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The purpose of this study was to determine low-grade inflammation associated with obesity that is mediated partially by TNF-α, an adipocytokine which stimulates sphingomyelinase activity in adipocytes. Circulating ceramide (Cer) and sphingosine 1-phosphate (S1P) are elevated in genetically obese ( ob/ob) mice. We aimed to determine whether serum sphingolipid concentrations correlate with measures of obesity, insulin resistance, and lipid profiles in overweight versus lean adolescents. This cross-sectional study recruited 30 healthy overweight (body mass index, BMI ≥ 85%) and 15 lean (BMI 10-84%) adolescents. Anthropometric measurements and fasting blood samples were collected at one clinic visit. Serum glucose, insulin, and fasting lipid profiles were measured. Serum adipocytokine concentrations were measured by ELISA or colorimetric assay and sphingolipids were measured by HPLC-mass spectrometry. Between group differences in serum sphingolipid concentrations were assessed. Correlations between sphingolipid concentrations and (i) body mass index, (ii) calculated homeostasis model assessment of insulin resistance (HOMA-IR), (iii) adipocytokines, and (iv) lipoproteins were determined. The results showed that significant differences in HOMA-IR (4.5 ± 3.2 vs. 1.2 ± 0.7), free fatty acids (0.8 ± 0.3 mmol/l vs. 0.4 ± 0.3 mmol/l), and adiponectin (6.4 ± 3.8 vs. 12.6 ± 9.9 μg/ml) were seen between groups (overweight vs. lean). There were significant correlations between Cer and TNF-α ( r = 0.429), S1P and TNF-α ( r = 0.288), Cer and adiponectin ( r = 0.321), Cer:S1P and adiponectin ( r = 0.324), Cer and HOMA-IR ( r = 0.307), and Cer:S1P and LDL cholesterol ( r = 0.453); these associations persisted after adjustment for BMI Z-score, sex, and Tanner stage. We concluded that elevated sphingolipid concentrations correlate with TNF-α, adiponectin, lipoprotein profiles, and HOMA-IR. Ceramide is associated with atherogenic lipid profiles and the development of insulin resistance in obese adolescents, similar to adults. [ABSTRACT FROM AUTHOR]