Purpose It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition. Methods Metabolic and HPA-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal day, PND) and after 70 days of a peaceful (unstressed) period (90PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC). Results At 21PND, SM presented an increased exhibition of hypothalamic CRH and pituitary POMC -derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs CTR. At 90PND, SM showed hyperglycemia, with also suppression of hypothalamic CRH , while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant versus CTR at 90PND. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90PND.
Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationConclusion These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene.
Response to Reviewers:Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice Endocrine Dear Dr. Loizzo, Your paper has now been carefully evaluated by an Associate Editor and ad hoc external Reviewers. We are sorry to say that it is not acceptable for publication in Endocrine in its present form. However, we would be ready to reconsider it if appropriately and extensively revised according to the enclosed comments. If you are prepared to undertake the work required we encourage you to resubmit your revised manuscript although at this stage no commitment can be made on our final decision.Dear Editor,We thank the Reviewer for their interest in our work. We did our best to respond to the point raised. As reported below, we have checked to the comment provided by the Reviewer and have made changes according to his indications.
COMMENTS FOR THE AUTHOR:Reviewer #1: The authors have demonstrated that the early-life stress can induce ACTH-dependent hypercortisolism after a 70 days unstressed period. This observation is a very interesting, and may be a clue for the elucidation of the etiology of Cushing's disease. I am very curious about the histology of mice pituitary histology. Can you show us the data of pituitary histology of PND and 90PND mice, since I wonder if the hypertro...