Abstract
Low body weight at birth has been shown to be a risk factor for future metabolic disorders, as well as stress response abnormalities and depression. We showed that low-birthweight rats had prolonged high blood corticosterone levels after stress exposure, and that an increase in Gas5 lncRNA, a decoy receptor for glucocorticoid receptors (GRs), reduces glucocorticoid responsiveness. Thus, we concluded that dampened pituitary glucocorticoid responsiveness disturbed the glucocorticoid feedback loop in low-birthweight rats. However, it remains unclear whether such glucocorticoid responsiveness is suppressed solely in the pituitary or systemically. The expression of Gas5 lncRNA increased only in the pituitary, and the intact induction of expression of the GR co-chaperone factor Fkbp5 against dexamethasone was seen in the liver, muscle, and adipose tissue. Intervention with a methyl-modulator diet (folate, VB12, choline, betaine, and zinc) immediately before or one week after delivery reversed the expression level of Gas5 lncRNA in the pituitary of the offspring. Consequently, it partially normalized the blood corticosterone levels after restraint stress exposure. In conclusion, the mode of glucocorticoid response in low-birthweight rats is impaired solely in the pituitary, and intervention with methyl-modulators ameliorates the impairment, but with a narrow therapeutic time window.
Highlights
Factors that determine the stress responsiveness of an infant are related to the growing environment in infancy, and to the nutritional or hygienic environment in the embryonic period
Glucocorticoid receptors regulate gene expression involved in the stress response, development, metabolism, and immune activity [21,22,23,24]
We have previously shown that LBW rat offspring have higher blood corticosterone levels after restraint stress exposure [14]
Summary
Factors that determine the stress responsiveness of an infant are related to the growing environment in infancy (i.e., maternal care), and to the nutritional or hygienic environment in the embryonic period. Cortisol suppresses unnecessary or harmful functions, especially in fight-or-flight situations [6]. It alters the response of the immune system [7] and suppresses digestive [8], reproductive [9], and growth [10]. We created a rat model to elucidate the mechanism by which embryonic nutrition affects the stress response [14]. LBW rats with embryonic malnutrition had higher levels of Gas lncRNA expression in the pituitary gland than control rats. In the pituitary gland of LBW rats, we concluded that GR could not bind to DNA due to the increased expression of
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