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.

The authors have declared no competing interest.

This work was supported by Cancer Research UK (grant number C18281/A29019). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). RMM is supported by a Cancer Research UK 25 (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is also supported by the NIHR Bristol Biomedical Research Centre which is funded by the NIHR (BRC-1215-20011) and is a partnership between University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. Department of Health and Social Care disclaimer: The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care

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Both UK Biobank and Epirus Health study underwent ethical review and were approved by the Northwest Multi-Centre Research Ethics Committee and the Research Ethics Committee of the University of Ioannina, respectively. This research has been conducted using the UK Biobank Resource under Application Number 79696.

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