Sex-specific metabolic signatures of adiposity associated with clinical biomarkers in the UK Biobank

Excessive adiposity increases disease risk, yet the exact underlying mechanisms remain unknown. We compared sex-specific metabolic signatures (MSs) of adiposity indices (non-allometric: body fat %, waist circumference, hip circumference, waist-to-hip ratio, body mass index; allometric: a body shape index, hip index, waist-to-hip-index ratio) and examined their associations with 29 clinical biomarkers in 151,526 UK Biobank participants. MSs performance was validated in an independent cohort. In females, MSs mainly consisted of lipoprotein particle concentrations, apolipoproteins, fatty acids and inflammation-linked glycoprotein acetyls, whereas in males lipoproteins rich in cholesteryl esters and aromatic/branched-chain amino acids predominated. The highest percentages of common metabolites were observed between non-allometric adiposity indices (median: 42.4%; range: 9%-56%). MSs were independently associated with over 25 biomarkers with differences observed by sex and adiposity index, and these associations were stronger compared to the respective phenotypic associations. MSABSI was found to be more atherogenic, whereas MSHI was more favourable for health. This study highlights i) that different regions of adipose tissue undergo distinct metabolic processes overall and by sex, each having unique impact on health, and ii) the importance of considering metabolic factors beyond simple adiposity indices in assessing health risk.