Eicosapentaenoic Acid Prevents Obesity‐induced Metabolic Impairments through The Host‐genetic Dependent Effects of Resolvin E1

Eicosapentaenoic acid (EPA) is a n‐3 polyunsaturated fatty acid that is poorly consumed in the western diet. Increased EPA consumption has been reported to improve glucose and insulin homeostasis in rodent models. We demonstrate that administration of pure EPA ethyl esters to C57BL/6J male mice improved obesity‐induced glucose intolerance, hyperinsulinemia, and hyperglycemia. Analyses of National Health and Nutrition Examination Survey data also revealed fasting glucose levels of obese adults to be inversely related with EPA intake in a sex‐dependent manner. To investigate potential mechanisms by which EPA improved glucose homeostasis, we compared rodent models consuming a control and a high fat diet in the presence or absence of EPA. 16S rRNA sequencing demonstrated that EPA supplementation was not associated with an improvement in the murine gut microbiome composition. Subsequent untargeted and targeted mass spectrometry analyses revealed distinct modifications to the lipidome. Notably, EPA dramatically enhanced the levels of 18‐hydroxyeicosapentaenoic acid (18‐HEPE) in the heart, white adipose tissue, and liver. Therefore, we investigated if administration of the downstream bioactive metabolite of 18‐HEPE, resolvin E1 (RvE1) could improve hyperinsulinemia and hyperglycemia. We also determined if these effects were mediated through the RvE1 receptor ERV1/ChemR23. RvE1 administration to obese mice mitigated hyperinsulinemia and hyperglycemia in a manner that was dependent on ERV1/ChemR23, as revealed with ERV1/ChemR23 knockout mice. Finally, we assessed if the host genome altered the metabolic outcomes of RvE1. Secondary SNP analyses revealed extensive genetic variation in human EPA and RvE1 metabolizing genes. RvE1’s effects on fasting insulin and glucose were divergent in diversity outbred mice that model human genetic variation. In conclusion, increased intake of EPA ethyl esters prevent obesity‐induced metabolic impairments through RvE1 binding to ChemR23. The data also underscore the critical need for precision prevention studies that account for host‐genetic variants in the EPA‐RvE1 axis.