RT Journal Article
SR Electronic
T1 Identification of early indicators of altered metabolism in normal development using a rodent model system
JF Disease Models & Mechanisms
JO Dis Models Mech
FD The Company of Biologists Limited
SP dmm031815
DO 10.1242/dmm.031815
VO 11
IS 3
A1 Prabakaran, Ashok Daniel
A1 Karakkat, Jimsheena Valiyakath
A1 Vijayan, Ranjit
A1 Chalissery, Jisha
A1 Ibrahim, Marwa F.
A1 Kaimala, Suneesh
A1 Adeghate, Ernest A.
A1 Al-Marzouqi, Ahmed Hassan
A1 Ansari, Suraiya Anjum
A1 Mensah-Brown, Eric
A1 Emerald, Bright Starling
YR 2018
UL http://dmm.biologists.org/content/11/3/dmm031815.abstract
AB 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.