AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome.
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
Mirjam
M
Department of Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary's School of Medicine, London EC1M 6BQ, UK.
Kola
Blerina
B
Lolli
Francesca
F
Fekete
Csaba
C
Seboek
Dalma
D
Wittmann
Gábor
G
Feltrin
Daniel
D
Igreja
Susana C
SC
Ajodha
Sharon
S
Harvey-White
Judith
J
Kunos
George
G
Müller
Beat
B
Pralong
Francois
F
Aubert
Gregory
G
Arnaldi
Giorgio
G
Giacchetti
Gilberta
G
Boscaro
Marco
M
Grossman
Ashley B
AB
Korbonits
Márta
M
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
D005938:Glucocorticoids; D009097:Multienzyme Complexes; D003907:Dexamethasone; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases