Early post-natal life stress induces permanent adrenocorticotropin-dependent hypercortisolism in male mice

• Published in: Endocrine 2021-07, Vol.73 (1), p.186-195
• Main Authors: Campana, Gabriele, Loizzo, Stefano, Fortuna, Andrea, Rimondini, Roberto, Maroccia, Zaira, Scillitani, Alfredo, Falchetti, Alberto, Spampinato, Santi Mario, Persani, Luca, Chiodini, Iacopo
• Format: Article
• Language: English
• Subjects: Adrenocorticotropic Hormone; Animals; Antisense oligonucleotides; Body weight; Corticosterone; Corticotropin-Releasing Hormone; Cushing Syndrome; Diabetes; Diabetes mellitus; Endocrinology; Feedback; Glucocorticoids; Humanities and Social Sciences; Hyperglycemia; Hypothalamus; Internal Medicine; Male; Medicine; Medicine & Public Health; Metabolism; Mice; multidisciplinary; Original Article; Pituitary; Pituitary-Adrenal System; Pro-Opiomelanocortin - genetics; Proopiomelanocortin; Science; Stress, Psychological - complications
• ISSN: 1355-008X; 1559-0100
• DOI: 10.1007/s12020-021-02659-4

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 hypothalamic–pituitary–adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). 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 21 PND, SM presented an increased secretion of hypothalamic CRH and pituitary POMC - derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs. CTR. At 90 PND, SM showed hyperglycemia, with 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 vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND. Conclusions 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.