Insulin and obesity transforms hypothalamic-pituitary-adrenal axis stemness and function in a hyperactive state

Abstract 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.