BACKGROUND: Altered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic approach was used to identify circulating markers for future obesity risk in translational murine models and validate in a human infant cohort. METHODS: Lipidomics was performed on the plasma of APOE*3 Leiden, Ldlr-/-.Leiden, and the wild-type C57BL/6J mice to capture candidate biomarkers predicting subsequent obesity parameters after exposure to high-fat diet. The identified candidate biomarkers were mapped onto corresponding lipid metabolism pathways and were investigated in the Cambridge Baby Growth Study. Infants' growth and adiposity were measured at 0-24 months. Capillary dried blood spots were sampled at 3 months for lipid profiling analysis. FINDINGS: From the mouse models, cholesteryl esters were correlated with subsequent weight gain and other obesity parameters after HFD period (Spearman's r≥0.5, FDR p values <0.05) among APOE*3 Leiden and Ldlr-/-.Leiden mice, but not among the wild-type C57BL/6J. Pathway analysis showed that those identified cholesteryl esters were educts or products of desaturases activities: stearoyl-CoA desaturase-1 (SCD1) and fatty acid desaturase (FADS) 1 and 2. In the human cohort, lipid ratios affected by SCD1 at 3 months was inversely associated with 3-12 months weight gain (B±SE=-0.31±0.14, p=0.027), but positively with 12-24 months weight and adiposity gains (0.17±0.07, p=0.02 and 0.17±0.07, 0.53±0.26, p=0.04, respectively). Lipid ratios affected by SCD1 and FADS2 were inversely associated with adiposity gain but positively with height gain between 3-12 months. INTERPRETATION: From murine models to human setting, the ratios of circulating lipid species indicating key desaturase activities in lipid metabolism were associated with subsequent body size increase, providing a potential tool to predict early life weight gain.