Objective

Metabolic diseases are an increasing problem in our society with the brain-metabolic axis as a master regulator of the human body for sustaining homeostasis under metabolic stress. On the other hand, metabolic inflammation and disease will trigger a sustained activation of the hypothalamic-pituitary-adrenal axis. In this study, we investigated the role of metabolic stress on progenitor cells of the hypothalamic-pituitary-adrenal axis.

Methods

In vitro, we applied insulin and leptin to murine progenitor cells isolated from the pituitary and the adrenal cortex and examined the role of these hormones on proliferation and differentiation. In vivo, we investigated two different mouse models of metabolic disease; obesity in leptin-deficient ob/ob mice and obesity achieved via feeding with a high-fat-diet.

Results

Insulin was shown to lead to enhanced proliferation and differentiation of both pituitary and adrenocortical progenitors. In our models of chronic metabolic stress no alterations in the progenitors were noted. However, hyperactivation of the hypothalamic-pituitary-adrenal axis was observed and the expression of the appetite regulating genes Npy and Agrp was changed in both the hypothalamus and the adrenal.

Conclusions

It is well-known that chronic stress and stress hormones such as glucocorticoids can induce metabolic changes including obesity and diabetes. Here, we show for the first time that this might be based on an early sensitization of stem cells of the hypothalamic-pituitary-adrenal axis. Thus, pituitary and adrenal progenitor cells exposed to high levels of insulin are metabolically primed to a hyperfunctional state leading to enhanced hormone production. Likewise, obese animals exhibit a hyperactive hypothalamic-pituitary-adrenal axis leading to adrenal hyperplasia. This might explain how stress in early life can increase the risk for developing metabolic syndrome in the adulthood.

中文翻译：

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胰岛素和肥胖改变下丘脑 - 垂体 - 肾上腺轴的干性和功能处于过度活跃状态

客观的

代谢疾病是我们社会中日益严重的问题，脑代谢轴是人体在代谢压力下维持体内平衡的主要调节器。另一方面，代谢性炎症和疾病会引发下丘脑-垂体-肾上腺轴的持续激活。在这项研究中，我们研究了代谢应激对下丘脑-垂体-肾上腺轴祖细胞的作用。

方法

在体外，我们将胰岛素和瘦素应用于从垂体和肾上腺皮质分离的鼠祖细胞，并检查这些激素对增殖和分化的作用。在体内，我们研究了两种不同的代谢疾病小鼠模型；瘦素缺乏 ob/ob 小鼠的肥胖和通过高脂肪饮食喂养实现的肥胖。

结果

显示胰岛素导致垂体和肾上腺皮质祖细胞的增殖和分化增强。在我们的慢性代谢应激模型中，没有注意到祖细胞的改变。然而，观察到下丘脑-垂体-肾上腺轴过度活化，食欲调节基因Npy和Agrp在下丘脑和肾上腺中的表达发生变化。

结论

众所周知，慢性压力和压力激素（如糖皮质激素）可诱发代谢变化，包括肥胖和糖尿病。在这里，我们首次表明这可能是基于下丘脑-垂体-肾上腺轴干细胞的早期致敏。因此，暴露于高水平胰岛素的垂体和肾上腺祖细胞在代谢上处于功能亢进状态，导致激素产生增加。同样，肥胖动物表现出过度活跃的下丘脑-垂体-肾上腺轴，导致肾上腺增生。这可能解释了早期生活中的压力如何增加成年后患代谢综合征的风险。