Maternal undernutrition programs tissue-specific epigenetic changes in the glucocorticoid receptor in adult offspring

Ghazala Begum, Alison Davies, Adam Stevens, Mark Oliver, Anne Jaquiery, John Challis, Jane Harding, Frank Bloomfield, Anne White

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)4560-9
Number of pages10
Issue number12
Publication statusPublished - Dec 2013


  • Animal Nutritional Physiological Phenomena
  • Animals
  • Epigenesis, Genetic
  • Female
  • Hypothalamus
  • Male
  • Malnutrition
  • Maternal Nutritional Physiological Phenomena
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Promoter Regions, Genetic
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Sheep
  • Sheep Diseases
  • Journal Article
  • Research Support, Non-U.S. Gov't


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