Sex-Specific Metabolic Outcomes in Offspring of Female Rats Born Small or Exposed to Stress During Pregnancy

Low birth weight increases adult metabolic disease risk in both the first (F1) and second (F2) generation. Physiological stress during pregnancy in F1 females that were born small induces F2 fetal growth restriction, but the long-term metabolic health of these F2 offspring is unknown. Uteroplacental insufficiency (restricted) or sham (control) surgery was performed in F0 rats. F1 females (control, restricted) were allocated to unstressed or stressed pregnancies. F2 offspring exposed to maternal stress in utero had reduced birth weight. At 6 months, F2 stressed males had elevated fasting glucose. In contrast, F2 restricted males had reduced pancreatic β-cell mass. Interestingly, these metabolic deficits were not present at 12 month. F2 males had increased adrenal mRNA expression of steroidogenic acute regulatory protein and IGF-1 receptor when their mothers were born small or exposed to stress during pregnancy. Stressed control F2 males had increased expression of adrenal genes that regulate androgen signaling at 6 months, whereas expression increased in restricted male and female offspring at 12 months. F2 females from stressed mothers had lower area under the glucose curve during glucose tolerance testing at 12 months compared with unstressed females but were otherwise unaffected. If F1 mothers were either born small or exposed to stress during her pregnancy, F2 offspring had impaired physiological outcomes in a sex- and age-specific manner. Importantly, stress during pregnancy did not exacerbate disease risk in F2 offspring of mothers born small, suggesting that they independently program disease in offspring through different mechanisms.