Resolvin E1 derived from eicosapentaenoic acid prevents hyperinsulinemia and hyperglycemia in a host genetic manner

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 RvE1metabolizing 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.

Obesity-Driven Deficiencies of Specialized Pro-resolving Mediators May Drive Adverse Outcomes During SARS-CoV-2 Infection

“…Supporting experiments with gain and loss of function approaches in animal models are also required to establish that SPM deficiencies in obesity exacerbate the response to the infection. It is also important to consider the host genetic profile (34), which could be a major consideration in developing dietary or pharmacological approaches to overcoming SPM deficiencies and improving outcomes to SARS-CoV-2 for the obese.…”

“…There is evidence that obesity generally drives a unique signature of SPM deficiency (19,(30)(31)(32)(33)(34)(35)(36)(37). Table 1 summarizes the results of these studies.…”

“…To exemplify, obese mice compared to lean controls display a rapid reduction in DHA-derived SPM precursors and SPMs in white adipose tissue within 4 days of consuming a high fat diet (37). Others have also reported a reduction of not only DHA-derived SPMs but also metabolites from the EPA pathway upon long term consumption of obesogenic diets in white adipose tissue and liver, which are central in driving complications of obesity (30,32,34,42). As described below, these deficiencies can be overcome through dietary administration of EPA-or DHA-enriched marine oils.…”

Impact of rs174537 on Critically Ill Patients with Acute Lung Injury: A Secondary Analysis of the OMEGA Randomized Clinical Trial

“…To date, few studies have highlighted potential associations between rs174537 and ω-3 fatty acids ( 34 ). It would be interesting to see if rs174537, and other related SNPs, impact the production of ω-3–derived lipid mediators and consequently modulate inflammatory processes ( 35 , 36 ).…”

Exploiting oxidized lipids and the lipid‐binding GPCRs against cardiometabolic diseases

“…The effects of 18‐HEPE might be attributed to its direct or indirect activities. This lipid metabolite can serve as a precursor for RvE1 biosynthesis, which in turn can prevent hyperglycaemia and hyperinsulinaemia (Pal et al, 2020), in addition to promoting the recovery of the cardiac function after myocardial infarction in mice (Liu et al, 2018). Conversely, 18‐HEPE can also directly exert a protective effect on cardiac function by promoting resistance to pressure overload‐induced maladaptive cardiac remodelling, which is the main phenomenon driving hypertension‐induced heart failure (Endo et al, 2014).…”