Changes in adenosine 5'-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing's syndrome.
OBJECTIVE
Features of the metabolic syndrome such as central obesity with insulin resistance and dyslipidemia are typical signs of Cushing's syndrome and common side effects of prolonged glucocorticoid treatment. AMP-activated protein kinase (AMPK), a key regulatory enzyme of lipid and carbohydrate metabolism as well as appetite, is involved in the development of the deleterious metabolic effects of excess glucocorticoids, but no data are available in humans. In the current study, we demonstrate the effect of high glucocorticoid levels on AMPK activity of human adipose tissue samples from patients with Cushing's syndrome.


METHODS
AMPK activity and mRNA expression of genes involved in lipid metabolism were assessed in visceral adipose tissue removed at abdominal surgery of 11 patients with Cushing's syndrome, nine sex-, age-, and weight-matched patients with adrenal incidentalomas, and in visceral adipose tissue from four patients with non-endocrine-related abdominal surgery.


RESULTS
The patients with Cushing's syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue as compared with both incidentalomas and control patients (P = 0.007 and P < 0.001, respectively). Downstream targets of AMPK fatty acid synthase and phosphoenol-pyruvate carboxykinase were up-regulated in patients with Cushing's syndrome. AMPK activity was inversely correlated with 0900 h serum cortisol and with urinary free cortisol.


CONCLUSIONS
Our data suggest that glucocorticoids inhibit AMPK activity in adipose tissue, suggesting a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity observed in patients with iatrogenic or endogenous Cushing's syndrome.
Kola
Blerina
B
Centre for Endocrinology, John Vane Science Centre, Barts and the London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom.
Christ-Crain
Mirjam
M
Lolli
Francesca
F
Arnaldi
Giorgio
G
Giacchetti
Gilberta
G
Boscaro
Marco
M
Grossman
Ashley B
AB
Korbonits
Márta
M
D000273:Adipose Tissue / Q000201:enzymology; D000310:Adrenal Gland Neoplasms / Q000235:genetics; D003480:Cushing Syndrome / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
D012333:RNA, Messenger; D064429:Fatty Acid Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D006854:Hydrocortisone
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