title: AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome.
abstract: 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.
authors.affiliation: Department of Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine, London EC1M 6BQ, UK.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Christ-Crain
authors.forename: Blerina
authors.initials: B
authors.lastname: Kola
authors.forename: Francesca
authors.initials: F
authors.lastname: Lolli
authors.forename: Csaba
authors.initials: C
authors.lastname: Fekete
authors.forename: Dalma
authors.initials: D
authors.lastname: Seboek
authors.forename: Gábor
authors.initials: G
authors.lastname: Wittmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Feltrin
authors.forename: Susana C
authors.initials: SC
authors.lastname: Igreja
authors.forename: Sharon
authors.initials: S
authors.lastname: Ajodha
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.forename: Beat
authors.initials: B
authors.lastname: Müller
authors.forename: Francois
authors.initials: F
authors.lastname: Pralong
authors.forename: Gregory
authors.initials: G
authors.lastname: Aubert
authors.forename: Giorgio
authors.initials: G
authors.lastname: Arnaldi
authors.forename: Gilberta
authors.initials: G
authors.lastname: Giacchetti
authors.forename: Marco
authors.initials: M
authors.lastname: Boscaro
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
mesh_terms: D055372:AMP-Activated Protein Kinases; D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003480:Cushing Syndrome / Q000201:enzymology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007031:Hypothalamus / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008660:Metabolism / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats
chemical_list: D005938:Glucocorticoids; D009097:Multienzyme Complexes; D003907:Dexamethasone; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases