Metabolomic Signatures of Adiposity Traits in the Hispanic Community Health Study/Study of Latinos

The public health burden of obesity is substantial, with Hispanic/Latino adults in the US being disproportionately affected yet understudied, and gaps in our knowledge of underlying metabolic characteristics and links to genetic risk. Central or abdominal obesity indicates excess visceral adipose and is associated with increased cardiometabolic risk and mortality independently of overall obesity. We aim to identify metabolites associated with adiposity and assess whether these metabolites mediate polygenic risk for body mass index (BMI) and waist-to-hip ratio (WHR) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a large ancestrally diverse cohort. In 3,543 individuals, we tested for association between 640 known metabolites from an untargeted panel with overall (BMI, body fat percentage (BF%) and obesity (BMI≥30kg/m2)) and central adiposity traits (WHR, waist circumference (WC), and central obesity). We carried forward significantly associated metabolites for pathway analyses and formal mediation analyses of polygenic risk score (PRS) associations. Of the 640 metabolites, 308 (48%) were significantly associated with BMI in females, 241 (38%) in males, and 238 (37%) in the sex-combined meta-analysis (Bonferroni-corrected p<0.05/640=7.81x10-5); 76 were associated with WHR, 36 were associated with WC, and 11 were associated with central obesity in the sex-combined meta-analysis. Metabolites and overrepresented pathways showed sex- and trait-specific effects. Importantly, we identified 18 metabolites that significantly mediated the PRS-BMI association, and three that mediated the PRS-WHR association. These may serve as modifiable targets for obesity prevention or intervention efforts.