Adenosine monophosphate-activated protein kinase (AMPK), a regulator of cellular and systemic energy homeostasis, can be influenced by several hormones. Tissue-specific alteration of AMPK activity by glucocorticoids may explain the increase in appetite, accumulation of lipids in adipose tissue, and the detrimental cardiac effects of Cushing’s syndrome. Endocannabinoids are known to mediate the effects of various hormones, and are known to influence AMPK activity. Cannabinoidshave central orexigenic and direct peripheral metabolic effects via the cannabinoid receptor type 1 (CB1). In our preliminary experiments, wild-type (WT) mice were implanted with a corticosterone containing pellet to establish a mouse model of Cushing’s syndrome. Subsequently, WT and CB1-knockout (CB1-KO) littermates were treated with corticosterone and AMPK activity was measured in the hypothalamus, various adipose tissues, liver and cardiac tissue. Corticosterone-treated CB1-KO animals showed lack of weight gain and lack of increase in hypothalamic and liver AMPK activity. In adipose tissues, baseline AMPK activity was higher in CB1-KO animals but a glucocorticoid-induced drop was observed, similar to WT mice. Cardiac AMPK levels were reduced in CB1-KO mice, but while WT mice had significantly reduced AMPK activity following glucocorticoid treatment, CB1-KO animals showed a paradoxical increase. Our findings indicate the importance of the CB1 receptor in the central orexigenic effect of glucocorticoid induced activation of hypothalamic AMPK. In the periphery adipose tissue changes may occur independently from the CB1 receptor, but the receptor appears to alter responsiveness of liver and myocardial tissues to glucocorticoids. In conclusion, our data suggests that an intact cannabinoid pathway is required for the full metabolic effects of chronic glucocorticoid excess.

PMID:

 

23884964

 

[PubMed – as supplied by publisher]