Dichloroacetate improves systemic energy balance and feeding behavior during sepsis

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to an infection. The metabolic aberrations associated with sepsis underly an acute and organism-wide hyperinflammatory response and multiple organ dysfunction; however, crosstalk between systemic metabolomic alterations and metabolic reprogramming at organ levels remains unknown. We analyzed substrate utilization by the respiratory exchange ratio, energy expenditure, metabolomic screening, and transcriptional profiling in a cecal ligation and puncture model to show that sepsis increases circulating free fatty acids and acylcarnitines but decreases levels of amino acids and carbohydrates, leading to a drastic shift in systemic fuel preference. Comparative analysis of previously published metabolomics from septic liver indicated a positive correlation with hepatic and plasma metabolites during sepsis. In particular, glycine deficiency was a common abnormality of the plasma and liver during sepsis. Interrogation of the hepatic transcriptome in septic mice suggested that the septic liver may contribute to systemic glycine deficiency by downregulating genes involved in glycine synthesis. Interestingly, intraperitoneal injection of the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate reversed sepsis-induced anorexia, energy imbalance, inflammation, dyslipidemia, hypoglycemia, and glycine deficiency. Collectively, our data indicated that PDK inhibition rescued systemic energy imbalance and metabolic dysfunction in sepsis partly through restoration of hepatic fuel metabolism.

Automated summary

This study reveals the relationship between sepsis and systemic metabolic abnormalities, as well as the interaction between liver and systemic metabolic reprogramming. It was found that sepsis leads to an increase in circulating free fatty acids and acylcarnitines, but a decrease in levels of amino acids and carbohydrates, resulting in a drastic shift in systemic fuel preference. Furthermore, glycine deficiency was identified as a common abnormality in the plasma and liver during sepsis, and the septic liver may contribute to systemic glycine deficiency by downregulating genes involved in glycine synthesis. Moreover, the study found that the intraperitoneal injection of the PDK inhibitor dichloroacetate reversed various metabolic abnormalities induced by sepsis, partly through the restoration of hepatic fuel metabolism.