Sex Differences in the Impact of Obesity on Immunity

Abstract

The prevalence of obesity has increased significantly worldwide in the past few decades and is anticipated to rise further in the future. Obesity, characterized by excessive fat accumulation and chronic low-grade inflammation, dysregulates innate and adaptive immune responses, thereby increasing the risk of infectious diseases, cardiovascular diseases, and cancers. Males and females differ considerably in patterns of fat distribution, adipose tissue inflammation, and adipocytokine production, resulting in substantial sex-specific differences in metabolic health outcomes during obesity. Despite growing evidence of its importance, biological sex remains underprioritized in preclinical, clinical, and epidemiological obesity-related research. In this review, we explore the impact of biological sex on obesity-associated immune dysregulation and its consequences for a range of health outcomes, including infectious diseases, vaccine-induced immunity, autoimmune diseases, cancer, and cardiometabolic risk. We highlight recent findings from animal models and human studies to discuss the mechanistic roles of sex steroids and chromosome complements in shaping fat distribution, adipose inflammation, gut microbiota composition, and systemic inflammation, which collectively drive sex differences in obesity-associated immune responses. Greater consideration of biological sex in obesity research is essential to better understand disease risk, develop targeted interventions, and improve care.