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

ABSTRACT Aims Eicosapentaenoic acid (EPA) is consumed in low levels in the western diet. Increased consumption of EPA may prevent impairments in insulin-glucose homeostasis that contribute toward cardiometabolic disorders. Here we investigated how EPA, through the biosynthesis of its downstream metabolites, prevents metabolic impairments driven by diet-induced obesity. Methods and Results Long-term administration of pure EPA ethyl esters to C57BL/6J male mice improved obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia. Supporting analyses of National Health and Nutrition Examination Survey data revealed fasting glucose levels of obese adults were inversely related to EPA intake in a sex-dependent manner and were dependent on the ratio of linoleic acid to EPA. We next investigated potential mechanisms by which EPA improved hyperinsulinemia and hyperglycemia. 16S rRNA sequencing showed EPA supplementation did not remodel the gut microbiome composition relative to obese mice. Subsequent untargeted and targeted mass spectrometry analyses revealed distinct modifications in the lipidome. Notably, EPA overturned the obesity-driven decrement in the concentration of 18-hydroxyeicosapentaenoic acid (18-HEPE) in metabolic tissues. Therefore, we probed if administration of the bioactive downstream metabolite of 18-HEPE known as resolvin E1 (RvE1) for four days could reverse hyperinsulinemia and hyperglycemia through RvE1’s receptor ERV1/ChemR23. Additionally, we determined if the metabolic effects of RvE1 were dependent on host genetics. Experiments with obese ERV1/ChemR23 knockout and wild type mice showed that RvE1 mitigated hyperinsulinemia and hyperglycemia in a manner dependent on ERV1/ChemR23. RvE1’s effects on fasting insulin and glucose were not uniform in diversity outbred mice that model human genetic variation. Furthermore, secondary SNP analyses revealed extensive genetic variation in human RvE1- and EPA-metabolizing genes. Conclusions The data suggest increased EPA intake prevents metabolic impairments in obesity through a mechanism mediated by RvE1. The data also underscore the critical need for precision prevention studies that account for host-genetics in the EPA-RvE1 axis. Translational Perspective EPA ethyl esters have attracted significant attention based on findings from the REDUCE-IT trial on cardiovascular disease risk reduction. This study investigated how EPA ethyl esters prevent obesity-induced hyperinsulinemia and hyperglycemia. Our data show that EPA ethyl esters improved murine fasting insulin and glucose levels through the actions of the downstream metabolite known as resolvin E1 (RvE1). Notably, RvE1’s effects on hyperinsulinemia and hyperglycemia were dependent on the host genetic profile. Collectively, these data suggest targeting the EPA-RvE1 pathway may be an effective approach for preventing impairments in insulin-glucose homeostasis in a host genetic dependent manner.