Ghrelin, cannabinoids and glucocorticoids have all orexigenic and widespread metabolic effects. AMPK is a major controller of many metabolic processes. We have studied the effects of ghrelin and glucocorticoids and their interaction with endocannabinoids using cannabinoid-receptor-1 (CB1) knock-out mice and CB1 antagonist-treated mice, and using tissue samples from patients with Cushings syndrome and from a rodent model of Cushings syndrome. AMPK activity and downstream targets and endocannabinoid content were studied. Electrophysiological changes in response to ghrelin and CB1-antagonists were recorded using hypothalamic cells. Hypothalamic AMPK activity was significantly increased by ghrelin and this effect was lost in CB1-KO or with CB1-antagonism. We also observed an increase in hypothalamic endocannabinoid content in wild-type mice, effect that was blocked by genetic or pharmacologic inhibition of CB1. Electrophysiology studies confirmed the role of CB1 in mediating the effects of ghrelin. In adipose and liver tissue ghrelin inhibited AMPK, and again this effect was blocked by CB1 antagonism. Corticosterone-treated rats showed many features of the metabolic syndrome including significantly higher insulin, leptin, lipid levels as well as an increase in visceral fat weight. AMPK activity was higher in the hypothalamus and significantly lower in visceral fat and heart. In addition, we showed an increased hypothalamic cannabinoid content with glucocorticoids, suggesting that the well-known orexigenic effect of cortisol is mediated by cannabinoids and AMPK activation. Human fat tissue samples from Cushings patients have reduced AMPK activity, explaining the lipogenic effect of cortisol in the human. These data were confirmed in in vitro cultured human adipocytes where 24 h dexamethasone treatment inhibited AMPK activity and upregulated mRNA expression of lipogenic genes. It is proposed that the metabolic hormones ghrelin and glucocorticoids markedly influence AMPK activity and this effect plays an important role in their orexigenic, diabetogenic and lipogenic actions: endocannabinoids appear to mediate many of these effects.
03 - 07 May 2008
European Society of Endocrinology