Exploring the Obesity Paradox in A Murine Model of Sepsis: Improved Survival Despite Increased Organ Injury in Obese Mice

The objective of this study was to test the existence of the obesity paradox in a murine model of cecal slurry (CS)-induced sepsis with insulin-resistant diet-induced obese mice. Male C57BL/6 mice were provided high-fat (HFD) or low-fat (LFD) diets for 20 weeks. HFD-fed mice experienced higher rates of survival compared to LFD-fed mice after septic challenge induced by CS injection (66% vs. 25%, P = 0.01, survival assessed for 14 days). Despite the survival advantage, HFD-fed mice had higher rates of positive bacterial cultures and increased markers of kidney injury. Circulating levels of IL-6, IL-1β, TNFα, and IL-23 were equivalent 24 h after CS-injection; however, IL-17A was uniquely increased in HFD-fed mice. While LFD-fed mice maintained euglycemia, HFD-fed mice were hyperglycemic 6 and 12 h after CS-injection. Stable isotope resolved metabolomics analysis of liver tissue showed diverging pathways of glucose utilization during sepsis, with LFD-fed mice significantly upregulating glycolytic activity and HFD-fed mice decreasing glucose entry into the TCA cycle. This murine study corroborates clinical data that obesity confers a survival benefit in sepsis, albeit at the expense of more significant organ injury. The mechanisms promoting survival in the obese remain unknown; however, this model appears to be well-poised to begin answering this question. Differences in glucose utilization are a novel target to investigate this paradox.
Source: Shock - Category: Emergency Medicine Tags: Basic Science Aspects Source Type: research