Circulating Sphingosine Levels Reflect Metabolic Flexibility in Healthy Adults

Introduction and Objective: Sphingolipids (SPL), bioactive lipids with specialized signaling functions, are synthesized from palmitic acid, the most abundant saturated fatty acid in plasma. We tested the association of circulating sphingolipids with self-reported health behaviors and metabolic flexibility in humans. Methods: We assayed plasma SPL levels {ceramides (Cer), monohexosylceramides (MHC), sphingomyelin (SM) and sphingosine (So)} using LC-MS/MS in healthy adults free of diabetes. The validated instruments food habit questionnaire (FHQ) and metabolic activity questionnaire (MAQ) were used to capture diet and exercise habits. Energy expenditure (EE) and respiratory quotient (RQ) were determined using indirect calorimetry. Other assessments included insulin sensitivity (ISI, using hyperinsulinemic euglycemic clamp) and insulin secretion (AIR, using intravenous glucose tolerance tests). Results: The participants (N=140, 64% female; 54% Black, 46% White) had a mean age of 47.7 ± 9.01 yr, BMI 30.4 ± 6.12 kg/m2 and waist circumference 95.9 ± 13.8 cm; FPG was 92.9 ± 6.86 mg/dl, 2hPG 130 ± 28.8 mg/dl, and HbA1c 5.57 ± 0.46%. Plasma sphingosine levels were significantly associated with MAQ (r= -0.22, P=0.015) and with physical activity adjusted for food habits (MAQ/FHQ; r= -0.21, P=0.018). The MAQ and FHQ showed opposite associations with ISI and AIR. Plasma sphingosine levels were significantly associated with RQ (r=0.24, P=0.007), BMI (r=0.22, P=0.01), and waist circumference (r=0.35, p<0.0001) but not ISI or AIR. No other circulating SPL species showed significant association with FHQ, MAQ, EE or RQ. Conclusion: An inverse association between plasma sphingosine (the backbone of all SPLs) and physical activity and direct association with RQ suggest that sphingosine levels signal metabolic flexibility and carbohydrate fuel preference in healthy adults. Disclosure: P. Asuzu: None. N. Feto: None. F.B. Stentz: None. J.Y. Wan: None. N. Mandal: None. S. Dagogo-Jack: None.