Abstract
Maternal malnutrition plays a critical role in the developmental programming of later metabolic diseases susceptibility in the offspring, such as obesity and type 2 diabetes. Because the liver is the major organ that produces and supplies blood glucose, we aimed at defining the potential role of liver glycogen autophagy in the programming of glucose metabolism disturbances. To this end, newborns were obtained from pregnant Wistar rats fed ad libitum with a standard diet or 65% food-restricted during the last week of gestation. We found that newborns from undernourished mothers showed markedly high basal insulin levels whereas those of glucagon were decreased. This unbalance led to activation of the mTORC1 pathway and inhibition of hepatic autophagy compromising the adequate handling of glycogen in the very early hours of extrauterine life. Restoration of autophagy with rapamycin but not with glucagon, indicated no defect in autophagy machinery per se, but in signals triggered by glucagon. Taken together, these results support the notion that hyperinsulinemia is an important mechanism by which mobilization of liver glycogen by autophagy is defective in food-restricted animals. This early alteration in the hormonal control of liver glycogen autophagy may influence the risk of developing metabolic diseases later in life.
Highlights
Maternal malnutrition plays a critical role in the developmental programming of later metabolic diseases susceptibility in the offspring, such as obesity and type 2 diabetes
These results are in agreement with a higher pancreatic beta-cell relative mass and with enhanced glucose-stimulated insulin secretion in islets from U newborns (Fig. 1E, F, respectively, upper panels)
When we analysed the effect of intrauterine growth restriction (IUGR) on skeletal muscle content of GLUT-4 and GLUT-1, we found that this condition led to a decrease in protein levels of both transporters (Fig. 4), suggesting decreased rate of glucose uptake by skeletal muscle likely contributing to the high blood glucose levels observed in U newborns
Summary
Maternal malnutrition plays a critical role in the developmental programming of later metabolic diseases susceptibility in the offspring, such as obesity and type 2 diabetes. Because the liver is the major organ that produces and supplies blood glucose, we aimed at defining the potential role of liver glycogen autophagy in the programming of glucose metabolism disturbances. We found that newborns from undernourished mothers showed markedly high basal insulin levels whereas those of glucagon were decreased This unbalance led to activation of the mTORC1 pathway and inhibition of hepatic autophagy compromising the adequate handling of glycogen in the very early hours of extrauterine life. Within the first few hours of life the mechanisms of glycogenolysis and gluconeogenesis are not fully established, so for the maintenance of glucose homeostasis in the newborn it is absolutely necessary the glycogen autophagy[4,5] This process is triggered by glucagon secreted during the hypoglycemia that follows birth, but inhibited by insulin[2,4]. In the present work we aimed at defining the potential role of liver glycogen autophagy in the programming of glucose metabolism disturbances
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