Eicosapentaenoic acid ethyl esters prevent obesity-driven impairments to glucose homeostasis through the biosynthesis of downstream hydroxylated metabolites

There is considerable debate on the clinical utility of the long n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for preventing dysregulation of obesity-driven glucose homeostasis. Herein, we first show that administration of ethyl esters of EPA, but not DHA, to C57BL/6J male mice improves hyperglycemia, hyperinsulinemia, and glucose tolerance. Mechanistically, we demonstrate that EPA reverses the obesity-driven decrease in the concentration of white adipose tissue and liver 18-hydroxyeicosapentaenoic acid (18-HEPE), the precursor for resolvin E1 (RvE1). A combination of add-back and receptor knockout experiments reveal that RvE1 is specifically driving the improvement in hyperinsulinemia and hyperglycemia through the receptor known as ERV1/ChemR23 by controlling pathways related to hepatic glucose metabolism and inflammation. Next, we show that EPA’s effects are distinct in female mice as EPA administration leads to improvements in body weight, hyperinsulinemia and hyperglycemia but not glucose tolerance. In this case, EPA exerts its effects through a mechanism potentially mediated by 8-HEPE and upregulation of key intestinal microbes. Finally, we present translation data showing that glucose levels in humans with obesity are inversely related to EPA but not DHA in a sex-specific manner. Furthermore, data from our pilot clinical trial demonstrate that an 18-HEPE-enriched marine oil supplement increases RvE1 levels by 3-fold in humans with obesity. Taken together, these results provide clarity to the field by suggesting that EPA but not DHA ethyl esters can prevent glucose dysregulation in a sex-specific manner through distinct mechanisms mediated by downstream hydroxylated metabolites.