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Prenatal and Postnatal Methyl-Modulator Intervention Corrects the Stress-Induced Glucocorticoid Response in
Takahiro Nemoto1, Yoshihiko Kakinuma1
1Department of Bioregulatory Science (Physiology), Nippon Medical School, Tokyo 113-8602, Japan.
Insights
Low birth weight impairs the pituitary
Area of Science:
- Endocrinology
- Neuroscience
- Developmental Biology
Background:
- Low birth weight is linked to metabolic disorders and abnormal stress responses.
- Glucocorticoid receptor (GR) responsiveness is crucial for stress regulation.
- Gas5 lncRNA acts as a decoy receptor, potentially modulating GR activity.
Purpose of the Study:
- To investigate the systemic versus pituitary-specific nature of impaired glucocorticoid responsiveness in low-birthweight rats.
- To determine if Gas5 lncRNA in the pituitary mediates this impairment.
- To evaluate the therapeutic potential of methyl-modulator diets.
Main Methods:
- Comparative analysis of Gas5 lncRNA and Fkbp5 expression in low-birthweight versus control rats.
- Assessment of corticosterone levels post-stress exposure.
- Intervention study using a methyl-modulator diet (folate, VB12, choline, betaine, zinc).
Main Results:
- Low-birthweight rats exhibited increased Gas5 lncRNA specifically in the pituitary, correlating with dampened glucocorticoid responsiveness.
- Systemic tissues (liver, muscle, adipose) showed intact GR co-chaperone induction, suggesting pituitary specificity.
- Methyl-modulator diet intervention partially normalized corticosterone levels and reversed Gas5 lncRNA expression.
Conclusions:
- Glucocorticoid response impairment in low-birthweight rats is localized to the pituitary.
- Increased pituitary Gas5 lncRNA is a key factor in this impairment.
- Methyl-modulator diets offer a potential therapeutic strategy with a limited time window.
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.
