Pulsatile cerebrospinal fluid and plasma ghrelin in relation to growth hormone secretion and food intake in the sheep.

As in other species, exogenous administration of ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptors can stimulates feeding behaviour and GH secretion in the sheep. However, the importance of endogenous ghrelin for these two functions as well as its central or peripheral origin remained to be established. In the present study, cerebrospinal fluid (CSF) ghrelin concentrations were measured in five anoestrous ewes and found to be more than 1000-fold lower than circulating plasma levels, in keeping with the even lower concentration in hypothalamic compared to abomasum tissue extracts. Cluster analysis indicated that CSF ghrelin levels were markedly pulsatile, with a greater number of peaks than plasma ghrelin. Pulsatility parameters were closer for GH and CSF ghrelin than between GH and plasma ghrelin. Plasma ghrelin and GH levels were significantly correlated in three out of five ewes but CSF ghrelin and GH in one ewe only. Half of the CSF ghrelin episodes were preceded by a ghrelin peak in plasma with a 22-min delay. Cross-correlations between plasma GH and plasma or CSF ghrelin did not reach significance but a trend towards cross-correlation was observed from 20 to 0 min between plasma and CSF ghrelin. At 09.00 h, when food was returned to ewes, voluntary food intake did not elicit a consistent change in plasma or CSF ghrelin levels. By contrast, a peripheral ghrelin injection (1 mg, i.v.) immediately stimulated feeding behaviour and GH secretion. These effects were concomitant with a more than ten-fold increase in plasma ghrelin levels, whereas CSF ghrelin values only doubled 40-50 min after the injection. This suggests that peripherally-injected ghrelin crosses the blood-brain barrier, but only in low amount and with relatively slow kinetics compared to its effects on GH release and food intake. Taken together, the results obtained in the present study support the notion that, in the ovariectomised-oestradiol implanted sheep model, peripheral ghrelin injection rapidly induces GH secretion, and feeding behaviour, probably by acting on growth hormone secretagogue receptor subtype 1 located in brain regions in which the blood-brain barrier is not complete (e.g. the arcuate nucleus).