Identification of early indicators of altered metabolism in normal development using a rodent model system

Dis Model Mech. 2018 Mar 1;11(3):dmm031815. doi: 10.1242/dmm.031815.


Although the existence of a close relationship between the early maternal developmental environment, fetal size at birth and the risk of developing disease in adulthood has been suggested, most studies, however, employed experimentally induced intrauterine growth restriction as a model to link this with later adult disease. Because embryonic size variation also occurs under normal growth and differentiation, elucidating the molecular mechanisms underlying these changes and their relevance to later adult disease risk becomes important. The birth weight of rat pups vary according to the uterine horn positions. Using birth weight as a marker, we compared two groups of rat pups - lower birth weight (LBW, 5th to 25th percentile) and average birth weight (ABW, 50th to 75th percentile) - using morphological, biochemical and molecular biology, and genetic techniques. Our results show that insulin metabolism, Pi3k/Akt and Pparγ signaling and the genes regulating growth and metabolism are significantly different in these groups. Methylation at the promoter of the InsII (Ins2) gene and DNA methyltransferase 1 in LBW pups are both increased. Additionally, the Dnmt1 repressor complex, which includes Hdac1, Rb (Rb1) and E2f1, was also upregulated in LBW pups. We conclude that the Dnmt1 repressor complex, which regulates the restriction point of the cell cycle, retards the rate at which cells traverse the G1 or G0 phase of the cell cycle in LBW pups, thereby slowing down growth. This regulatory mechanism mediated by Dnmt1 might contribute to the production of small-size pups and altered physiology and pathology in adult life.

Keywords: Average birth weight; DNA methylation; Dnmt1 repressor complex; Expression array; Lower birth weight; Normal birth weight; Pi3k/Akt and Pparγ signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Birth Weight
  • Cell Cycle / genetics
  • DNA Methylation / genetics
  • Fatty Acids / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Glucagon / metabolism
  • Glucose / metabolism
  • Growth and Development* / genetics
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism
  • Metabolism* / genetics
  • Methyltransferases / metabolism
  • Models, Animal
  • Muscle, Skeletal / metabolism
  • Oligonucleotide Array Sequence Analysis
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats, Wistar
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction


  • Fatty Acids
  • Insulin
  • PPAR gamma
  • Glucagon
  • Methyltransferases
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose