Sex-specific effects of prenatal stress on glucose homeostasis and peripheral metabolism in rats

Glucocorticoid overexposure during pregnancy programmes offspring physiology and predisposes to later disease. However, any impact of ethologically-relevant maternal stress is less clear, yet of physiological importance. Here we investigated in rats, the short and long-term effects in adult offspring of repeated social stress (exposure to an aggressive lactating female) during late pregnancy on glucose regulation following stress, glucose-insulin homeostasis and on peripheral expression of genes important in regulating glucose and lipid metabolism and glucocorticoid action.Prenatal stress (PNS) was associated with reduced birth weight in female, but not male offspring. The increase in blood glucose with restraint was exaggerated in adult PNS males compared with controls, but not in females. Oral glucose tolerance testing showed no effects on plasma glucose or insulin concentrations in either sex at 3 months, however at 6 months PNS females were hyperinsulinaemic following an oral glucose load. In PNS males plasma triglyceride concentrations were increased, with reduced hepatic mRNA expression of 5α-reductase and peroxisome proliferator-activated receptor-α (PPARα) and a strong trend towards reduced peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and PPAR expression, whereas only PGC1α mRNA was affected in PNS females. Conversely, in subcutaneous fat, PNS reduced mRNA expression of 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD1), phosphoenolpyruvate carboxykinase (PEPCK), adipose triglyceride lipase (ATGL) and diglyceride acyltransferase-2 (DGAT2) in females, but only PEPCK mRNA expression was reduced in PNS males.Thus prenatal social stress differentially programmes glucose homeostasis and peripheral metabolism in male and female offspring. These long-term alterations in physiology may increase susceptibility to metabolic disease.