Pulsatile Cerebrospinal Fluid and Plasma Ghrelin in Relation to Growth Hormone Secretion and Food Intake in the Sheep

Abstract

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...

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

“…injection (32). Although systemic administration of ghrelin has previously been shown to induce hypothalamic c-fos expression (17), the current studies demonstrate sensing of hormone by ARH neurons over timescales (5 vs. 30 min) that are more compatible with the acute orexigenic effects of ghrelin on food intake (15). In addition, the close proximity of ghrelin-labeled neurons to fenestrated capillaries projecting from the ME into the ARH supports an important functional role for this vascular route in rapid molecule entry into the metabolic brain.…”

“…Ghrelin was chosen as a candidate hormone because its acute effects upon feeding behavior (15), together with a short circulating half-life, demand the presence of rapid and precise sensing mechanisms. Although ghrelin's orexigenic effects on hypothalamic feeding centers are well documented (16,17), it remains unclear how peripherally secreted hormone accesses this BBB-protected site, as a specialized transport system from the circulation to the brain is yet to be identified (18).…”

The pig model in brain imaging and neurosurgery

“…Furthermore, as a seasonal animal, leptin secretion and sensitivity in the adult sheep is altered during the year, unlike in pigs or humans (Zieba et al, 2008). Finally, there are remaining questions regarding similarities with human in the role of ghrelin in the control of food intake in sheep (Sugino et al, 2004;Grouselle et al, 2008). Consequences of differences in digestive physiology overwhelmed the context of digestive behaviour.…”

Ghrelin-mediated sympathoinhibition and suppression of inflammation in sepsis

“…Banks et al (7) demonstrated that human ghrelin is able to cross the blood-brain barrier in mice through a saturable transport mechanism. However, recent evidence suggests that, even if such a transport mechanism existed, it would be too slow, as it was shown that a time lapse of 40 -50 min was required after intravenous injection to increase cerebrospinal fluid ghrelin levels twofold (28). Other investigators have suggested that ghrelin may act at the circumventricular organs, where the blood-brain barrier is nonexistent and ghrelin receptors are expressed (63,95).…”