Hepatic insulin signaling changes: possible mechanism in prenatal hypoxia-increased susceptibility of fatty liver in adulthood.

Nonalcoholic fatty liver disease (NAFLD) is strongly linked to insulin resistance. Prenatal hypoxia (PH) is a risk factor in programming of insulin resistance, glucose intolerance, and metabolic dysfunctions in later life, although the mechanisms are unclear. In this study, the role of metabolic and histological changes as well as the hepatic insulin signaling mechanisms were determined in increasing susceptibility of NAFLD in the fetus and offspring exposed to PH. Pregnant rats exposed to hypoxia (O(2) 10%) during pregnancy demonstrated decreased fetal body and liver weight as well as liver to body weight ratio, whereas these changes were not observed in the offspring. However, male liver to body weight ratio increased after PH stress. Microscopic analysis demonstrated that exposure to PH resulted in distorted architecture of the hepatic parenchyma cells with reduced cellularity in the fetus and offspring. Blood glucose and insulin levels were lower with enhanced insulin sensitivity and increased expression of hepatic insulin-signaling elements in the fetus. Furthermore, insulin resistance, impaired glucose homeostasis, and altered expression of insulin-signaling elements occurred in the offspring. Postnatal hypoxia increased hepatic lipid droplets and triglyceride in liver, whereas expressions of insulin-signaling elements were less in the offspring exposed to PH except glucose transporters 2. The results indicated that PH contributed to hepatocyte heteroplasia and metabolic changes that enhanced vulnerability for NAFLD in the offspring, probably via affecting insulin signaling pathway, including glucose transporters 2.