Fetal metabolic programming and epigenetic modifications: a systems biology approach

Abstract

A growing body of evidence supports the notion that epigenetic changes such as DNA methylation and histone modifications, both involving chromatin remodeling, contribute to fetal metabolic programming. We use a combination of gene-protein enrichment analysis resources along with functional annotations and protein interaction networks for an integrative approach to understanding the mechanisms underlying fetal metabolic programming. systems biology approaches suggested that fetal adaptation to an impaired nutritional environment presumes profound changes in gene expression that involve regulation of tissue-specific patterns of methylated cytosine residues, modulation of the histone acetylation-deacetylation switch, cell differentiation, and stem cell pluripotency. The hypothalamus and the liver seem to be differently involved. In addition, new putative explanations have emerged about the question of whether in utero overnutrition modulates fetal metabolic programming in the same fashion as that of a maternal environment of undernutrition, suggesting that the mechanisms behind these two fetal nutritional imbalances are different. In conclusion, intrauterine growth restriction is most likely to be associated with the induction of persistent changes in tissue structure and functionality. conversely, a maternal obesogenic environment is most probably associated with metabolic reprogramming of glucose and lipid metabolism, as well as future risk of metabolic syndrome (Ms), fatty liver, and insulin (INs) resistance.L arge amounts of epidemiological data showed that impaired intrauterine growth and adult metabolic and cardiovascular disorders, including coronary heart disease, type 2 diabetes, and insulin (INS) resistance, are strongly associated (1-4). Actually, the first exploration of a putative connection between environmental influence in early life and the risk of cardiovascular disease in adulthood was done by David Barker and coworkers, who followed-up a cohort of 499 men and women born in Preston (Lancashire, UK) during 1935-1943, and observed that as adults the highest blood pressures occurred in people who had been small babies with large placentas (5).Of note, the concept of a relationship between birth weight and adult chronic diseases initially described in low-birthweight babies was further extended to large-for-gestational age (LGA) babies, and the term of inappropriate gestational weight gained acceptance to better illustrate changes in earlylife metabolic environment that contribute to the risk of metabolic syndrome (MS) in adulthood (6).Barker and Hales also provided the initial answer to the question of how birth weight and adult chronic diseases are connected. They explained that fetuses adapt to an impaired supply of nutrients by changing their physiology and metabolism, and altering the sensitivity of tissues causes an abnormal structure and function in adult life; thereby, they formulated the "thrifty phenotype hypothesis" (7,8).Altogether, the above-mentioned clinico-epidemiological evidence str...

Metabolic programming mediated by an essential fatty acid alters body composition and survival skills of a marine fish

“…and various molecular, cellular, metabolic, neuroendocrine, physiological, and epigenetic pathways have been proposed for the resulting permanent effects on metabolism [14,15]. Our findings provide a clear demonstration of metabolic programming that connects maternal nutrition to measures of offspring fitness in a fish and indications of the general mechanism involved.…”

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

“…Systems biology approaches have indicated that the maternal intrauterine environment modulates fetal metabolic programming, which in turn can have a profound effect on gene expression early in life and can be passed across generations through epigenetic modifications (53). Recent reports have shown that NO affects global histone methylation patterns, particularly by directly inhibiting the lysine-specific histone demethylase Kdm3a and likely other Jumonji C domain-containing demethylases (29,30).…”

Cord Blood Metabolome Is Highly Associated with Birth Weight, but Less Predictive for Later Weight Development

“…Developmental plasticity during pre- and postnatal development allows the organism to adapt to environmental cues by cellular, metabolic, and other physiological changes. Hence different phenotypes can originate from the same genotype due to environmental stimuli via mechanisms such as epigenetic modifications [3]. For example, it has been proposed that intrauterine undernutrition can cause changes in endocrine response, body size, and composition as the fetus adapts to encounter the threat to survival [4,5].…”