Sexually dimorphic metal alterations in childhood obesity are modulated by a complex interplay between inflammation, insulin, and sex hormones

• Published in: BioFactors (Oxford) 2023-07, Vol.49 (4), p.849-860
• Main Authors: González‐Domínguez, Álvaro, Domínguez‐Riscart, Jesús, Millán‐Martínez, María, Lechuga‐Sancho, Alfonso María, González‐Domínguez, Raúl
• Format: Article
• Language: English
• Subjects: childhood obesity; inflammation; insulin; sex; trace elements
• ISSN: 0951-6433; 1872-8081
• DOI: 10.1002/biof.1948

Although growing evidence points to a pivotal role of perturbed metal homeostasis in childhood obesity, sexual dimorphisms in this association have rarely been investigated. In this study, we applied multi‐elemental analysis to plasma and erythrocyte samples from an observational cohort comprising children with obesity, with and without insulin resistance, and healthy control children. Furthermore, a wide number of variables related to carbohydrate and lipid metabolism, inflammation, and sex hormones were also determined. Children with obesity, regardless of sex and insulin resistance status, showed increased plasma copper‐to‐zinc ratios. More interestingly, obesity‐related erythroid alterations were found to be sex‐dependent, with increased contents of iron, zinc, and copper being exclusively detected among female subjects. Our findings suggest that a sexually dimorphic hormonal dysregulation in response to a pathological cascade involving inflammatory processes and hyperinsulinemia could be the main trigger of this female‐specific intracellular sequestration of trace elements. Therefore, the present study highlights the relevance of genotypic sex as a susceptibility factor influencing the pathogenic events behind childhood obesity, thereby opening the door to develop sex‐personalized approaches in the context of precision medicine. Children with obesity, regardless of sex and insulin resistance status, showed elevated plasma copper‐to‐zinc ratios. In contrast, obesity‐related erythroid metal alterations were interestingly found to be sex‐dependent, with increased contents of iron, zinc, and copper being exclusively detected among female subjects. In this respect, our results point to a complex interplay between inflammatory processes, hyperinsulinemia, and enhanced production of sexual hormones as pivotal elicitors of these sex‐specific pathological perturbations.