Ketone bodies as chemical signals for the immune system.

Ketone bodies are short-chain fatty acids produced by the liver during periods of limited glucose availability, such as during fasting or low carbohydrate feeding. Recent studies have highlighted important nonmetabolic functions of the most abundant ketone body, β-hydroxybutyrate (BHB). Notably, many of these functions, including limiting specific sources of inflammation, histone deacetylase inhibition, NFκB inhibition, and GPCR stimulation, are particularly important to consider in immune cells. Likewise, dietary manipulations like caloric restriction or ketogenic diet feeding have been associated with lowered inflammation, improved health outcomes, and improved host defense against infection. However, the underlying mechanisms of the broad benefits of ketosis remain incompletely understood. In this Perspective, we contextualize the current state of the field of nonmetabolic functions of ketone bodies specifically in the immune system and speculate on the molecular explanations and broader physiological significance.