BACKGROUND/OBJECTIVES: Circulating phospholipids and sphingolipids are implicated in obesity related- comorbidities such as insulin resistance and cardiovascular disease. How bariatric surgery affects these important lipid markers is poorly understood. We sought to determine whether Roux-en-Y gastric bypass (RYGB), which is associated with greater metabolic improvement, differentially affects the phosphosphingolipidome compared to adjustable gastric banding (AGB).SUBJECTS/METHODS: Fasting sera were available from 59 obese women (BMI range 37–51 kg/m2; n=37 RYGB and 22 AGB) before surgery, then at 1 (21 RYGB, 12 AGB) and 3 months follow-up (19 RYGB, 12 AGB). HPLC-MS/MS was used to quantify 131 lipids from 9 structural classes. DXA measurements and laboratory parameters were also obtained. The associations between lipids and clinical measurements were studied with P-values adjusted for the false discovery rate (fdr).RESULTS: Both surgical procedures rapidly induced weight loss and improved clinical profiles, with RYGB producing better improvements in fat mass, and serum TC, LDL-C, and orosomucoid (fdr<10%). Ninety-three (of 131) lipids were altered by surgery—the majority decreasing—with 29 lipids differentially affected by RYGB during the study period. The differential effect of the surgeries remained statistically significant for 20 of these lipids after adjusting for differences in weight loss between surgery types. The RYGB signature consisted of phosphatidylcholine species not exceeding 36 carbons, and ceramides and sphingomyelins containing C22 to C25 fatty acids. RYGB also led to a sustained increase in unsaturated ceramide and sphingomyelin species. The RYGB-specific lipid changes were associated with decreases in body weight, total and LDL-C, orosomucoid and increased HOMA-S (fdr<10%).CONCLUSIONS: Concomitant with greater metabolic improvement, RYGB induced early and sustained changes in phosphatidylcholines, sphingomyelins, and ceramides that were independent of greater weight loss. These data suggest that RYGB may specifically alter sphingolipid metabolism, which, in part, could explain the better metabolic outcomes of this surgical procedure.