% fat) or pathological conditions e.g. type 2 diabetes. Free fatty acids (FFA) liberated from adipose tissue are the primary substrate for ketone body production. Ketogenic amino acids e.g. leucine, lysine, isoleucine, tyrosine also contribute to ketogensis but play a minor role. Acetyl-CoA is formed after these FFA undergo b-oxidation and because oxaloacetate is being used in gluconeogensis, it is unable to condense and enter the citric acid cycle. Acetyl Co-A is shuttled into the ketogenic pathway as a result. After a series of reactions the first ketone body, AcAc, is formed and is reduced in a reversible reaction catalysed by 3-hydroxybutyrate dehydrogenase to form BHB, the most abundant ketone body in the blood. These ketone bodies are transported into circulation via the solute ligand carrier 16A family of monocarboxylate transporters (MCTs) that are present on mitochondrial and sarcolemmal membranes. 

Ketone Body Breakdown (Ketolysis) - Skeletal Muscle

Once the ketone bodies reach extra hepatic tissues e.g brain, skeletal muscle they will be broken down. They are again transported inside via the MCTs and BHB is reoxidised to AcAc, which undergoes further reactions to form two molecules of acetyl CoA. This can not occur in the liver because it lacks the enzyme succinyl-CoA:3-oxoacid CoA Transferase (OXCT). Once acetyl-CoA has been formed it enters the TCA cycle via citrate synthase and ends with production of ATP to fuel muscular work. 

The levels of ketone bodies in the blood is a balance between production and breakdown. Concentrations range from <0.1mM in the post prandial state to >10mM in patients with diabetic ketoacidosis. Hyperketonemia is defined as levels above >0.2mM. Levels can be increased through fasting, ketogenic diets and supplementation and can have a range of metabolic effects e.g. lowering glucose utilisation, anti-lipolytic effetcs and lowering proteolysis, all of which are involved in survival during an energy crisis by preserving precious fuel. 

Next: Ketone Bodies and Exercise

References:

https://en.wikipedia.org/wiki/Ketone_bodies

Evans, M., Cogan, K. E. and Egan, B. (2016), Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J Physiol. doi:10.1113/JP273185

Laffel L (1999). Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 15, 412–426. 

Paoli A, Rubini A, Volek JS & Grimaldi KA (2013). Beyond weight loss: a review of the therapeutic uses of very- low-carbohydrate (ketogenic) diets. Eur J Clin Nutr 67, 789–796. 

Robinson AM & Williamson DH (1980). Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 60, 143–187.