Lipidomic perturbations of normal-weight adiposity phenotypes and their mediations on diet–adiposity associations

Background & aims: Normal-weight obesity (NWO) and normal-weight central obesity (NWCO) have been linked to higher cardiometabolic risks, but their etiological bases and attributable dietary factors remain unclear. In this study we therefore aimed to identify lipidomic signatures and dietary factors related to NWO and NWCO and to explore the mediation associations of lipids in diet–adiposity associations. Methods: Using a high-coverage targeted lipidomic approach, we quantified 1245 serum lipids in participants with NWO (n = 150), NWCO (n = 150), or propensity-score-matched normal-weight controls (n = 150) based on the Regional Ethnic Cohort Study in Northwest China. Consumption frequency of 28 major food items was recorded using a food frequency questionnaire. Results: Profound lipidomic perturbations of NWCO relative to NWO were observed, and 249 (dominantly glycerolipids) as well as 48 (dominantly glycerophospholipids) lipids were exclusively associated with NWCO or NWO. Based on strong lipidomic signatures identified by a LASSO model, phospholipid biosynthesis was the top enriched pathway of NWCO, and sphingolipid metabolism was the top pathway of NWO. Remarkably, sphingolipids were positively associated with NWO and NWCO, but lyso-phosphatidylcholines were negatively associated with them. Rice, fruit juice, and carbonated drink intakes were positively associated with the risk of NWCO. Both global and individual lipidomic signatures, including SE(28:1_22:6) and HexCer(d18:1/20:1), mediated these diet-NWCO associations (mediation proportion: 15.92%–26.10%). Conclusions: Differential lipidomic signatures were identified for overall and abdominal adiposity accumulation in normal-weight individuals, underlining their core mediation roles in dietary contributions to adiposity deposition.