AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing’s syndrome Mirjam Christ-Crain * ,1 , Blerina Kola * ,1 , Francesca Lolli * , Csaba Fekete † , Dalma Seboek ‡ , Gábor Wittmann † , Daniel Feltrin * , Susana C. Igreja * , Sharon Ajodha * , Judith Harvey-White § , George Kunos § , Beat Müller ‡ , Francois Pralong || , Gregory Aubert || , Giorgio Arnaldi ¶ , Gilberta Giacchetti ¶ , Marco Boscaro ¶ , Ashley B. Grossman * and Márta Korbonits * ,2 * Department of Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary’s School of Medicine, University of London, London, UK; † Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary, and Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Tufts-New England Medical Center, Boston, Massachusetts, USA; ‡ Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, Basel, Switzerland; § Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, U.S. National Institutes of Health, Bethesda, Maryland, USA; || Service d’Endocrinologie, Diabetologie et Metabolism, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and ¶ Department of Internal Medicine, University of Ancona, Ancona, Italy 2 Correspondence: Department of Endocrinology, John Vane Science Centre, Barts and the London, Queen Mary’s School of Medicine, London EC1M 6BQ, UK. E-mail: m.korbonits@qmul.ac.uk Chronic exposure to glucocorticoid hormones, resulting from either drug treatment or Cushing’s syndrome, results in insulin resistance, central obesity, and symptoms similar to the metabolic syndrome. We hypothesized that the major metabolic effects of corticosteroids are mediated by changes in the key metabolic enzyme adenosine monophosphate-activated protein kinase (AMPK) activity. Activation of AMPK is known to stimulate appetite in the hypothalamus and stimulate catabolic processes in the periphery. We assessed AMPK activity and the expression of several metabolic enzymes in the hypothalamus, liver, adipose tissue, and heart of a rat glucocorticoid-excess model as well as in in vitro studies using primary human adipose and primary rat hypothalamic cell cultures, and a human hepatoma cell line treated with dexamethasone and metformin. Glucocorticoid treatment inhibited AMPK activity in rat adipose tissue and heart, while stimulating it in the liver and hypothalamus. Similar data were observed in vitro in the primary adipose and hypothalamic cells and in the liver cell line. Metformin, a known AMPK regulator, prevented the corticosteroid-induced effects on AMPK in human adipocytes and rat hypothalamic neurons. Our data suggest that glucocorticoid-induced changes in AMPK constitute a novel mechanism that could explain the increase in appetite, the deposition of lipids in visceral adipose and hepatic tissue, as well as the cardiac changes that are all characteristic of glucocorticoid excess. Our data suggest that metformin treatment could be effective in preventing the metabolic complications of chronic glucocorticoid excess.—Christ-Crain, M., Kola, B., Lolli, F., Fekete, C., Seboek, D., Wittmann, G., Feltrin, D., Igreja, S. C., Ajodha, S., Harvey-White, J., Kunos, G., Müller, B., Pralong, F., Aubert, G., Arnaldi, G., Giacchetti, G., Boscaro, M., Grossman, A. B., Korbonits, M. AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing’s syndrome. Key Words: obesity • insulin resistance • lipid metabolism

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