Abstract
Obesity is a significant public health concern that is associated with numerous health risks. Infections are a major complication of obesity, but the mechanisms responsible for increased infection risk are poorly defined. Here, we use a diet induced obesity mouse model and investigate how obesity impacts urinary tract infection (UTI) susceptibility and bladder immune defenses. Our results show that high-fat diet fed female and male mice exhibit increased susceptibility to uropathogenic E. coli (UPEC) following experimental UTI. Transcriptomic analysis of bladder urothelial cells shows that obesity alters gene expression in a sex-specific manner, with distinct differentially expressed genes in male and female mice, but shared activation of focal adhesion and extracellular matrix signaling. Western blot and immunostaining confirm activation of focal adhesion kinase, a central component of the focal adhesion pathway, in the bladders of obese female and male mice. Mechanistically, experiments using primary human urothelial cells demonstrate that focal adhesion kinase overexpression promotes UPEC invasion. These findings demonstrate that obesity enhances UTI susceptibility by activating focal adhesion kinase and promoting bacterial invasion of the urothelium. Together, they explain how obesity promotes UTI vulnerability and identify modifiable targets for managing obesity-associated UTI. SIGNIFICANCE STATEMENT: Obesity is associated with an increased risk of urinary tract infections (UTIs), but the underlying mechanisms promoting infection susceptibility remain poorly understood. Here, we show that diet-induced obesity drives sex-specific changes in bladder urothelial gene expression, including distinct immune responses in male and female mice. Despite these differences, both sexes exhibit activation of focal adhesion kinase (FAK). FAK overexpression promotes bacterial invasion into human bladder cells. These findings provide a mechanistic explanation for obesity-associated UTI susceptibility and suggest that targeting FAK signaling could offer a therapeutic strategy to prevent UTIs, with implications for personalized interventions in obesity.