Impaired miR449a-induced downregulation of Crhr1 expression in low-birth-weight rats

Abstract

Low birth weight (LBW) is related to increased incidence of common cardiovascular and metabolic disorders, and psychopathologies later in life. Recent studies have suggested that maternal malnutrition affects fetal hypothalamic-pituitary-adrenal (HPA) axis programing although the mechanism is unknown. We demonstrated that LBW offspring delivered from malnourished dams showed prolonged elevated plasma corticosterone concentrations when compared with those of normal-birth-weight (NBW) offspring and impaired downregulation of corticotropin-releasing factor receptor type 1 (CRF-R1, Crhr1) in the anterior pituitary in restraint. Restraint increased expression of miR449a, which we had previously demonstrated to be involved in Crhr1 downregulation, in the anterior pituitary and serum exosomal miR449a contents through glucocorticoids in NBW offspring, but not in LBW offspring. Although plasma corticosterone concentrations were higher at 2000 h than at 0800 h in both LBW and NBW offspring, they were significantly higher in LBW offspring than in NBW offspring at 2000 and 0200 h. There were no significant diurnal changes in miR449a expression levels in the anterior pituitary of either NBW or LBW offspring, but the expression was significantly lower in LBW offspring than in NBW offspring at 1400, 2000, and 0200 h. The expression levels of GAS5, which inhibits glucocorticoid receptor (GR) binding to glucocorticoid-responsive element, in the anterior pituitary of LBW offspring were elevated when compared with those of NBW offspring. The downregulation of GR found in NBW offspring did not occur in restrained LBW offspring. These results indicate that impaired miR449a expression, probably induced by increased GAS5 expression, causes dysregulation of Crhr1 expression in the anterior pituitary, resulting in prolonged HPA axis activation in restrained LBW offspring.

Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

“…Another potential insight into the biological mechanisms related to KITLG methylation comes from our co-expression network analyses showing that KITLG is part of a gene network enriched for genes regulated by miRNAs 449 (miR449), 23A/23B (miR23A/miR23B) and 9 (miR9). Notably, in rodents two of these miRNAs were previously linked to stress system functionality 30 31 . Specifically, miR449 is involved in the regulation of corticotropin-releasing factor type 1 receptor in the anterior pituitary and HPA-axis activation 31 .…”

Elevated blood pressure in high-fat diet-exposed low birthweight rat offspring is most likely caused by elevated glucocorticoid levels

“…Thus, prolonged exposure to high-fat diets can generate a negative loop of metabolic disease. We have previously reported that LBW rats show long-term high blood corticosterone after restraint stress, and that CRF-R1 fails to downregulate without inducing miR-449a expression in the pituitary gland 17, 18 . Since pituitary miR-449a is induced by glucocorticoids and downregulates corticotropin releasing factor receptor (CRF-R1) expression, miR-449a is thought to be one of the mechanisms of negative feedback of the HPA-axis by glucocorticoids.…”

“…We performed mRNA and miRNA quantification as previously reported 17 . Total RNA was extracted from rat infrarenal aortas, hearts, kidneys, and pituitaries using RNAiso Plus (Takara, Shiga, Japan).…”

“…Although the rats did not deliver prematurely, the offspring weighed less and some of them failed to catch up during postnatal growth. In addition, we found that when they were exposed to restraint stress, blood corticosterone levels were further elevated due to a dysfunctional glucocorticoid-mediated feedback system in the pituitary gland 17, 18 . Therefore, the purpose of the present study was to clarify whether LBW caused by low carbohydrate and calorie restriction in fetuses increases blood pressure after growth, and if a mismatch between the acquired constitution and the growth environment further increases blood pressure, and which organs are involved.…”

“…Finally, we examined the relationship between blood adrenal steroid levels and blood pressure in high-fat diet-exposed LBW rats. We previously reported that LBW rats maintain elevated blood corticosterone under restraint stress 17, 18 . Therefore, we investigated whether a high-fat diet, which is a chronic metabolic stress, could increase blood corticosterone levels in LBW rats.…”