Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats

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.

How stra(i)nge are your controls? A comparative analysis of metabolic phenotypes in commonly used C57 substrains

“…Incidentally, sex differences in hepatic ischemia/reperfusion injury have been found to be mediated by a male specific gene SRY (sex determining region on the Y chromosome) through the upregulation of GSK3β phosphorylation [31]. Increased GSK3β activation has been linked to glucose intolerance and insulin resistance, which may explain phenotypes observed in male 6JRccEnv animals [32][33][34].…”

The Role of Cellular Stress in Intrauterine Growth Restriction and Postnatal Dysmetabolism

“…In the IUGR liver, perinatal nutritional status seems to have a critical role in regulating autophagy. In newborn rat offspring exposed to caloric restriction during the final week of gestation, hepatic autophagy was inhibited by increased activation of mTORC1 and decreased activation of AMPK [114]. This occurred alongside hyperinsulinemia and poor glycogen mobilization immediately after birth, while the inhibition of hepatic autophagy was found to occur as a result of defective glucagon signalling [114].…”

“…In newborn rat offspring exposed to caloric restriction during the final week of gestation, hepatic autophagy was inhibited by increased activation of mTORC1 and decreased activation of AMPK [114]. This occurred alongside hyperinsulinemia and poor glycogen mobilization immediately after birth, while the inhibition of hepatic autophagy was found to occur as a result of defective glucagon signalling [114]. Another study investigating the effects of early postnatal caloric restriction found that adult male offspring have increased hepatic autophagy following restoration of a normal diet at PND 21, again due to activation of the AMPK pathway [44].…”

The Role of Cellular Stress in Intrauterine Growth Restriction and Postnatal Dysmetabolism

“…In the IUGR liver, perinatal nutritional status seems to have a critical role in regulating autophagy. In newborn rat offspring exposed to caloric restriction during the final week of gestation, hepatic autophagy was inhibited by increased activation of mTORC1 and decreased activation of AMPK [112]. This occurred alongside hyperinsulinemia and poor glycogen mobilization immediately after birth, while the inhibition of hepatic autophagy was found to occur as a result of defective glucagon signaling [112].…”

“…In newborn rat offspring exposed to caloric restriction during the final week of gestation, hepatic autophagy was inhibited by increased activation of mTORC1 and decreased activation of AMPK [112]. This occurred alongside hyperinsulinemia and poor glycogen mobilization immediately after birth, while the inhibition of hepatic autophagy was found to occur as a result of defective glucagon signaling [112]. Another study investigating the effects of early postnatal caloric restriction found that adult male offspring have increased hepatic autophagy following the restoration of a normal diet at PND 21, again due to activation of the AMPK pathway [44].…”