Abstract
Obesity comorbidities are closely associated with chronic low-grade adipose tissue inflammation. A number of SNPs associated with inflammation has been identified, underscoring the impact of genetic determinants on this process. Here, we screened SNPs in genes with pro-inflammatory (IL-1β, IL-6, STAT3 and JAK2), anti-inflammatory (IL-10 and SOCS3) and pro-resolving (ERV1/ChemR23) properties in 101 obese and 99 non-obese individuals. Among the SNPs analyzed, we identified that individuals carrying a C allele in the rs1878022 polymorphism of the ERV1/ChemR23 gene, which encodes for the receptor of the pro-resolving mediator RvE1, had increased ERV1/ChemR23 protein expression and reduced levels of the inflammatory cytokine IL-6 in adipose tissue. Moreover, patients carrying the C allele in homozygosity had lower plasma levels of IL-6, IFN-α2, IL-15, IL-1ra, IL-10, GM-CSF, G-CSF and VEGF and enhanced leukocyte responsiveness to RvE1. C-carriers also exhibited decreased TAG to HDL ratio, a surrogate marker of insulin resistance and a predictor of incident fatty liver. Finally, we confirmed in vivo that the ERV1/ChemR23 receptor regulates systemic and tissue inflammation since mice lacking ERV1/ChemR23 expression showed increased IL-6 levels in adipose tissue and peritoneal macrophages. Together, our study identified an ERV1/ChemR23 variant that protects patients with obesity from excessive inflammatory burden.
Highlights
Obesity is defined as increased adipose tissue mass and is the net result of an imbalance between energy intake and energy expenditure
We identified a functional SNP in the gene encoding for ERV1/ChemR23, the receptor that recognizes the anti-inflammatory and pro-resolving mediator resolvin E1 (RvE1), a specialized pro-resolving mediators (SPMs) endogenously derived from the long-chain highly-unsaturated fatty acid, eicosapentaenoic acid (EPA)[13,14]
In this study we provide evidence that in comparison to obese individuals carrying the ancestral allele T, those individuals carrying the C variant in the ERV1/ChemR23 rs1878022 SNP exhibit a higher expression of this receptor in visceral adipose tissue, a reduced degree of adipose tissue inflammation and hepatic insulin resistance and significantly lower levels of circulating inflammatory cytokines and chemokines
Summary
Obesity is defined as increased adipose tissue mass and is the net result of an imbalance between energy intake and energy expenditure. Recent studies have confirmed the positive association between comorbidities and inflammation in obesity In this regard, insulin resistance and non-alcoholic fatty liver disease in obese individuals have been linked to a chronic state of low-grade inflammation in adipose tissue[3,4]. Recent evidence indicates that this persistent inflammation in obese adipose tissue is characterized by an unbalanced production of pro-inflammatory versus anti-inflammatory and pro-resolving mediators[5,6,7]. Among the latter, resolvins are the most widely known specialized pro-resolving mediators (SPMs) and they play a prominent role in inflammation because of their ability to expedite resolution with minimal damage to the surrounding tissue (reviewed in 8). Our data provide evidence of the influence of genetic factors on SPM actions and resolution of inflammation in patients with obesity
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