Implications of Ketosis George Cahill, Jr., M.D. (Harvard School of Medicine, Cambridge, MA) “Ketosis” refers primarily to increased levels of D- ß-hydroxybutyrate (BOHB), namely above 1mM. When BOHB is low, acetoacetate is equally low (both ~0.1mM or less) , but when BOHB is high (5-10mM) , there may be a 3 to 10-fold difference. Very long chain polyBOHB molecules serve as an energy reserve in many bacteria, up to 90% dry weight in some, but shorter chain polymers appear in all living organisms as components of cell membranes. Triglyceride for energy storage first appears in animals (worms, flies. etc.) and thanks to its extrea-aqueous nature becomes the primary fuel storage where mobility is critical, particularly in a terrestrial or airborne environment. Thus fatty acids become the primary caloric fuel for creatures challenged by gravity. The exclusion of nerve tissue from body fluids, even in lower vertebrates and some invertebrates and other lower forms, is necessary for nerve function ( particularly very rapid responses). This prevents fatty acid entry, permitting access of only small aqueous-soluble molecules like glucose and BOHB. With the evolutionary enlargement of the brain, dramatically explosive in man, BOHB has become the primary brain fuel when carbohydrate is not available from glycogen or diet. High dietary protein can provide sufficient gluconeogenic substrate for brain glucose use. However, it is interesting to point out that the maximum rate of urea synthesis permits man to ingest an amount of protein permitting the 125 grams of glucose for brain to be made by liver (with a little extra by kidney). Otherwise, as in the neonate or the starving child or adult, ketosis is required to spare the rapid and fatal nitrogen mobilization needed to supply the gluconeogenic substrate. Any creature whose brain is less than 5% of total metabolism need not get ketotic with starvation, since the glycerol released with the fatty acids is an adequate gluconeogenic substrate for brain glucose use. These creatures include marine mammals, the black bear, the emperor penguin and many others which endure prolonged starvation. Fasting levels of BOHB of about 5mM or higher are essentially unique to H. sapiens and probably date back 2-3 million years to the earliest hominids. The bonobo, our closest primate relative, has a brain of only 3% body weight and bets are, if fasted, does not develop, like the bear or whale or seal, ketosis on starvation. We are really unique!