Abstract
ABSTRACTAlthough 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.
Highlights
IntroductionThe fetus encounters a high-nutrient environment in later life, it would probably adjust in a manner that predisposes it to metabolic diseases, such as type 2 diabetes, obesity, hyperlipidemia and insulin resistance (Gluckman and Hanson, 2004; Simmons, 2005; Barnes and Ozanne, 2011; Gluckman et al, 2011; Vickers, 2014)
Percentage of insulin-secreting β cells and glucagonsecreting α cells and their expression differ between average birth weight (ABW) and lower birth weight (LBW) pups Having observed changes in the glucose levels and growth rates of the different groups of pups, we examined the expression of insulin and glucagon in the pancreatic islets of ABW and LBW pups by immunohistochemistry, to determine whether any differences existed between the two groups of pups
He argued that an optimal fetal developmental environment is crucial for a healthy adult life and that any perturbations during this period will lead to a higher risk of developing metabolic diseases
Summary
The fetus encounters a high-nutrient environment in later life, it would probably adjust in a manner that predisposes it to metabolic diseases, such as type 2 diabetes, obesity, hyperlipidemia and insulin resistance (Gluckman and Hanson, 2004; Simmons, 2005; Barnes and Ozanne, 2011; Gluckman et al, 2011; Vickers, 2014) These observations are significant, most of these data have been obtained from animal studies using experimentally induced intrauterine growth restriction (IUGR) (Vickers et al, 2000, 2003; Simmons et al, 2001; Simmons, 2005; Park et al, 2008). The need to understand the molecular and epigenetic regulatory mechanisms that mediate these processes has become even more important, with the observation that administration of exogenous leptin could reverse changes in Pparα expression (Vickers et al, 2005), and that omega fatty acids can reduce hyperleptinemia and hypertension (Wyrwoll et al, 2006)
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