Abstract Body (Do not enter title and authors here): Introduction: The specific molecular pathways from obesity to inflammation to cardiovascular disease remain unclear. Eicosanoids are a unique class of bioactive lipids that govern the upstream initiation of pro- and anti-inflammatory activity.

Objective: We leveraged a novel lipidomic platform to quantify > 800 eicosanoid metabolites and examined their association with body mass index (BMI).

Methods: We studied Multi-Ethnic Study of Atherosclerosis (MESA) participants with available samples for eicosanoid analysis. Eicosanoids and related metabolites were assessed using a directed, non-targeted mass spectrometry-based platform. We examined the cross-sectional association of eicosanoid metabolites with BMI using multivariable linear regression models. Analyses were considered significant at FDR q-value <0.01.

Results: A total of 5101 individuals (age 63 ± 10 years; 53% women, 60% non-Whites) were included. The mean BMI was 28.3 ± 5.1 kg/m2. Of 811 eicosanoids analyzed, 255 showed a significant association with BMI (see Figure for putative metabolite identities; FDR q-value <0.01 for all). Derivatives of docosahexaenoic acid (DHA; 19,20 DiHDPA, β = - 0.206, standard error [SE] = 0.013) and eicosatetraenoic acid (11(S) HEPE, β = - 0.180, SE = 0.014) were associated with lower BMI. Linoleic acid derivatives (12,13 diHOME, an exercise-induced lipokine) had a similar association. Conversely, derivatives of linoleic acid (13-oxoODE, β = 0.241, SE = 0.01) and arachidonic acid (11-HETE, β = 0.236, SE = 0.017) were associated with higher BMI. Other derivatives of linoleic acid (15 (S) HETrE) and prostaglandin (11b PGF2α) were also associated with higher BMI.

Conclusions: We found that specific eicosanoid metabolites, including DHA and linoleic acid derivatives with known anti-inflammatory, atheroprotective, and beneficial metabolic effects (e.g., 19,20 DiHDPA; 12,13 diHOME), were associated with lower BMI. By contrast, specific arachidonic acid and prostaglandin derivatives with known pro-inflammatory and adverse CV effects (e.g. oxylipin 11-HETE; PGF2α; 13-oxoODE) were associated with higher BMI. These findings further the understanding of specific inflammatory pathways underlying the development of obesity-related CVD.