Fetal programming of adult metabolism in rats

The importance of the prenatal period for adult health is underscored by epidemiological correlations between prematurity and diseases such as coronary heart disease, stroke, and diabetes. To address questions in fetal development and the effect of fetal gene regulation on postnatal phenotype, adenoviral in utero gene therapy was used to transiently alter gene expression during late stages of gestation in the rat.;Several lines of evidence suggest that cystic fibrosis transmembrane conductance regulator (CFTR, the gene defective in cystic fibrosis) plays a role in proper development of the intestine. To analyze the temporal aspects of that requirement, CFTR expression in the intestine of rat fetuses was transiently suppressed using in utero gene therapy. Depending on the gestational age of the fetus, transient reduction of CFTR function resulted in phenotypes ranging from meconium ileus and subsequent death to obesity.;Of particular interest are animals treated during day 17 (E17) of embryonic development. At weaning, the intestines are morphologically normal and appear properly developed. However, older animals have dilated intestines with abnormal histology, suggesting functional deficiency. Also, these animals display dysregulated production of intestinal hormones responsible for promoting satiety, resulting in increased food intake and excess body fat. Glucose and insulin tolerance tests and clamp studies showed significant peripheral tissue resistance to insulin leading to diabetes in aged animals.;This study provides a clear example of an adult onset disease originating from disruption of fetal development but undetectable in young animals. In addition, it demonstrates that weight gain and insulin resistance in adults can result solely from changes in gene expression during gestation.