Association of Eicosanoids and Eicosanoid-Related Metabolites With Obesity and Cardiometabolic Traits

The molecular pathways by which obesity contributes to systemic inflammation are unclear. Eicosanoids are bioactive lipids that govern the upstream initiation of pro- and anti-inflammatory activity. We sought to investigate the association of eicosanoids with obesity, adiposity, and cardiometabolic traits.

We conducted a cross-sectional analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) study with external validation in two community-based cohorts: Framingham Heart Study and Atherosclerosis Risk in Communities Study. We measured 811 eicosanoids using a directed, non-targeted mass spectrometry-based platform and examined their associations with BMI and eight related adiposity and cardiometabolic traits using multivariable-adjusted linear regression.

Among 5101 MESA participants (mean age 63 years, 53% women), we found 255 eicosanoids and related metabolites associated with BMI (FDR q < 0.01 for all). Among these, 82 showed consistent associations across all three cohorts, including 18 metabolites with known identities: 9 were associated with lower BMI including docosahexaenoic acid derivative 19,20-DiHDPA, arachidonic acid derivatives (20-carboxy-arachidonic acid, 5,6-diHETrE, 14,15-diHETrE, 15-HpETE), and eicosapentaenoic acid derivative 5-HpEPE. By contrast, 9 metabolites associated with higher BMI including hydroxyoctadecenoic acid (HOME), 11-hydroxy-9-octadecenoic acid (11-HOME), and adrenic acid. Many BMI-associated metabolites overlapped with other adipose traits including 240 (94%) with waist circumference and 93 (36%) with visceral adipose tissue.

We identified 82 BMI-associated eicosanoids, including docosanoids and arachidonic acid derivatives associated with lower BMI, while octadecanoids and adrenic acid derivatives were associated with higher BMI. Our findings highlight the role of bioactive lipids and specific pro- and anti-inflammatory pathways that may underlie adverse cardiometabolic consequences of obesity.