Obesity promotes urinary tract infection by disrupting urothelial immune defenses.

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 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.