Oxytocin (OXT) and ghrelin have several common properties such as the involvement in the first phase response to stressors, in appetite regulation, and in the modulation of neural functions. Despite a recent study showing that intraventricular administration of ghrelin activates OXT neurons, little is known on the cross-talk between these two peptides. Here, we investigated the role of the i.v. administration of OXT on circulating ghrelin concentrations under fasting conditions and during the lipopolysaccharide (LPS)-induced endotoxemia. A randomized placebo-controlled cross-over study was performed in ten healthy men. In four study sessions, the participants received once placebo, once OXT (1 pmol/kg per min over 90 min), once LPS (2 ng/kg), and once both OXT and LPS. Plasma ghrelin, glucose, and free fatty acid (FFA) levels were measured at regular intervals during the first 6 h following the LPS bolus. Systemic administration of OXT decreased within 1 h plasma ghrelin levels (611±54 vs 697±52 pg/ml in placebo days, P=0.013) and increased plasma glucose and FFA concentrations (P=0.002 and P=0.005 respectively). OXT also reduced the LPS-induced surge in ghrelin at time point 2 h (P=0.021). In summary, i.v. administration of OXT decreases circulating levels of ghrelin during fasting, as well as following LPS-induced endotoxemia in healthy men. The cross-talk between OXT and ghrelin might be important in the regulation of energy homeostasis and stress responses.
Greisa Vila, Michaela Riedl, Michael Resl, Aart Jan van der Lely, Leo J Hofland, Martin Clodi and Anton Luger
Federico Gatto, R A Feelders, Rob van der Pas, P M van Koetsveld, Eleonora Bruzzone, Marica Arvigo, Fadime Dogan, Steven W Lamberts, Diego Ferone and Leo Hofland
Pituitary-directed medical treatment for Cushing’s disease (CD) is currently represented by membrane receptor targeting drugs (somatostatin analogs and dopamine agonists). Somatostatin and dopamine receptors are regulated by β-arrestins, which have been shown to be differentially regulated by glucocorticoids in non-neuroendocrine cells. In this study we investigated the effects of glucocorticoids on β-arrestin expression in corticotroph tumor cells. First, AtT20 cells, a mouse model of CD, were exposed to dexamethasone (Dex) at different time points and β-arrestin expression was evaluated at mRNA and protein level. Futhermore, β-arrestin mRNA expression was evaluated in 17 human corticotroph adenoma samples and correlated to patients’ pre-operative cortisol level. We observed that Dex treatment induced a time dependent increase in β-arrestin 1 mRNA expression and a decrease in β-arrestin 2. The same modulation pattern was observed at protein level. Dex-mediated modulation of β-arrestins was abolished by co-treatment with mifepristone, and Dex withdrawal restored β-arrestin expression to basal levels after 72h. The evaluation of β-arrestin mRNA in corticotroph adenomas from CD patients with variable disease activity showed a significant positive correlation between β-arrestin 1 mRNA and urinary cortisol levels. The effect of glucocorticoids on β-arrestin levels was confirmed by the analysis of two samples from a single patient, which underwent adenomectomy twice, with different pre-operative cortisol levels. In conclusion, glucocorticoids induce an inverse modulation of the two β-arrestin isofoms in corticotroph tumor cells. Since β-arrestins regulate membrane receptor functions, this finding may help to better understand the variable response to pituitary-targeting drugs in patients with Cushing’s disease.