Sex Differences in the Impact of Obesity on Immunity.

Obesity prevalence has increased significantly worldwide and is anticipated to rise further, with obesity characterized by excessive fat accumulation and chronic low-grade inflammation that dysregulates both innate and adaptive immune responses.

• Obesity increases risk of infectious diseases, cardiovascular diseases, and cancers through immune dysregulation.
• Chronic low-grade inflammation is a hallmark feature of obesity that underlies its immunological consequences.
• The review synthesizes findings from both animal models and human studies.

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.

• Sex differences in fat distribution contribute to divergent metabolic and immune consequences of obesity.
• Adipose tissue inflammation differs between sexes in the context of obesity.
• Adipocytokine production varies by sex and contributes to sex-specific metabolic health outcomes.

Sex steroids and chromosome complements play mechanistic roles in shaping fat distribution, adipose inflammation, gut microbiota composition, and systemic inflammation during obesity.

• Sex steroids are identified as key mechanistic drivers of sex differences in obesity-associated immune responses.
• Chromosome complements, distinct from hormonal effects, also contribute to shaping these differences.
• These factors collectively influence gut microbiota composition in a sex-dependent manner.
• Systemic inflammation patterns differ by sex through these combined mechanisms.

Obesity-associated immune dysregulation has sex-specific consequences for infectious disease susceptibility and outcomes.

• The review discusses sex differences in obesity-related infectious disease risk as a distinct health outcome domain.
• Both innate and adaptive immune responses are differentially dysregulated by obesity in males versus females.
• Findings are drawn from animal models and human studies examining infectious disease outcomes.

Vaccine-induced immunity is affected by obesity in a sex-dependent manner.

• Sex differences in obesity-associated immune dysregulation extend to vaccine-induced immune responses.
• This represents a distinct health outcome category examined in the review.
• Both preclinical and clinical data are incorporated in the discussion of vaccine responses.

Obesity influences autoimmune disease risk and outcomes in a sex-specific fashion.

• Autoimmune diseases are identified as a health outcome category with sex-specific obesity-associated immune consequences.
• The mechanistic roles of sex steroids and adipose inflammation are relevant to autoimmune disease risk.
• Both animal model and human study findings are reviewed to address this relationship.

Obesity-associated immune dysregulation contributes to cancer risk with sex-specific differences.

• Cancer is identified as a distinct health outcome category shaped by sex differences in obesity-associated immunity.
• Chronic low-grade inflammation and adipocytokine dysregulation in obesity contribute to cancer risk.
• Sex-specific patterns of fat distribution and immune dysregulation are relevant to sex differences in obesity-related cancer.

Cardiometabolic risk associated with obesity differs by sex and is linked to sex-specific immune and inflammatory dysregulation.

• Cardiometabolic risk is a key health outcome category with sex-specific obesity-associated immune consequences.
• Fat distribution patterns, which differ by sex, contribute to differential cardiometabolic risk.
• Systemic inflammation driven by adipose tissue dysfunction underlies sex differences in cardiometabolic outcomes.

Biological sex remains underprioritized in preclinical, clinical, and epidemiological obesity-related research despite growing evidence of its importance.

• The authors identify failure to adequately consider biological sex as a gap in current obesity research.
• This gap spans preclinical, clinical, and epidemiological research domains.
• Greater consideration of biological sex is described as essential to better understand disease risk, develop targeted interventions, and improve care.