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Updated: Jan 31, 2026
Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice
Published on: March 10, 2017
Hepatic STAT3 inhibition amplifies the inflammatory response in obese mice during sepsis
Lauren Williamson1, Itay Ayalon1, Hui Shen1
1Cincinnati Children's Hospital Medical Center, Division of Critical Care Medicine , Cincinnati, Ohio.
Abstract:
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.
Insights
Obesity amplifies the inflammatory response during sepsis when STAT3 signaling is inhibited. This study shows STAT3 plays a key role in regulating sepsis inflammation, with obesity worsening outcomes.
Area of Science:
- Immunology
- Metabolic Disorders
- Hepatology
Background:
- Sepsis triggers a complex inflammatory response, crucial for pathogen clearance but potentially damaging if dysregulated.
- Obesity is increasingly recognized as a risk factor influencing sepsis severity and outcomes.
- The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, particularly STAT3, is implicated in inflammatory and metabolic processes.
Purpose of the Study:
- To investigate the role of obesity in modulating the inflammatory response during sepsis, focusing on the hepatic JAK/STAT pathway.
- To determine the impact of inhibiting Signal Transducer and Activator of Transcription 3 (STAT3) on sepsis outcomes in lean and obese mice.
- To elucidate whether obesity exacerbates the effects of STAT3 inhibition on inflammation and liver injury during sepsis.
Main Methods:
- Utilized male C57BL/6 mice fed either high-fat (60% kcal) or normal (16% kcal) diets to induce obesity.
- Administered pharmacological systemic STAT3 inhibition using Stattic or genetic hepatic-specific STAT3 inhibition.
- Induced sepsis via cecal ligation and puncture (CLP) and assessed body composition, inflammation markers, mortality, and liver injury.
Main Results:
- Systemic STAT3 inhibition increased the inflammatory response during sepsis, an effect amplified by obesity.
- Genetic hepatic STAT3 inhibition led to increased mortality, heightened inflammation, and significant liver injury.
- Obese mice with hepatic STAT3 inhibition exhibited greater weight gain and fat mass, with increased neutrophil infiltration into the liver during sepsis.
Conclusions:
- STAT3 is a critical regulator of the inflammatory response in sepsis, particularly within the liver.
- Obesity significantly contributes to a dysregulated inflammatory response and poorer outcomes when STAT3 signaling is compromised during sepsis.
- Targeting STAT3 or managing obesity may be crucial therapeutic strategies for sepsis patients.
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