The obesity paradox in murine sepsis models: a systematic review and meta-analysis

The obesity paradox, suggesting improved survival in obese individuals compared to those with normal weight, remains debated, particularly in sepsis. While it has been explored in clinical and experimental settings, conclusive evidence is lacking. This study systematically reviews and meta-analyses the relationship between obesity and survival in murine sepsis models. This systematic review and meta-analysis following PRISMA guidelines included studies from PubMed/Medline (up to January 31, 2025) comparing sepsis survival in obese and non-obese mice. All eligible murine studies were systema-tically reviewed, whereas only those employing diet induced obesity (DIO) and cecal ligation and puncture (CLP) were pooled in the meta-analysis and meta-regression. Twenty-one studies (38 survival experiments) met the criteria: CLP (n = 14), intraperitoneal lipopolysaccharide (n = 7), and other bacterial inoculation models (n = 17). Across all models, obesity increased survival in 10, decreased it in 9, and had no effect in 19 experiments. Quantitative synthesis of 10 CLP-DIO experiments (159 obese vs. 149 lean mice) showed no overall mortality difference (P = 0.391). Meta-regression explained 86% of heterogeneity: later highfat diet (HFD) initiation and longer feeding reduced mortality, whereas older age at sepsis induction increased mortality (all P < 0.001). Across the studies, obesity exerted mixed effects; pooled analysis of CLP DIO experiments showed no survival benefit. Variability among studies was associated with time related factors: age at HFD initiation, feeding duration, and age at sepsis induction, highlighting the need to investigate these relationships and to develop a time point standardized CLP DIO sepsis model.