PPARα agonist administration worsens survival and kidney function in a mouse polymicrobial sepsis model

Sepsis and septic shock cause significant morbidity and mortality worldwide, yet effective therapeutic strategies targeting the underlying metabolic dysfunction remain limited. Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of fatty acid oxidation and has been proposed as a potential therapeutic target in sepsis due to its role in modulating metabolic and inflammatory pathways. We hypothesized that augmenting fatty acid oxidation through PPARα agonist administration would improve survival and organ function in sepsis. To test this, mice were fed fenofibrate for 5 days prior to inducing sepsis with cecal ligation and puncture. Contrary to our hypothesis, we observed that fenofibrate-treated mice exhibited worse 7-day survival compared to controls (27% vs. 84%, p < 0.0001). Fenofibrate administration resulted in lower serum non-esterified fatty acids and increased inflammatory interleukin-6 levels. Septic fenofibrate-treated mice demonstrated elevated blood urea nitrogen and creatinine levels, indicating worsening renal function. Renal cortical fatty acid oxidation rates were increased in fenofibrate-treated mice. No significant differences in cardiac function were observed by echocardiography. We conclude that fenofibrate administration effectively augmented fatty acid oxidation rates yet worsened sepsis outcomes in our mouse model of sepsis by increasing inflammation and worsening kidney function without affecting heart function.