Campana Gabriele, Loizzo Stefano, Fortuna Andrea, Rimondini Roberto, Maroccia Zaira, Scillitani Alfredo, Falchetti Alberto, Spampinato Santi Mario, Persani Luca, Chiodini Iacopo
Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
Department of Cardiovascular and Endocrine-Metabolic Diseases and Aging, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy.
Endocrine. 2021 Jul;73(1):186-195. doi: 10.1007/s12020-021-02659-4. Epub 2021 Feb 25.
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.
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).
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.
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.
据推测，对CD-1雄性小鼠进行特定的早期生活应激（ES）程序会因垂体中糖皮质激素的负反馈功能失效而导致类似糖尿病的改变。本研究的目的是探究导致这种病理模型的可能机制，并将其置于更具体的临床情境中。
在应激程序后（出生后21天，PND）以及经过70天的平静（无应激）期后（90 PND），立即分析应激小鼠（SM）的代谢和下丘脑-垂体-肾上腺相关激素。这些数据已与年龄匹配的对照组（CTR）以及在ES程序期间用促阿片黑素皮质素反义寡核苷酸（AS-POMC）处理的小鼠的参数进行了比较。
在21 PND时，与CTR相比，SM的下丘脑促肾上腺皮质激素释放激素（CRH）和垂体促阿片黑素皮质素（POMC）衍生肽的分泌增加，同时促肾上腺皮质激素（ACTH）和皮质酮的血浆水平更高。在90 PND时，SM出现高血糖，下丘脑CRH受到抑制，而垂体和血浆ACTH水平以及血浆皮质酮水平持续高于CTR。这些值伴随着总体重增加的逐渐加速，在90 PND时与CTR相比变得显著，同时垂体重量更高。用AS-POMC处理可预防在21和90 PND时SM中观察到的所有激素和代谢改变。
这些发现表明，这些特定的ES程序影响垂体中的糖皮质激素负反馈，但不影响下丘脑，提示了一种依赖ACTH的皮质醇增多症的新模型，可通过沉默POMC基因来预防。
