Elevated glucocorticoids during ovine pregnancy increase appetite and produce glucose dysregulation and adiposity in their granddaughters in response to ad libitum feeding at 1 year of age

ObjectiveSynthetic glucocorticoids (sGCs) are administered to women threatening preterm labor. We have shown multigenerational endocrine and metabolic effects of fetal sGC exposure. We hypothesized that sGC exposure would alter the second filial generation (F2) offspring neonatal leptin peak that controls development of appetitive behavior with metabolic consequences.Study DesignF0 nulliparous ewes were bred to a single ram. Beginning at day 103 of gestation (term 150 days), dexamethasone (DEX) ewes received 4 injections of 2 mg DEX intramuscularly, 12 hours apart. Control ewes received saline. Ewes lambed naturally. At 22 months of age, F1 offspring were mated to produce F2 offspring. At 10 months of age, F2 female offspring were placed on an ad libitum feeding challenge for 12 weeks.ResultsDEX F2 female offspring did not show a postnatal leptin peak and their plasma cortisol concentration was elevated in the first days of life. During the feeding challenge, DEX F2 offspring consumed 10% more feed and gained 20% more weight compared with control F2 offspring. At the end of the feeding challenge, DEX F2 offspring had greater adiposity compared with control F2 offspring. F2 sGC offspring showed impaired insulin secretion in response to an intravenous glucose tolerance test.ConclusionsGC administration to F0 mothers eliminates the neonatal leptin peak in F2 female offspring potentially by inhibition caused by elevated cortisol in the DEX F2 offspring. F2 offspring showed increased appetite, weight gain, and adiposity during an ad libitum feeding challenge accompanied by decreased insulin response to an intravenous glucose tolerance test.