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bioRxiv · 10.1101/848093

Targeting the resolvin E1 - eicosapentaenoic acid axis improves hyperinsulinemia and hyperglycemia in a host genetic dependent manner

Pal, A.·Al-Shaer, A. E.·Guesdon, W.·Torres, M. J.·Armstrong, M.·Quinn, K.·Davis, T.·Reisdorph, N.·Neufer, P. D.·Spangenburg, E. E.·Carroll, I.·Bazinet, R. P.·Clària, J.·Shaikh, S. R.
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Abstract

ObjectiveEicosapentaenoic acid (EPA) has recently garnered strong attention given the success of the REDUCE-IT trial, which overturned previous conclusions on EPA and led to its FDA approval for lowering cardiovascular disease risk. Therefore, there is a need to study EPA for cardiometabolic risk factors. Here we focused on EPAs preventative role on hyperglycemia and hyperinsulinemia. MethodsC57BL/6J male mice were fed a high fat diet in the absence or presence of pure EPA. Mass spectrometry was used to identify how EPA prevents hyperinsulinemia and hyperglycemia that drove subsequent experiments with resolvin E1 (RvE1) across inbred and outbred models. ResultsAdministration of EPA to C57BL/6J mice prevented obesity-induced glucose intolerance, hyperinsulinemia, and hyperglycemia. Supporting analyses of National Health and Nutrition Examination Survey data showed fasting glucose levels of obese adults were inversely related to EPA intake in a sex-specific manner. We next investigated how EPA improved murine hyperinsulinemia and hyperglycemia. Mass spectrometry revealed EPA overturned the obesity-driven decrement in the concentration of 18-hydroxyeicosapentaenoic acid (18-HEPE) in white adipose tissue and liver. Treatment of obese mice with RvE1, the immunoresolvant metabolite of 18-HEPE, reversed hyperinsulinemia and hyperglycemia through the G-protein coupled receptor ERV1/ChemR23. RvE1s effects were not mediated by macrophage enrichment in white adipose tissue. Finally, we determined if the metabolic effects of RvE1 were dependent on host genetics. RvE1s effects on hyperinsulinemia and hyperglycemia were divergent in diversity outbred mice that model human genetic variation. Secondary SNP analyses further revealed extensive genetic variation in human RvE1- and EPA- metabolizing genes. ConclusionsThe data suggest EPA prevents hyperinsulinemia and hyperglycemia through the endogenous bioactive metabolite RvE1 that activates ERV1/ChemR23. Importantly, the studies reveal host genetics are an overlooked but critical factor in the metabolic response to RvE1. These results underscore the need for personalized administration of EPA-derived RvE1 based on genetic/metabolic enzyme profiles.

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Pal, A., Al-Shaer, A. E., Guesdon, W., Torres, M. J., Armstrong, M., Quinn, K., Davis, T., Reisdorph, N., Neufer, P. D., Spangenburg, E. E., Carroll, I., Bazinet, R. P., Clària, J., Shaikh, S. R.. 2019-11-20. Targeting the resolvin E1 - eicosapentaenoic acid axis improves hyperinsulinemia and hyperglycemia in a host genetic dependent manner. https://doi.org/10.1101/848093

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