SAT-224 - Potential Role for Oxylipin Metabolites as Correlates of Adolescent Metabolic Health

Oxylipins are bioactive lipid mediators derived from polyunsaturated fatty acids (C18, C20, C22 in length) that integrate inflammatory, metabolic, and vascular signaling, influencing energy homeostasis and glucose regulation. While cytochrome P450 (CYP450)–derived oxylipins, particularly ω-3–derived diols, have been implicated in metabolic regulation in adults, their role in pediatric metabolic health and as diabetes risk factors are incompletely understood.
We examined associations between circulating oxylipins and glucose tolerance, insulin sensitivity, β-cell function, and adiposity in 548 children aged 10–14 years from the Hyperglycemia and Adverse Pregnancy Outcomes Follow-up Study. Plasma oxylipin profiles were quantified using targeted lipidomics, capturing CYP450, lipoxygenase, and cyclooxygenase pathway metabolites. Insulin sensitivity was assessed using a C-peptide–derived Matsuda index, β-cell function via the disposition index, glucose tolerance using 1- and 2-hour post–oral glucose load concentrations from a 75-g Oral Glucose Tolerance Test and direct adiposity measures from air displacement plethysmography. Partial correlation analyses adjusted for relevant covariates revealed distinct oxylipin signatures associated with metabolic traits after Benjamini–Hochberg false discovery rate (FDR) correction.
In this diverse cohort, at mean age 11.6 (SD 1.1) years and mean BMI z-score 0.52 (SD=1.33), DHA(ω-3)-derived CYP450 diols, particularly 19(20)-DiHDPA, were positively associated with insulin sensitivity (r=0.278, BH adjusted p=1.00x10⁻⁶) and inversely associated with bodyfat % (r=−0.360, BH adjusted p=5.26x10⁻¹⁴). Similar inverse associations with BMI Z-scores were observed for additional diols derived from DHA and eicosapentaenoic acid (EPA, ω-3), as well as the pro-resolving mediator Protectin D1(r= -0.123, BH adjusted p=6.46x10⁻2), consistent with anti-inflammatory and metabolically protective effects. In contrast, oxidized linoleic acid (ω-6)- derived metabolites, including 9-OxoODE, were positively associated with 1- and 2-hour glucose (r=0.242, BH adjusted p=2.5x10-5, r=0.122, BH adjusted p=6.46x10⁻2), suggesting (ω-6)-oxidative lipid pathways may contribute to early dysglycemia. Several prostaglandins like 15-keto PGE2 were inversely associated with β-cell function (r= -0.167, BH adjusted p=3.21x10-4), indicating potential detrimental effects of inflammatory mediators on insulin secretion. These findings highlight a balance between pro-inflammatory and anti-inflammatory oxylipin pathways in shaping early metabolic trajectories. CYP450-derived (ω-3)-oxylipins may be early correlates for insulin sensitivity, while (ω-6)-oxylipins may identify adolescent youth at risk for adverse metabolic outcomes.