The hypothalamic transcriptional response to stress is severely impaired in offspring exposed to adverse nutrition during gestation

Gestation is a time of profound vulnerability, as insults during pregnancy increase the lifelong risk of morbidity for the offspring. Increasingly, maternal diet is recognized as a key factor influencing the developing fetus. Poor-quality maternal diets, whether they provide an excess or an insufficiency of nutrients, lead to overt gestational growth disturbances in the offspring, and elevated risk for a common cluster of metabolic and mental disorders. Metabolic disturbances, particularly a substantially increased risk of obesity, have been linked in both maternal overnutrition and maternal undernutrition with abnormal development of the offspring hypothalamus, which serves a vital role in the central regulation of feeding. Additionally, the hypothalamus also coordinates physiological responses to stressors, and may thus play a role in vulnerability to psychiatric disease in these offspring. We examined hypothalamic molecular and endocrine responses to a psychological stressor (restraint) and a physiological stressor (lipopolysaccharide; LPS) in adult offspring from dams fed a high-fat diet or a low-protein diet during gestation and lactation. Targeted gene expression in the hypothalamus for 26 genes of interest sorted via hierarchical clustering revealed that the vast majority of these transcripts were substantially upregulated by both stressors. In contrast, offspring of maternal high-fat and low-protein diets mounted essentially no gene expression response to either stressor. However, male and female offspring of all conditions showed elevated hypothalamic-pituitary-adrenal glucocorticoid responses to both stressors, though the recovery of corticosterone responses after stress termination was significantly impaired in offspring of poor-quality maternal diets. Overall, it appears that the ability of the hypothalamus to respond in the immediate aftermath of stressful experiences is severely impaired in offspring of poor-quality maternal diets, regardless of whether the diet provided insufficient nutrients or excessive nutrients.