Sex differences in the association of circulating miRNAs and inflammation biomarkers in children with overweight and obesity: results of the I.Family Study

Background: During the past decade, obesity has become a global epidemic with interconnected health, social, and economic concerns. Cumulative evidence proposes that over-nutrition-induced obesity leads to an upturn in the innate immune system and local inflammatory process in adipose tissue. The resulting persistent chronic low-grade inflammation designates a hallmark of obesity that leads to and perpetuates the metabolic alterations and insulin resistance in target organs. Of note, inflammation and its supporting mechanisms are considered closely related to the progression of numerous diseases. Several actors have been involved in governing the inflammatory response, including epigenetic players. Among these, miRNAs are emerging as crucial regulators of immune cell development, immune responses, autoimmunity, and inflammation. Objective: In this study, we aimed at recognizing the involvement of candidate miRNAs in relation to inflammation-associated biomarkers in a subsample of European children with overweight and obesity participating in the I.Family Study (www.ifamilystudy.eu). The study subjects included healthy individuals (n=79) with increased adiposity since this condition contributes to the early occurrence of chronic low-grade inflammation and the intertwisted metabolic changes. We focused on the acute phase reagent CRP and several cytokines selected as conceivable inflammation biomarkers. Associations of miRNAs expression with CRP and the different interleukins were performed using linear regression analyses adjusting for covariates including country of origin, age, BMI z-score, puberty status. Results: We found that the chronic low-grade CRP elevation exhibited a highly significant association with miR-26b-3p and miR-576-5p in the boys' subgroup. Furthermore, the association of CRP with miR-10b-5p and miR-31-5p was highly significant in girls. We also found major sex-related associations of candidate miRNAs with cytokines: except for IL-6, significant associations of miR-10b-5p and miR-26b-3p with TNF-?, IL1-Ra, IL-8, and IL-15 levels were found exclusively in boys. Conclusion: The findings of this exploratory study propose major differences in the relationship of circulating miRNAs and inflammatory biomarkers across sexes pointing to a conceivable role of miRNAs among the candidate epigenetic mechanisms related to the low-grade inflammation process in childhood obesity, calling for more attention in this largely underexplored area.