Hepatic STAT3 inhibition amplifies the inflammatory response in obese mice during sepsis

The purpose of this study was to better understand the role obesity plays in the inflammatory response during sepsis, specifically regarding the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway in the liver. We hypothesized that inhibiting STAT3 would lead to an increase in the inflammatory response and that obesity would amplify this effect. To investigate this, we inhibited STAT3 in two ways: pharmacological systemic inhibition and genetic hepatic-specific inhibition. In pharmacological inhibition studies, male C57BL/6 mice were randomized to a high-fat (60% kcal fat) or normal (16% kcal fat) diet for 6-7 wk and pretreated with Stattic before inducing sepsis by cecal ligation and puncture. In genetic inhibition studies, mice were randomized by genotype before induction of sepsis. To investigate obesity in mice with hepatic-specific STAT3 inhibition, we randomized mice to a high-fat or normal diet as described above for 6 mo before induction of sepsis. Body composition was analyzed using EchoMRI. We found that systemic STAT3 inhibition by Stattic resulted in an increased inflammatory response and that obesity amplified this effect. We also found that genetically inhibiting STAT3 in the liver resulted in higher mortality, increased inflammation, and liver injury. High-fat-fed mice with hepatic STAT3 inhibition gained more weight and had more fat than control mice on the same diet, and obesity increased neutrophil infiltration to the liver of these mice during sepsis. In conclusion, STAT3 plays an important regulatory role in the inflammatory response during sepsis, and obesity contributes to the dysregulated response observed when STAT3 is inhibited.