Epigenetic mechanisms in the developmental programming of childhood obesity

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Author(s):

	Szilvia Bokor
	Szilvia Bokor (MD, PhD) is an Assistant Professor at the Department of Paediatrics, Medical School, University of Pécs, Hungary, with specialist qualifications in paediatrics and paediatric endocrinology.
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INTRODUCTION
Childhood obesity has emerged as a major global public health challenge, with prevalence rates increasing substantially over recent decades. Although obesity is acknowledged as a highly heritable condition, genetic predisposition alone cannot account for the rapid rise observed at the population level (1). Numerous studies have demonstrated considerable interindividual variability in body weight, fat distribution, and susceptibility to obesity-related metabolic complications, suggesting the involvement of additional regulatory mechanisms beyond DNA sequence variation (2). These mechanisms are likely influenced by population-level shifts in lifestyle and dietary patterns, reflecting an increasingly obesogenic environment (3). Together, these observations highlight the importance of gene–environment interactions in the development and progression of obesity (4,5).
Epigenetic mechanisms provide a molecular framework for understanding how environmental exposures influence gene regulation, individual disease susceptibility, and intergenerational transmission of phenotypic effects (5–9). A well-established experimental example of this concept is the agouti viable yellow (Avy) mouse model, in which maternal dietary methyl-donor supplementation increases DNA methylation at the agouti locus in the offspring and partially reverses the obesity-prone phenotype (10). In humans, one of the best-known examples of developmental programming comes from the Dutch Hunger Winter, where prenatal famine exposure during critical periods of gestation was associated with persistent epigenetic alterations and an increased risk of metabolic disease later in life (11). Such observations have raised interest in epigenetically mediated inheritance effects. In this context, although epigenetic reprogramming during gametogenesis and early embryonic development is expected to limit the long-term persistence of environmentally induced marks across generations (12,13), a growing body of evidence supports intergenerational transmission of epigenetically related phenotypic effects in both experimental and epidemiological studies. At the same time, evidence for stable transgenerational epigenetic inheritance across multiple generations in humans remains limited (13,14).
Epigenetic mechanisms are increasingly being investigated in childhood obesity, with accumulating evidence supporting associations between epigenetic alterations and obesity-related phenotypes (4). However, the currently available data remain limited and heterogeneous, with important gaps in several areas (4,6). Furthermore, the relationship appears to be bidirectional, as epigenetic changes may not only contribute to the development of obesity but also arise as a consequence of obesity-related metabolic disturbances (4,15).
Understanding how epigenetic modifications contribute to obesity susceptibility and metabolic dysfunction may help explain the increasing prevalence of childhood obesity and may ultimately provide novel opportunities for early prevention, risk stratification, and targeted therapeutic intervention (5).

I. EPIGENETIC PROCESSES RELATED TO CHILDHOOD OBESITY
Epigenetic regulation
Since its introduction by Conrad Waddington in 1942, the concept of epigenetics has evolved substantially. Today, epigenetics is generally defined as the regulation of gene activity through mechanisms that do not involve changes in DNA sequence (16). The major epigenetic mechanisms include DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) (17). These regulatory layers do not act in isolation but are dynamically interconnected, with changes in one layer often influencing the others, although a strict hierarchical organization has not been clearly established (4).
Epigenetic regulation plays a fundamental role in controlling cellular identity, developmental processes, and tissue-specific gene expression programs. Through these mechanisms, genes can be activated or silenced in a context-dependent manner (5), thereby shaping phenotypic outcomes. Gene expression regulation occurs in a highly tissue-specific manner, reflecting the functional requirements of different cell types. Epigenetic marks are generally stable enough to maintain cellular identity during cell division, yet remain sufficiently plastic to respond to environmental stimuli across the lifespan (18). These processes are essential for normal development but also represent windows of increased vulnerability to environmental influences.
Overall, epigenetic mechanisms represent a dynamic interface between environmental exposures and gene regulation, providing a biological framework for understanding complex disease susceptibility such as obesity (Figure 1.). However, studying epigenetic mechanisms remains challenging due to their tissue-specific and time-dependent nature, the difficulty of accurately characterizing environmental exposures, and the dynamic changes occurring throughout life.

Figure 1. Epigenetic regulation in mediating gene–environment interactions in childhood obesity.

DNA methylation
DNA methylation refers to the enzymatic addition of a methyl group to the 5′ carbon of cytosine residues, predominantly at cytosine–phosphate–guanine (CpG) sites located in gene promoters and other genomic regions (6). When present at gene promoters and enhancers, it is commonly associated with gene silencing. Among epigenetic mechanisms, DNA methylation is the most extensively studied in the context of childhood obesity. Numerous candidate gene studies and epigenome-wide association studies (EWAS) have demonstrated that differences in DNA methylation at specific genomic loci are associated with differences in adiposity, body composition, and metabolic traits from early life onwards (9,19–23). These loci are enriched in genes involved in key biological pathways regulating energy homeostasis, including appetite control, adipogenesis, metabolic regulation, growth and developmental programming, and inflammation. Both hypermethylation and hypomethylation of obesity-associated loci have been reported, although their functional consequences depend on the genomic context and regulatory location of the affected CpG sites.
Table 1 summarizes representative genes and EWAS-derived loci with reported obesity-associated DNA methylation changes according to their major biological functions (4,9).

Table 1. Representative genes and EWAS-derived loci with reported obesity-associated DNA methylation changes.

Functional / evidence category
Genes/loci with reported obesity-associated methylation changes Main obesity-related associations
Appetite regulation LEP, LEPR, MC4R, POMC, NPY, BDNF Appetite control, satiety, adiposity, obesity susceptibility
Adipogenesis and energy metabolism PPARG, ADIPOQ, RXRA, CPT1A, SREBF1 BMI, adiposity, lipid metabolism, insulin sensitivity
Growth and developmental programming IGF2, H19, MEST Growth trajectories, adiposity, metabolic outcomes
Inflammation and metabolic dysfunction TNF, IL6, SOCS3 Insulin resistance, metabolic dysfunction, cardiometabolic risk
Representative EWAS-derived loci/genes ABCG1 (cg06500161), CPT1A (cg00574958), HIF3A (cg27146050), SLC7A11, SBNO2, SOCS3 Adiposity, BMI, metabolic traits, cardiometabolic risk

LEP: leptin, LEPR: leptin receptor, MC4R: melanocortin 4 receptor, POMC: proopiomelanocortin, NPY: neuropeptide Y, BDNF: brain-derived neurotrophic factor, PPARG: peroxisome proliferator-activated receptor gamma, ADIPOQ: adiponectin, RXRA: retinoid X receptor alpha, CPT1A: carnitine palmitoyltransferase 1A, SREBF1: sterol regulatory element-binding transcription factor 1, IGF2: insulin-like growth factor 2, H19: long non-coding RNA H19, MEST: mesoderm-specific transcript, TNF: tumor necrosis factor, IL6: interleukin 6, SOCS3: suppressor of cytokine signaling 3, ABCG1: ATP binding cassette subfamily G member 1, HIF3A: hypoxia-inducible factor 3 subunit alpha, SLC7A11: solute carrier family 7 member 11, SBNO2: strawberry notch homolog 2.

Overall, DNA methylation is a key molecular mechanism linking environmental exposures to gene regulation in childhood obesity. Although causal relationships remain to be fully elucidated, these epigenetic signatures may serve as potential biomarkers for early risk stratification and may provide novel targets for future preventive and therapeutic strategies.
However, current evidence should be interpreted with caution because findings are often heterogeneous and largely derived from observational studies. In addition, most investigations use blood-based samples, which may not fully reflect epigenetic regulation in metabolically relevant tissues. Consequently, the causal role and clinical significance of many obesity-associated epigenetic alterations remain uncertain.

Non-coding RNAs
ncRNAs comprise a diverse class of RNA molecules that do not encode proteins and can be broadly categorized into long non-coding RNAs (lncRNAs) and small non-coding RNAs, including microRNAs (miRNAs) and other regulatory RNA species. These molecules regulate gene expression through multiple mechanisms acting at transcriptional, post-transcriptional, translational, and post-translational levels, thereby contributing to cellular processes (24).
Among ncRNAs, miRNAs represent the most extensively studied class in childhood obesity, with evidence indicating altered circulating and tissue-specific expression profiles associated with adiposity, inflammation, and metabolic dysfunction (4,25). Studies consistently report differential expression of miRNAs in peripheral blood and, to a lesser extent, in adipose tissue and other metabolic tissues, supporting a role for miRNA-mediated regulation in early-life metabolic programming.
Several miRNAs (most notably miR-122, miR-221/222, miR-423, and miR-486) (4,6,25) have shown recurrent associations with childhood anthropometric traits across independent studies. However, these findings are increasingly interpreted within multi-miRNA signature frameworks rather than as single candidate markers, reflecting substantial heterogeneity across cohorts. Overall, although a growing number of ncRNAs have been associated with obesity-related phenotypes in infancy and childhood, most evidence remains derived from heterogeneous datasets and requires further validation in larger, well-characterized cohorts.

Histone modifications
Histone modifications comprise a diverse group of post-translational changes, including acetylation, methylation, phosphorylation, and ubiquitination, that regulate chromatin structure and gene transcription (8,26). Among these, histone acetylation and methylation are the most extensively studied in the context of metabolic diseases. Histone acetylation is generally associated with transcriptional activation through chromatin relaxation, whereas histone methylation may exert either activating or repressive effects depending on the specific residue and degree of methylation (8,27).
In contrast to DNA methylation and non-coding RNAs, evidence linking histone modifications to childhood obesity in human studies remains limited. Most available data are derived from experimental models or broader metabolic research, and large-scale pediatric epigenome-wide studies are currently lacking. Consequently, histone modifications are considered a potentially important but still emerging and insufficiently characterized epigenetic mechanism in childhood obesity (4,6).

II. FACTORS INFLUENCING EPIGENETIC REGULATION IN CHILDHOOD OBESITY

Prenatal and perinatal determinants of epigenetic programming
The perinatal period is a critical window for epigenetic programming, characterized by dynamic DNA methylation reconfiguration, including post-fertilization global demethylation followed by de novo methylation during implantation and tissue-specific remodeling during fetal development (28,29). This high degree of epigenetic plasticity renders the developing organism particularly sensitive to environmental influences, allowing early-life exposures to induce stable and potentially long-lasting changes in gene regulation (4,7).
Within the prenatal and perinatal window, a broad range of interrelated maternal and environmental exposures has been associated with epigenetic programming in childhood obesity, reflecting a continuum of metabolic, nutritional, chemical, and psychosocial influences rather than isolated determinants. These exposures have been linked to DNA methylation changes in genes involved in energy homeostasis, insulin signaling, adipokine regulation, inflammation, and growth, thereby connecting early environmental conditions with long-term metabolic phenotypes (4,7,30).
Among the various prenatal and perinatal exposures investigated to date, maternal metabolic characteristics, including pre-pregnancy obesity, excessive gestational weight gain, and gestational diabetes, represent one of the best-established exposure domains in epigenetic programming of obesity, with consistent associations linking offspring DNA methylation variation to later obesity risk (4,31–35). Maternal nutritional exposures during pregnancy, including evidence from historical natural experiments such as the Dutch Hunger Winter, the Överkalix cohort, and the Chinese Great Leap Forward famine cohorts, have been associated with long-term alterations in offspring epigenetic regulation (11,36). In addition to extreme energy restriction, more common dietary patterns, including macronutrient imbalance (high-fat and high-sugar intake) and differences in the availability of several micronutrients, particularly methyl-group donors involved in one-carbon metabolism (e.g., folate, choline, betaine, and methionine), have also been associated with offspring DNA methylation patterns in genes involved in metabolic regulation, which have in turn been linked to variation in growth, adiposity, and later metabolic health outcomes (32,37). Beyond nutrients themselves, dietary bioactive compounds such as polyphenols and genistein may also influence epigenetic regulation through similar biological pathways, although the available evidence is less consistent (9). More broadly, environmental chemical exposures during pregnancy, including endocrine-disrupting compounds (such as bisphenol A), tobacco smoke, and selected pesticides, have been associated with reproducible offspring DNA methylation signatures and reported links to altered fetal growth and later metabolic risk profiles (8,38,39). However, the strength of evidence differs considerably across exposure classes and study designs.
In addition to nutritional and environmental influences, maternal psychosocial stress has also been associated with differential DNA methylation in stress-response pathways, particularly genes involved in glucocorticoid signaling, with reported associations to altered stress responsivity and metabolic regulation phenotypes in offspring (40). Emerging evidence further suggests that maternal gut microbiome composition may represent an indirect prenatal exposure influencing developmental programming through microbial metabolites and inflammatory mediators that may interact with host epigenetic regulatory mechanisms, including DNA methylation pathways (7,30,41).
Overall, despite heterogeneity in exposure specificity and evidence strength, converging findings support the concept that prenatal and perinatal environmental factors are associated with DNA methylation variation in key developmental and metabolic regulatory pathways, which in turn have been linked to long-term differences in growth trajectories, adiposity, and cardiometabolic risk (7,30,41).

Postnatal environmental and developmental exposures influencing epigenetic programming
Postnatal environmental and developmental exposures may modify epigenetic patterns established during prenatal development, thereby influencing the long-term trajectory of metabolic programming (42). Although epigenetic marks progressively stabilize with age, sustained nutritional, developmental, and psychosocial influences may still contribute to epigenetic drift and interindividual variability in metabolic regulation and obesity susceptibility (4,9,32,42). Compared with prenatal exposures, evidence for postnatal epigenetic programming of obesity remains more limited and heterogeneous. Nevertheless, available studies suggest that postnatal influences may affect obesity-related epigenetic regulation through several interconnected domains, including growth patterns, nutritional exposures, psychosocial factors, and broader environmental influences.
Among the postnatal factors investigated, rapid infant weight gain and catch-up growth have been associated with differences in DNA methylation in metabolic regulatory pathways and with increased adiposity later in life, although effect sizes and replication remain variable across studies (9). Closely related to early growth trajectories, nutritional exposures during infancy and childhood (including breastfeeding, complementary feeding practices, and overall dietary quality) have likewise been linked to differential methylation of genes involved in metabolic and endocrine regulation. In later childhood, obesogenic dietary patterns and lower physical activity levels have been associated with epigenetic variation in pathways related to energy metabolism, inflammation, and mitochondrial function (9).
Beyond growth and lifestyle-related factors, psychosocial stress, selected environmental exposures such as early-life tobacco smoke exposure, and emerging factors including microbiome-related characteristics, antibiotic exposure, and sleep-related traits have been linked to epigenetic variation associated with childhood obesity risk; however, available evidence remains limited and inconsistent, and the biological significance of these findings is not yet fully understood (4,9).
Taken together, current evidence suggests that postnatal exposures primarily act as modifiers of prenatally established epigenetic programming rather than independent drivers of obesity-related epigenetic architecture. Although a growing number of postnatal factors have been associated with DNA methylation variation, the functional significance, reproducibility, and causal role of many reported alterations remain incompletely understood (9).

Figure 2. Major prenatal and postnatal exposures involved in the epigenetic programming of childhood obesity.

Methodological considerations and current limitations
Interpretation of the available evidence is complicated by substantial heterogeneity across studies. Differences in study design, sample size, tissue type, age at epigenetic assessment, exposure characterization, analytical platforms, and bioinformatic approaches limit direct comparability and may contribute to inconsistencies between findings. Furthermore, most reported associations are derived from observational studies, making it difficult to distinguish causal epigenetic mechanisms from biomarkers reflecting underlying environmental or metabolic exposures. An additional challenge is the possibility of reverse causation, particularly in postnatal studies, where adiposity itself may induce DNA methylation changes. Consequently, although numerous epigenetic alterations associated with prenatal and postnatal exposures have been linked to obesity-related phenotypes, their causal relevance and functional significance remain incompletely understood.

III. FROM EPIGENETIC PROGRAMMING TO PREVENTION: CLINICAL IMPLICATIONS FOR OBESITY
The potentially reversible nature of epigenetic modifications has generated considerable interest in their application as targets for obesity prevention and intervention (2,32,41). Current evidence suggests that the greatest opportunities for influencing obesity risk may lie in preventive strategies implemented during sensitive developmental windows, particularly before conception, during pregnancy, and throughout early childhood. Interventions targeting maternal metabolic health, nutritional status, gestational weight gain, and early-life nutrition have been associated with favorable metabolic outcomes in offspring and may, at least partly, act through epigenetic mechanisms (2,32,41).
From a clinical perspective, these findings reinforce the importance of established preventive measures, including healthy nutrition, regular physical activity, breastfeeding, adequate sleep, and optimization of maternal metabolic health. Although not specifically designed as epigenetic interventions, these strategies may partly exert their long-term benefits through epigenetic pathways (4,32). Thus, epigenetic research provides additional biological support for life-course approaches to obesity prevention.
Beyond their role in prevention, epigenetic signatures have also attracted interest as potential biomarkers of obesity susceptibility and metabolic risk. Among these, DNA methylation-based risk scores (MRSs), which combine information from multiple obesity-associated methylation sites, have emerged as promising tools for risk stratification. However, their interpretation is complicated by biological and technical variability, and current evidence suggests that many obesity-associated methylation patterns may represent consequences rather than causes of adiposity (9). In parallel, DNA methylation-based biomarkers of ageing, known as epigenetic clocks, provide an estimate of epigenetic age derived from genome-wide methylation patterns (43). Epigenetic age acceleration (defined as epigenetic age exceeding chronological age) has been associated with obesity, insulin resistance, and adverse cardiometabolic outcomes (44–46). Overall, while both DNA methylation-based risk scores and epigenetic clocks offer complementary insights into metabolic and ageing-related processes, they remain research tools with limited clinical applicability at present (38).
Despite increasing knowledge of epigenetic regulation, no epigenetic therapies are currently available for the prevention or treatment of childhood obesity. This reflects the complexity of obesity-associated epigenetic alterations, which are often tissue-specific, environmentally responsive, and incompletely understood in terms of causality.

At present, lifestyle-based interventions and optimization of the early-life environment remain the most realistic and evidence-based approaches for modifying obesity-related epigenetic risk. As research continues to evolve, epigenetic biomarkers may eventually complement traditional clinical and anthropometric measures and improve early identification of children at increased cardiometabolic risk.

CONCLUSION
Epigenetic mechanisms provide a molecular framework linking environmental exposures to gene regulation and help explain inter-individual differences in susceptibility to childhood obesity. Early developmental periods, including preconception, pregnancy, and early childhood, represent critical windows during which environmental influences may shape long-term metabolic trajectories through epigenetic programming. Among the various mechanisms involved, DNA methylation has been most extensively studied and most consistently associated with childhood obesity and related metabolic outcomes. However, current evidence remains largely observational, and epigenetic alterations may reflect both causal pathways and downstream consequences of metabolic dysregulation. Importantly, experimental and epidemiological data also raise the possibility that some environmentally induced epigenetic signals may extend beyond the individual, potentially contributing to intergenerational effects mediated through both maternal and paternal lineages, although robust evidence for stable transmission across multiple generations in humans remains limited. Overall, the greatest current clinical relevance of epigenetic research lies in strengthening the biological rationale for early-life preventive strategies rather than enabling routine diagnostic or therapeutic application.

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