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.

Metabolic comorbidities in Cushing's syndrome

“…5). In an animal model of CS, corticosterone treatment inhibited adipose tissue AMPK, which would support the accumulation of lipids in VAT (44). GC-induced adipose AMPK inhibition has also been confirmed in patients with CS who exhibited a 70% lower AMPK activity in VAT as compared with both non-functioning adrenal adenoma and control patients and was associated with increased mRNA expression of fatty acid synthase.…”

“…These can be combined with agents that increase postprandial insulin secretion such as sulphonylureas and meglitinides. The effect of metformin (and possibly thiazolidinediones) on fat tissue and other organ AMP-activated protein kinases (AMPK) could be beneficial (44,45). Pioglitazone may have a potential negative effect on heart and bone (46).…”

AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study

“…The data in the current study represent, to the authors' knowledge, the first report of the effect of metformin on insulin-stimulated glucose transport in 3T3-L1 adipocytes. Previous studies in human adipocytes differentiated from mesenchymal stem cells or pre-adipocytes indicate that metformin stimulation for 24 h increased basal and insulinstimulated glucose uptake [22,42], yet incubation of adipocytes isolated from individuals with type 2 diabetes with metformin for 1 h has been reported to have no effect on basal or insulin-stimulated glucose uptake [38]. Increased levels of GLUT4 protein have been associated with AMPK activation in cultured adipocytes [30], and metformin has been reported to increase mRNA expression of GLUT4 (also known as SLC2A4) in adipose from women with polycystic ovary syndrome [43], yet the amount of GLUT4 protein was unaltered in the current study in either human adipose tissue or 3T3-L1 adipocytes, indicating that changes in GLUT4 expression are unlikely to underlie the difference in the fold stimulation by insulin.…”

“…In addition, we and others have reported that AMPK activation is associated with reduced insulinstimulated glucose transport in adipocytes [14][15][16], although a conflicting study has reported no effect of AMPK stimulation when assessing translocation of the insulinsensitive glucose transporter, GLUT4 [17]. Several physiological and pharmacological stimuli have been reported to stimulate rodent adipose tissue AMPK, including exercise, starvation, troglitazone and adrenaline (epinephrine) [10,[18][19][20], whereas AMPK is inhibited in response to ghrelin, corticosterone and a high-fat diet [21][22][23] in vivo. However, only one study has investigated AMPK activity in human adipose in vivo; in this study, insulin-resistant patients with Cushing's syndrome exhibited reduced AMPK activity compared with controls [24].…”

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…Activity of the cellular energy sensor AMPK system is inhibited by glucocorticoids and may contribute to central fat deposition in Cushing's disease (Christ-Crain et al, 2008), explaining the seemingly paradoxical increase in fat accumulation through fatty acid synthesis, as well as increased lipolysis through HSL. Glucocorticoids can cause both release and inhibition of inflammatory mediators from adipocytes.…”