Maternal Undernutrition Programs Tissue-Specific Epigenetic Changes in the Glucocorticoid Receptor in Adult Offspring

Abstract

Epidemiological data indicate that an adverse maternal environment during pregnancy predisposes offspring to metabolic syndrome with increased obesity, and type 2 diabetes. The mechanisms are still unclear although epigenetic modifications are implicated and the hypothalamus is a likely target. We hypothesized that maternal undernutrition (UN) around conception in sheep would lead to epigenetic changes in hypothalamic neurons regulating energy balance in the offspring, up to 5 years after the maternal insult. We found striking evidence of decreased glucocorticoid receptor (GR) promoter methylation, decreased histone lysine 27 trimethylation, and increased histone H3 lysine 9 acetylation in hypothalami from male and female adult offspring of UN mothers. These findings are entirely compatible with the increased GR mRNA and protein observed in the hypothalami. The increased GR predicted the decreased hypothalamic proopiomelanocortin expression and increased obesity that we observed in the 5-year-old adult males. The epigenetic and expression changes in GR were specific to the hypothalamus. Hippocampal GR mRNA and protein were decreased in UN offspring, whereas pituitary GR was altered in a sex-specific manner. In peripheral polymorphonuclear leukocytes there were no changes in GR methylation or protein, indicating that this epigenetic analysis did not predict changes in the brain. Overall, these results suggest that moderate changes in maternal nutrition, around the time of conception, signal life-long and tissue-specific epigenetic alterations in a key gene regulating energy balance in the hypothalamus.

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

“…These findings significantly extend previous work reporting epigenetic dysregulation after prenatal malnutrition(36, 40–42). Given that DNA and histone methylation landscapes show highly dynamic developmental regulation of neuronal and to some extent also non-neuronal chromatin of human cerebral cortex during infancy and early childhood(43–47), the blood DNA methylation changes as reported here could reflect on epigenetic maladaptations in brain, in analogy to epigenetic changes in the brain and behavioral dysregulation in response to early life adversity(48, 49).…”

A prospective study of maternal prenatal weight and offspring cardiometabolic health in midchildhood

“…In rodents, maternal obesity prior to and during pregnancy induces dysregulated feeding behavior and altered adipose tissue cellularity in offspring, resulting in obesity and related metabolic derangements later in life (2–5). Although epidemiologic studies in humans indicate that higher maternal pre-pregnancy body mass index (ppBMI) (6) and greater gestational weight gain (GWG) (7–10) are both associated with offspring obesity risk, there are gaps in literature that need to be addressed.…”

Epigenetic Markers to Predict Conversion From Gestational Diabetes to Type 2 Diabetes

“…For example, pancreatic cells from diabetic tissue had greater than 100 genes with epigenetic modifications that influenced insulin secretion, where the epigenetic changes were attributable to lifestyle factors including high body mass index (11). Maternal undernutrition during conception induces life-long and tissue-specific epigenetic alterations affecting energy balance in the offspring (12). In diabetic women the in-utero fetal environment increases the risk for the development of obesity in the offspring with strong evidence for the involvement of epigenetic mechanisms (13).…”