Figure 4. Lipolysis, fatty acid oxidation, and ketogenesis in sepsis.

Sepsis is associated with the development of an anorectic response since patients are often unwilling or unable to eat. During a normal starvation response and during sepsis, lipolysis in white and brown adipose tissue is being upregulated by several pro‐lipolytic signals. The inhibitory effect on lipolysis of insulin, which is upregulated in sepsis due to high glucose levels, is however absent due to insulin resistance. Free fatty acids (FFAs) in the blood are upregulated in both conditions and can be taken up by peripheral organs to produce energy. The increased FFA levels activate and upregulate the expression of PPAR‐α, the main transcription factor responsible for the induction of genes involved in the β‐oxidation of fatty acids and the production of ketone bodies (KBs). During sepsis, PPAR‐α levels are downregulated and the breakdown of fatty acids through β‐oxidation is compromised, causing FFAs to accumulate in organs such as the liver, heart, and kidney, but also in the blood. Overall, the deficits in FFA breakdown during sepsis cause a shortage of energy and lipotoxicity and mitochondrial damage due to FFA accumulation. Green represents the normal starvation response, and red represents the response during sepsis.