The circulating lipidome in severe obesity.

Severe obesity (SevO; BMI ≥ 40 kg/m2) is rising globally yet remains understudied mechanistically. To characterize lipidomic alterations at the species level, we analyzed Border Health Research Cohort participants with fasting plasma lipidomics and genetic data, comparing SevO (n = 185) to non-obese controls (18.5 ≥ BMI < 25; n = 393). We quantified 830 lipid species across 49 classes and assessed associations using logistic regression, orthogonal projections to latent structures discriminant analysis (OPLS-DA), and network deconvolution Mendelian randomization (NDMR). SevO participants showed more adverse cardiometabolic traits. Lipidomics revealed broad dysregulation: shorter, saturated, and monounsaturated triacylglycerols were elevated in individuals living with SevO compared to controls, while lysophospholipids, plasmalogens, cholesteryl esters, and long-chain species were reduced. OPLS-DA identified over 300 lipids strongly predictive of SevO, and NDMR implicated specific triacylglycerols as potentially contributing to SevO status. Influential lipids correlated with insulin resistance, liver fat, body composition, and high-density lipoprotein cholesterol (HDL-C). Short-chain triacylglycerols emerged as a distinctive, consistently elevated SevO signature.