Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning

Ghazala Begum, Adam Stevens, Emma Bolton Smith, Kristin Connor, John R G Challis, Frank Bloomfield, Anne White

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)


Undernutrition during pregnancy is implicated in the programming of offspring for the development of obesity and diabetes. We hypothesized that maternal programming causes epigenetic changes in fetal hypothalamic pathways regulating metabolism. This study used sheep to examine the effect of moderate maternal undernutrition (60 d before to 30 d after mating) and twinning to investigate changes in the key metabolic regulators proopiomelanocortin (POMC) and the glucocorticoid receptor (GR) in fetal hypothalami. Methylation of the fetal hypothalamic POMC promoter was reduced in underfed singleton, fed twin, and underfed twin groups (60, 73, and 63% decrease, respectively). This was associated with reduced DNA methyltransferase activity and altered histone methylation and acetylation. Methylation of the hypothalamic GR promoter was decreased in both twin groups and in maternally underfed singleton fetuses (52, 65, and 55% decrease, respectively). This correlated with changes in histone methylation and acetylation and increased GR mRNA expression in the maternally underfed singleton group. Alterations in GR were hypothalamic specific, with no changes in hippocampi. Unaltered levels of OCT4 promoter methylation indicated gene-specific effects. In conclusion, twinning and periconceptional undernutrition are associated with epigenetic changes in fetal hypothalamic POMC and GR genes, potentially resulting in altered energy balance regulation in the offspring.

Original languageEnglish
Pages (from-to)1694-703
Number of pages10
JournalFASEB Journal
Issue number4
Publication statusPublished - Apr 2012


  • Animals
  • DNA Methylation
  • Energy Metabolism
  • Epigenesis, Genetic
  • Female
  • Fetus
  • Gene Expression Regulation, Developmental
  • Humans
  • Hypothalamus
  • Malnutrition
  • Maternal Nutritional Physiological Phenomena
  • Pregnancy
  • Pregnancy Complications
  • Pro-Opiomelanocortin
  • Promoter Regions, Genetic
  • Random Allocation
  • Receptors, Glucocorticoid
  • Sheep
  • Twins
  • Journal Article
  • Research Support, Non-U.S. Gov't


Dive into the research topics of 'Epigenetic changes in fetal hypothalamic energy regulating pathways are associated with maternal undernutrition and twinning'. Together they form a unique fingerprint.

Cite this