Integrative analysis of blood cells DNA methylation, transcriptomics and genomics identifies novel epigenetic regulatory mechanisms of insulin resistance during puberty in children with obesity

Background Puberty is a time of considerable metabolic and hormonal changes associated with a physiological increase in peripheral tissue insulin resistance (IR). There is evidence that physiological IR does not resolve in youth who are obese, which may result in increased cardio-metabolic risk. Understanding the molecular and biological processes underlying the development of IR in puberty and the additional impact of obesity on these processes is crucial to prevent type 2 diabetes. Methods This is a longitudinal study based on the follow-up until puberty of a cohort of prepubertal Spanish boys and girls. The study population was composed of 139 children organized in a longitudinal approach of 90 subjects (47 females) and two cross-sectional approaches of 99 (52 females) and 130 (71 females) subjects for prepubertal and pubertal stages, respectively. Children were allocated into experimental groups according to their obesity and IR status before and after the onset of puberty. All participants presented blood DNA samples for GWAS and EWAS analyses. In 44 children of the pubertal stage, we counted on blood RNA samples for RNA-seq analysis. Results Our large-scale integrative molecular analysis identified novel blood multi-omics signatures (mapping the loci ABCG1, ESR1 and VASN , among others) significantly associated with IR longitudinal trajectories in children with obesity during pubertal maturation. Functional enrichment analysis revealed that identified loci participate in systemic metabolic pathways and sexual maturation processes relevant to the pathogenesis of IR in the context of puberty. Additional analyses on cardiometabolic and inflammatory phenotypes showed that blood DNAm patterns of some of the identified loci are further associated, beyond IR, with an overall risky-cardiometabolic profile in children. Serum protein levels of vasorin (VASN), one of the most promising novel biomarkers identified in this study, were further associated with IR in the pubertal stage. Conclusions To our knowledge, this is the first longitudinal multi-omics approach characterizing molecular blood alterations for IR and obesity during the metabolically critical period of puberty. Our results shed light on the molecular mechanisms underlying epigenetic alterations in obesity and propose novel and promising biomarkers for IR and metabolic alterations in children.