Obesity and insulin resistance trigger the early onset of adolescent-like sexually dimorphic metabotypes in middle childhood

The pathophysiology of obesity and insulin resistance are differentially affected by sexual dimorphisms along lifespan, being female children often at higher metabolic risk although presenting lower obesity rates, whereas puberty induces a switch in their prevalence. However, scarce data is available in middle childhood, when crucial hormonal maturation processes begin. In this study, we recruited a cohort of prepubertal children (6–12 years, Tanner I) of both sexes, comprising subjects with obesity and insulin resistance (N = 19 girls, 20 boys), children with obesity without insulin resistance (N = 10 girls, 12 boys), and healthy controls (N = 12 girls, 16 boys). Plasma and erythrocyte samples were collected for exhaustive clinical biochemistry assessment (insulin/glucose metabolism, inflammatory markers, hormonal profile) and state-of-the-art metabolomics. Then, sex-stratified multivariate and univariate statistical analyses were applied to decipher obesity- and insulin resistance-driven metabolic impairments separately in boys and girls. Surprisingly, we found boys to exhibit a more unfavorable metabolic profile, with exacerbated insulin resistance and raised inflammatory markers compared to girls, as expected for adolescents rather than prepubertal children. This was accompanied by a sexually dimorphic increase of steroid levels in children with obesity (i.e., androgens in boys, but also estrogens and progestogens in girls) compared to controls, as well as by male-specific alterations in metabolites associated with the pathophysiology of obesity and insulin resistance (e.g., carbohydrate, lipid, and protein metabolism, oxidative stress, phospholipid turnover). Altogether, we hypothesize that premature obesity-driven hormonal development may induce an adolescent-like metabotype in mid-aged children (i.e., protective estrogenic profile in girls vs. deleterious androgenic profile in boys), which could be responsible for sex differences in related metabolic complications.