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Greisa Vila, Michaela Riedl, Michael Resl, Aart Jan van der Lely, Leo J Hofland, Martin Clodi and Anton Luger

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.

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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.