35. Ketone Homeostasis During Fasting

Ketone homeostasis has two central objectives: 1) keep ketone levels high enough to feed the brain, and 2) keep ketone levels low enough to avoid the serious and life-threatening condition of ketoacidosis. While proportion of circulating ketones taken up by skeletal muscle, heart, and other tissues during fasting is initially high, these tissues limit their absolute uptake of ketones and may even lower their uptake in response to increased availability of free fatty acids. As a result, ketone concentrations rapidly outpace production rates, and this is exactly what allows them to reach high enough concentrations to feed the brain. To outcompete glucose for transport across the blood brain barrier, they also act on the liver to suppress glucose output, causing blood glucose to lower. While high ketones and low glucose favor maximal penetration of ketones into the brain, the threat of ketoacidosis requires a negative feedback loop. Thus, ketones suppress adipose tissue lipolysis, restraining their own production so that blood concentrations stay in the sweet spot to safely nourish the brain.