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

Abstract

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.

QComics: Recommendations and Guidelines for Robust, Easily Implementable and Reportable Quality Control of Metabolomics Data

“…Although it was initially designed for MS-based metabolomics, it should be noted that QC omics can also be used to manage other omics and MS data. In this sense, we would like to stress that some features of this QC protocol have successfully been applied in recent metabolomics and metallomics studies, − which highlights its reliability to deal with complex and heterogeneous data. Therefore, we strongly believe that QC omics will facilitate the implementation of good QC practices, at both application and reporting levels, and thus become a gold standard in metabolomics research.…”

Association between childhood obesity, trace elements, and heavy metals: Recent discoveries and future perspectives

“…When considering the entire population, we found childhood obesity to be associated with copper overloads, lower plasma levels of various trace elements (i.e., chromium, cobalt, iron, manganese, molybdenum, selenium, and zinc) contained in the metalloprotein fraction, and the sequestration of copper, iron, and selenium within the erythroid cytosol 44 . Additional analyses have demonstrated that children with obesity have increased plasma copper‐to‐zinc ratios regardless of sex, whereas the accumulation of metals within erythrocytes was exclusively detected among girls 46 . These female‐specific results were allocated to sexually dimorphic dysregulations in inflammation and hormone control, which in turn may differentially affect metal homeostasis as a consequence of the well‐known involvement of cytokines and sex steroids in the transport and uptake of trace elements (Figure 1).…”

“…Interplay between adiposity, inflammation, insulinemia, and hormone control in modulating metal homeostasis in childhood obesity. Reproduced from González‐Domínguez et al 46 with permission from Wiley.…”

Metal Homeostasis and Exposure in Distinct Phenotypic Subtypes of Insulin Resistance among Children with Obesity

“…Observational studies have reported that childhood obesity is characterized by an increased blood content of copper together with decreased iron, zinc, and selenium levels, but the results are contradictory for other minor elements [ 9 , 10 , 11 , 12 ]. Furthermore, recent evidence suggests that sex and pubertal status could influence obesity-related metal alterations [ 13 , 14 ]. However, the significance of IR subtypes in these metal disturbances remains unexplored.…”