Abstract
The insulin/glucose-sensitizing properties of specialized pro-resolving mediators (SPMs) are emerging. We investigated the role of resolvin E1 (RvE1) and its parent molecule eicosapentaenoic acid (EPA) on insulin/glucose homeostasis. We first identified a decrease in the RvE1 precursor 18-hydroxyeicosapentaenoic acid in obese male C57BL/6J mice. Therefore, we investigated the effects of intraperitoneal administration of exogenous RvE1 on obese inbred and outbred male mice. RvE1 administered to obese C57BL/6J mice for just four days improved hyperglycemia and hyperinsulinemia, which was partially dependent on the receptor ERV1/ChemR23. In contrast, RvE1’s effects on fasting insulin/glucose were divergent in diversity outbred mice modeling human genetic variation. Next, we studied the preventative effects of pure dietary EPA ethyl esters on obese C57BL/6J mice. EPA ameliorated obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia and this was independent from remodeling of the gut microbiome. Supporting analyses of NHANES data revealed that glucose levels were inversely related with EPA intake in obese adults in a sex-specific manner. Finally, secondary SNP analyses revealed extensive genetic variation of human EPA- and RvE1-metabolizing genes. Collectively, the data underscore the importance of the resolvin E1-EPA axis in controlling insulin/glucose homeostasis and point to a therapeutic role for RvE1 that depends on the host genome.
Footnotes
The research was supported by: R01AT008375 (SRS), P30DK05635 (SRS), R01AR066660 (ES), NIH/NCRR S10 RR026522-01A1 (NR), R01DK096907 (PDN), Canadian Institutes of Health Research 303157 (RPB) and SAF15-63674-R/2017SGR1449 (JC). This material is also based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. 1650116 to AEA. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. The microbiome studies were supported by the Microbiome Core Facilities, supported in part by NIDDK P30DK34987