Sepsis: a failing starvation response

Sepsis is associated with severe metabolic dysregulation. Two key metabolic transcription factors, GR and PPARα, are dysfunctional in sepsis, leading to failure of the starvation response. Metabolites such as lactate and free fatty acids accumulate and contribute to disease progression in sepsis. Further characterization of metabolic dysregulation might uncover novel therapeutic targets for treating sepsis patients. 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. 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. reduced food intake. the gold-standard method for inducing peritonitis in animal models. It involves a combination of three insults: tissue trauma through laparotomy, necrosis caused by ligation of the cecum, and infection due to leakage of peritoneal microbial flora into the peritoneum. a metabolic pathway in which lactate produced by anaerobic glycolysis in muscle moves to the liver and is converted to glucose, which in turn is metabolized back to lactate in muscle. non-esterified fatty acids that are released by the hydrolysis of triglycerides in adipose tissues. FFAs can be used as an immediate source of energy by many organs and can be converted into ketone bodies by the liver. the metabolic process by which glucose is generated from smaller precursors such as amino acids and glycerol. the generation of ATP through glucose degradation that is usually associated with anaerobic conditions. a means that animals use to conserve energy (by reducing activity and/or metabolism) and survive adverse weather conditions or lack of food. a metabolite that serves as a signal transducer to regulate immune cell function and disease outcome. the production of ketone bodies (KBs) by breaking down fatty acids and ketogenic amino acids. KBs generated by ketogenesis supply energy to some organs, especially the brain. the addition of a lactyl group to a molecule. the process of breaking down of lipids into fatty acids and glycerol. the accumulation of lipid intermediates in tissues other than adipose tissues that cause cell damage in these tissues. a metabolic pathway in which fatty acids are metabolized to generate energy. malnutrition following, for example, anorexia, gastrointestinal disease, cancer, or coma. The metabolic response to starvation is to provide energy via catabolism of body tissues (muscle, adipose tissue, liver).