Administration of ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHSR 1a), induces potent stimulating effects on GH secretion and food intake. However, more than 7 yr after its discovery, the role of endogenous ghrelin remains elusive. Recently, a second peptide, obestatin, also generated from proteolytic cleavage of preproghrelin has been identified. This peptide inhibits food intake and gastrointestinal motility but does not modify in vitro GH release from pituitary cells. In this study, we have reinvestigated obestatin functions by measuring plasma ghrelin and obestatin levels in a period of spontaneous feeding in ad libitum-fed and 24-h fasted mice. Whereas fasting resulted in elevated ghrelin levels, obestatin levels were significantly reduced. Exogenous obestatin per se did not modify food intake in fasted and fed mice. However, it inhibited ghrelin orexigenic effect that were evident in fed mice only. The effects of obestatin on GH secretion were monitored in superfused pituitary explants and in freely moving rats. Obestatin was only effective in vivo to inhibit ghrelin stimulation of GH levels. Finally, the relationship between octanoylated ghrelin, obestatin, and GH secretions was evaluated by iterative blood sampling every 20 min during 6 h in freely moving adult male rats. The half-life of exogenous obestatin (10 microg iv) in plasma was about 22 min. Plasma obestatin levels exhibited an ultradian pulsatility with a frequency slightly lower than octanoylated ghrelin and GH. Ghrelin and obestatin levels were not strictly correlated. In conclusion, these results show that obestatin, like ghrelin, is secreted in a pulsatile manner and that in some conditions; obestatin can modulate exogenous ghrelin action. It remains to be determined whether obestatin modulates endogenous ghrelin actions.
This short review is focused on the neuroendocrine regulation of growth hormone (GH) pulsatile secretory pattern and GH gene expression. The neuronal network involved in the central control of GH includes extrahypothalamic neurons such as the noradrenergic and cholinergic systems, which regulate the two antagonistic neurohormonal systems: somatostatin (SRIH) and GH-releasing hormone (GHRH). Intrahypothalamic Proopiomelanocortin- and Galanin-containing interneurons also participate in the regulation of SRIH and GHRH neuronal activity, which also is dependent on sex steroids and GH and/or insulin-like growth factor I (IGF-I) feedback. cAMP (controlled mainly by GHRH and SRIH), thyroid and glucocorticoid hormones. IGF-I and activin are among the factors that regulate GH gene expression at the transcriptional level and may play a role in somatotroph differentiation and proliferation during ontogeny as well as physiological and pathological states such as acromegaly.
et al.. Pulsatile cerebrospinal fluid and plasma ghrelin in relation to growth hormone secretion and food intake in the sheep.. Journal of Neuroendocrinology, Wiley, 2008, 20 (10), pp.1138-46. 10.1111/j.1365-2826.2008 Pulsatile CSF and plasma ghrelin in relation with GH secretion and food intake in the sheep.Grouselle Dominique, * Chaillou Elodie, *Caraty Alain, Bluet-Pajot Marie-Therese, Zizzari Philippe, *Tillet Yves, Epelbaum Jacques. Key words : plasma, CSF, pulsatile patterns. AddressesElodie Chaillou and Dominique Grouselle contributed equally to this work.The definitive version is available at www.blackwell-synergy.com ABSTRACTAs in other species, exogenous administration of ghrelin, an endogenous ligand for the 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 this study, 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 as compared to abomasum tissue extracts. CSF and plasma ghrelin levels were measured every 10 minutes over a 6 hours sampling period in 5 unanesthetised ovariectomised-estradiol implanted ewes. Mean CSF ghrelin concentrations were 1400-fold lower than circulating plasma levels. 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 09h00, when food was returned to ewes, voluntary food intake did not elicit a consistent change in plasma or CSF ghrelin levels. In contrast, a peripheral ghrelin injection (1 mg, i.v.) immediately stimulated food intake, feeding behaviour, and GH secretion. These effects were concomitant with a more than ten-fold increase in plasma ghrelin levels while CSF ghrelin values only doubled 40 to 50 minutes after the injection. This suggests that peripherally-injected ghrelin crosses the blood brain barrier but only in low amount 2/29 and with relatively slow kinetics when compared to its effects on GH release and food intake. Taken together, these results support the notion that, in the ovariectomised-oestradiol implanted sheep model, peripheral ghrelin injection rapidly induces GH secretion, food intake and feeding behaviour, probably by acting on GHS-R1 receptors located in brain regions in which the blood brain barrier is not complete such as, for instance, the arcu...
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