Hormonal control of specific gene expression in the rat liver during the suckling-weaning transition

Abstract

In the rat, the suckling-weaning transition is accompanied by marked changes in nutrition. During the suckling period, the pups are fed with milk which is a high-fat low-carbohydrate diet. At weaning, milk is progressively replaced by the rat chow which is a high-carbohydrate low-fat diet. This is accompanied by considerable hormonal modifications: an increase in plasma insulin and a decrease in plasma glucagon concentrations, as well as by marked changes in metabolic pathways in liver: decrease in hepatic gluconeogenesis, increase in lipogenesis, and appearance of liver glucokinase. Most of the data concerning these changes are related to maximal activity of enzymes. The recent availability of specific cDNA probes for phosphoenolpyruvate carboxykinase, acetyl-CoA carboxylase, fatty acid synthase and glucokinase has allowed study of the role of pancreatic hormones and of nutrition in the changes of the expression of these genes at weaning in the rat. Fatty acid synthase and acetyl-CoA carboxylase mRNA in liver. The concentration of mRNA as well as the activity of acetyl-CoA carboxylase and fatty acid synthase are both very low in the liver of suckling rats. At weaning to a high-carbohydrate diet, the rapid increment in acetyl-CoA carboxylase and fatty acid synthase mRNA concentrations (10–20-fold) is followed by parallel changes in enzyme activities. In contrast, weaning on a high-fat diet prevents the increase in mRNA and activity of acetyl-CoA carboxylase and fatty acid synthase. Force-feeding suckling rats with carbohydrate is not associated with an increase in liver acetyl-CoA carboxylase and fatty acid synthase mRNA concentrations within 6 hr, despite marked increase in blood glucose and plasma insulin. This suggests that the accumulation of lipogenic enzyme mRNA in liver, 24–48 hr after carbohydrate feeding, could involve the synthesis of a factor needed for activation of gene transcription by insulin and glucose. Phosphoenolpyruvate carboxykinase mRNA in liver. The concentration of mRNA as well as the activity of phosphoenolpyruvate carboxykinase are elevated in the liver of suckling rat until the onset of weaning, 21 days after delivery. After weaning to a high-carbohydrate diet, both mRNA and activity of phosphoenolpyruvate carboxykinase rapidly decrease to a very low level. In contrast, weaning on a high-fat diet, which maintains high plasma glucagon and low plasma insulin levels, does not decrease mRNA and activity of phosphoenolpyruvate carboxykinase. Force-feeding suckling rats with carbohydrate results in increased plasma glucose and insulin concentrations and a 90% decrease in phosphoenolpyruvate carboxykinase mRNA in less than 1 hr. This suggests that hyperinsulinemia is the primary factor responsible for inhibition of liver phosphoenolpyruvate carboxykinase gene transcription. Glucokinase mRNA in liver. The concentration of mRNA as well as the activity of glucokinase are not detectable before 15 days after birth in the liver of the rat. They markedly increase when the newborns are weaned on a high-carbohydrate diet but not when they are weaned on a high-fat diet. Force-feeding suckling rats with carbohydrate is associated with a rapid (2 hr) increase of liver glucokinase mRNA. This suggests that hyperinsulinemia is involved in the stimulation of liver glucokinase gene transcription.