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. 2008 Dec;93(12):4969-73.
doi: 10.1210/jc.2008-1297. Epub 2008 Sep 9.

Changes in adenosine 5'-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing's syndrome

Blerina Kola  1 , Mirjam Christ-Crain, Francesca Lolli, Giorgio Arnaldi, Gilberta Giacchetti, Marco Boscaro, Ashley B Grossman, Márta Korbonits
Affiliations

Changes in adenosine 5'-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing's syndrome

Blerina Kola et al. J Clin Endocrinol Metab. 2008 Dec.

Abstract

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.

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Figures

Fig. 1
Fig. 1
A, AMPK activity in visceral adipose tissue of patient with Cushing’s syndrome compared with patients with nonhypersecreting adrenal adenomas (incidentalomas) and controls. B, Correlation of AMPK activity to urinary free cortisol (UFC) in patients with Cushing’s syndrome and adrenal incidentaloma. The patient with exceptionally high UFC of 2215 μg per 24 h was not included in this figure to allow better representation of the data. C, Correlation of AMPK activity to 0900 h serum cortisol in patients with Cushing’s syndrome and adrenal incidentaloma. D, FAS mRNA expression in visceral adipose tissue of patients with Cushing’s syndrome compared with patients with nonhypersecreting adrenal adenomas (incidentalomas) and controls. Data are shown as mean ± SEM, n = 4–13 patients/group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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