Dichloroacetate improves systemic energy balance and feeding behavior during sepsis

Abstract

Sepsis is a life-threatening organ dysfunction by dysregulated host response to an infection. The metabolic aberrations associated with sepsis underly an acute and organism wide hyper-inflammatory response and multiple organ dysfunction; however, crosstalk between systemic metabolomic alterations and metabolic reprograming 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 (CLP) 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 indicates a positive correlation with hepatic and plasma metabolites during sepsis. In particular, glycine deficiency was a common abnormality of both plasma and the liver during sepsis. Interrogation of the hepatic transcriptome in septic mice suggests 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 (DCA) reverses sepsis-induced anorexia, energy imbalance, dyslipidemia, hypoglycemia, and glycine deficiency. Collectively, our data indicate that PDK inhibition rescues systemic energy imbalance and metabolic dysfunction in sepsis partly through restoration of hepatic fuel metabolism.

Pyruvate dehydrogenase kinase supports macrophage NLRP3 inflammasome activation during acute inflammation

“…Previous studies of murine sepsis demonstrate that in vivo targeting of PDHK with DCA, administered as a single dose of 25 mg/kg 24 h post CLP, increases the septic survival rate to 71%, whereas the CLP animals not receiving DCA treatment had a survival rate of only 10% over the 14-day observation period (McCall et al, 2018). Despite the less effect of PDHK inhibition on LPS-induced cytokine expression in BMDMs ( Figures S1H-S1I ), very recently, our group demonstrated that in vivo PDHK inhibition by DCA lowered plasma non-inflammasome cytokines, including TNF and IL-6 in the CLP mice (Oh et al, 2022), suggesting an anti-inflammatory effect of PDHK inhibitors in bacteria-infected animals. Given that macrophage NLRP3 inflammasome plays a critical role in the pathogenesis of sepsis, we asked whether DCA confers survival partially through down-regulation of the NLRP3 inflammasome during sepsis.…”