Diet-induced obesity disrupts sexually dimorphic gene expression in mice

Biological sex significantly influences the prevalence, incidence, and severity of numerous human diseases, yet it remains an underappreciated variable in biomedical research. Although sexually dimorphic genes contribute to sex-specific traits and disease manifestations, their regulation under metabolic stress is poorly understood. To explore sex-specific metabolic adaptations, we analyzed responses to high-fat diet (HFD)-induced obesity in male and female mice, focusing on the regulation of sex-biased genes. Despite similar adiposity, HFD-fed males displayed more severe metabolic impairments than females, highlighting divergent metabolic outcomes. To investigate the basis for these sex-specific differences, we performed whole transcriptomic profiling of liver and white adipose tissue (WAT) at early (2 wk) and late (12 wk) stages of HFD exposure. Our analysis revealed marked sex-specific gene expression changes across multiple categories, particularly pronounced in male WAT after prolonged HFD feeding. Strikingly, genes exhibiting sexual dimorphism under normal conditions were preferentially modulated in both sexes, comprising up to 46% of all HFD-regulated genes. This led to a substantial loss of sex-biased gene expression in both liver and WAT after HFD exposure, correlating with metabolic dysfunction. Male-biased genes associated with cilia function and estrogen response were among the most affected, showing significant downregulation in male WAT under HFD. Our findings provide a novel perspective on how obesity disrupts sex-specific gene expression in key metabolic tissues, particularly targeting sex-biased genes. By revealing that a considerable proportion of sex-biased genes exhibit HFD-regulated modulation, our study highlights the critical role of these genes in maintaining metabolic health.<b>NEW & NOTEWORTHY</b> Biological sex shapes metabolic tissue physiology, largely through sex-biased gene regulation. Our comprehensive transcriptomic analysis reveals that sex-biased genes in liver and white adipose tissue undergo the most significant regulation during obesity-driven metabolic dysfunction, resulting in a loss of their bias. This disruption highlights a previously unrecognized role of sex-biased genes in maintaining metabolic health in both males and females.