Maternal obesity and gestational diabetes reprogram the methylome of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways

Abstract

Background Obesity is a negative chronic metabolic health condition that represents an additional risk for the development of multiple pathologies. Epidemiological studies have shown how maternal obesity or gestational diabetes mellitus during pregnancy constitute serious risk factors in relation to the appearance of cardiometabolic diseases in the offspring. Furthermore, epigenetic remodelling may help explain the molecular mechanisms that underlie these epidemiological findings. Thus, in this study we explored the DNA methylation landscape of children born to mothers with obesity and gestational diabetes during their first year of life. Methods We used Illumina Infinium MethylationEPIC BeadChip arrays to profile more than 770,000 genome-wide CpG sites in blood samples from a paediatric longitudinal cohort consisting of 26 children born to mothers who suffered from obesity or obesity with gestational diabetes mellitus during pregnancy and 13 healthy controls (measurements taken at 0, 6 and 12 month; total N = 90). We carried out cross-sectional and longitudinal analyses to derive DNA methylation alterations associated with developmental and pathology-related epigenomics. Results We identified abundant DNA methylation changes during child development from birth to 6 months and, to a lesser extent, up to 12 months of age. Using cross-sectional analyses, we discovered DNA methylation biomarkers maintained across the first year of life that could discriminate children born to mothers who suffered from obesity or obesity with gestational diabetes. Importantly, enrichment analyses suggested that these alterations constitute epigenetic signatures that affect genes and pathways involved in the metabolism of fatty acids, postnatal developmental processes and mitochondrial bioenergetics, such as CPT1B, SLC38A4, SLC35F3 and FN3K. Finally, we observed evidence of an interaction between developmental DNA methylation changes and maternal metabolic condition alterations. Conclusions Our observations highlight the first six months of development as being the most crucial for epigenetic remodelling. Furthermore, our results support the existence of systemic intrauterine foetal programming linked to obesity and gestational diabetes that affects the childhood methylome beyond birth, which involves alterations related to metabolic pathways, and which may interact with ordinary postnatal development programmes.

Dilemma of Epigenetic Changes Causing or Reducing Metabolic Disorders in Offsprings of Obese Mothers

“…It is already known that adiponectin and leptin gene expression is controlled by histone modifications and thus suggesting its implication on fetal metabolism and development [20,21]. Alba-Linares et al found that maternal obesity and maternal obesity with gestational diabetes led to abundant DNA methylation alteration during the first six months of child development into the genes including CPT1B, FN3K, SLC35F3, and SLC38A4 involved in the metabolism of fatty acids, mitochondrial bioenergetics, and postnatal development processes [29].…”

Epigenetic implications in maternal diabetes and metabolic syndrome‐associated risk of orofacial clefts

“…For example, maternal obesity was associated with altered histone methylation during embryonic development and histone H3 Lysine 4 dimethylation (H3K4me2) was reduced in the embryos of obese mice (Pan et al, 2020). Epigenetic studies using human blood samples have demonstrated that both maternal diabetes and obesity can reprogram the DNA methylome of newborns or offspring beyond birth (Alba‐Linares et al, 2023; Rizzo et al, 2020). Thus, while maternal metabolic disorders can negatively influence fetal and offspring development through epigenetic alterations, the effects may be preventable or even reversible.…”

Trained immunity in diabetes and hyperlipidemia: Emerging opportunities to target cardiovascular complications and design new therapies

“…There is evidence that systemic intrauterine fetal programming displays hallmarks of trained immunity, in particular epigenetic changes, which are critical in the transmission of cardiometabolic disease from mothers to their offspring (reviewed in 48 ). For example, a recent study found that DNA methylation biomarkers in peripheral blood cells maintained across the first year of life could discriminate children born to mothers who suffered from obesity or gestational diabetes, and crucially, these alterations affected genes related to immune system activation ( ETS1, ITGB2 , and TNF family), metabolism ( FN3K, SLC38A4, SLC35F3 , and CPT1B ), and epigenetics ( HDAC4, PRDM16 ) 49 . Maternal obesity and diabetes could constitute serious risk factors in relation to the appearance of cardiometabolic diseases in the offspring and it remains to be studied whether parental trained immunity is transmitted across generations to predispose offspring to cardiometabolic diseases.…”

“…For example, a recent study found that DNA methylation biomarkers in peripheral blood cells maintained across the first year of life could discriminate children born to mothers who suffered from obesity or gestational diabetes, and crucially, these alterations affected genes related to immune system activation ( ETS1, ITGB2 , and TNF family), metabolism ( FN3K, SLC38A4, SLC35F3 , and CPT1B ), and epigenetics ( HDAC4, PRDM16 ). 49 Maternal obesity and diabetes could constitute serious risk factors in relation to the appearance of cardiometabolic diseases in the offspring and it remains to be studied whether parental trained immunity is transmitted across generations to predispose offspring to cardiometabolic diseases. If proven, the identification and treatment of trained immunity in cardiometabolic diseases in women of childbearing age could help mitigate the acquisition of trained immunity and its associated risk of cardiovascular disease in the next generation.…”