Sepsis: a failing starvation response.

Sepsis is involved in ~ 20% of annual global deaths. Despite decades of research, the current management of sepsis remains supportive rather than curative. Clinical trials in sepsis have mainly been focused on targeting the inflammatory pathway, but without success. Recent data indicate that metabolic dysregulation takes place in sepsis, and targeting metabolic pathways might hold much promise for the management of sepsis. Sepsis yields a strong starvation response, including the release of high-energy metabolites such as lactate and free fatty acids. However, the activity of two major transcription factors, GR and PPARα, is downregulated in hepatocytes, leading to the accumulation and toxicity of metabolites that, moreover, fail to be transformed into useful molecules such as glucose and ketones. We review the literature and suggest mechanisms and potential therapeutic targets that might prevent or revert the fatal metabolic dysregulation in sepsis.