Epigenetics and childhood obesity: DNA methylation coordinates environment and gene regulation.

Abstract

Childhood obesity is a complex disorder which results from the combined contribution of genetics, the environment, and development, which is programmed and coordinated by epigenetic mechanisms. Of them, DNA methylation has emerged as an important molecular interface between environmental inputs and changes in gene expression. In this review, we provide an overview of the role of DNA methylation in childhood obesity during the key developmental stages, from prenatal life and childhood to adolescence. We also highlight the available evidence from candidate genes and genome-wide association studies implicating critical loci involved in energy homeostasis and adipogenesis, where DNA methylation is altered. Further, we also provide an overview of how maternal obesity, nutritional status, and bariatric surgery shape offspring's methylation profiles and contribute to the increased risk of programming obesity across generations. Although aberrant methylation patterns are consistently associated with altered metabolic phenotypes, disentangling causality remains a significant challenge. Herein, we highlight emerging approaches, such as rigorous longitudinal cohorts, epigenetic Mendelian randomization, and CRISPR-based epigenome editing, that are beginning to provide the analytical clarity needed to move beyond association. Finally, we examine the potential of DNA methylation signatures to inform early risk stratification and prevention possibilities. Although yet to be clinically validated, whole-genome methylation profiling is increasingly integrated with systems biology and multi-omics frameworks, making the identification of robust, clinically actionable markers more promising. A more precise understanding of how epigenetic processes shape susceptibility to childhood obesity could ultimately support strategies capable of altering lifelong metabolic trajectories.