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

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Martin Werdermann, Ilona Berger, Laura D. Scriba, Alice Santambrogio, Pia Schlinkert, Heike Brendel, Henning Morawietz, Andreas Schedl, Mirko Peitzsch, Aileen J.F. King, Cynthia L. Andoniadou, Stefan R. Bornstein, Charlotte Steenblock

Original languageEnglish
Article number101112
JournalMolecular Metabolism
Volume43
DOIs
PublishedJan 2021

Bibliographical note

Funding Information: This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research foundation) project no. 314061271 , TRR 205/1 : “ The Adrenal: Central Relay in Health and Disease ” and project no. 288034826 , IRTG 2251 : “ Immunological and Cellular Strategies in Metabolic Disease ”. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Objective: Metabolic 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. Methods: In 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. Results: Insulin 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. Conclusions: It 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.

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