Abstract
ObjectiveMetabolic diseases are an increasing problem in society with the brain-metabolic axis as a master regulator of the human body for sustaining homeostasis under metabolic stress. However, metabolic inflammation and disease will trigger sustained activation of the hypothalamic-pituitary-adrenal axis. In this study, we investigated the role of metabolic stress on progenitor cells in the hypothalamic-pituitary-adrenal axis. MethodsIn vitro, we applied insulin and leptin to murine progenitor cells isolated from the pituitary and 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. ResultsInsulin was shown to lead to enhanced proliferation and differentiation of both pituitary and adrenocortical progenitors. No alterations in the progenitors were noted in our chronic metabolic stress models. However, hyperactivation of the hypothalamic-pituitary-adrenal axis was observed and the expression of the appetite-regulating genes Npy and Agrp changed in both the hypothalamus and adrenal. ConclusionsIt is well-known that chronic stress and stress hormones such as glucocorticoids can induce metabolic changes including obesity and diabetes. In this article, 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 hyper-functional 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 adulthood.
Highlights
Metabolic diseases such as obesity, type 2 diabetes (T2D), or metabolic syndrome are major challenges in modern medicine, and psychological stress has been incriminated as a contributing factor [1,2].Dysregulation of the sympatho-adrenomedullary system and frequent or chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis have been implicated and may contribute to the current increase in metabolic disorders [3,4]
We show for the first time that this might be based on an early sensitization of stem cells of the hypothalamicpituitary-adrenal axis
In vitro differentiation of adrenal progenitors was influenced by insulin Nestin (þ) progenitors are present in both the adrenal medulla and cortex
Summary
Metabolic diseases such as obesity, type 2 diabetes (T2D), or metabolic syndrome are major challenges in modern medicine, and psychological stress has been incriminated as a contributing factor [1,2].Dysregulation of the sympatho-adrenomedullary system and frequent or chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis have been implicated and may contribute to the current increase in metabolic disorders [3,4]. The hypothalamus synthesizes and secretes corticotropin-releasing hormone (CRH), which regulates pituitary adrenocorticotropic hormone (ACTH) secretion, leading to glucocorticoid release from the adrenal cortex [9] In addition to this function, CRH in the arcuate nucleus in the hypothalamus inhibits neuropeptide Y (NPY) and agouti-related peptide (AgRP)expressing neurons [10,11]. These cells are of specific interest in our studies In this investigation, we examined whether Nestin (þ) cell populations can be stimulated by factors regulating feeding behavior and thereby contribute to altered HPA function in metabolic disease. We characterized the effects of metabolic factors on Nestin (þ) cells in both the adrenal cortex and anterior lobe of the pituitary gland These cells show progenitor characteristics and are stimulated by insulin in vitro. This may suggest a uniform and coordinated signature and programming within the entire endocrine stress axis
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