Regulation of active ghrelin levels by various feedback mechanisms

Background: Ghrelin is a potent stimulator of growth hormone (GH) secretion. Furthermore, it is involved in energy homeostasis. Octanoylation of the peptide at serine-3 is necessary for biological activity. We investigated changes in active ghrelin plasma levels due to two different putative feedback mechanisms. Methods: Twelve healthy humans were tested by intravenous administration of the synthetic ghrelin analogue GHRP6 (1µg/kg), possibly activating a short feedback loop. On a different day, GH levels were increased by intravenous administration of growth hormone-releasing hormone (GHRH, 100µg iv) plus Arginine (30g iv over 30′) to test for a GH-dependent feedback mechanism. Blood samples were taken for measurement of ghrelin and GH. Active ghrelin-levels were determined by a specific radioimmunoassay that exclusively detects the octanoylated form of ghrelin. Results: Basal active ghrelin levels demonstrated significant inter-individual differences, but very little intra-individual variation (r=0.93, p<0,005). Administration of GHRP6 resulted in a 20-fold increase in GH levels. However, no significant changes of active ghrelin levels were observed over a 90′ period. Application of GHRH+Arginine led to an even higher 63-fold increase of GH levels, again without any significant change in levels of active ghrelin over a period of 120′. Conclusions: Acute increases in GH levels either by GHRP6 or by GHRH+Arginine did not feedback on systemic concentrations of active ghrelin. Furthermore, a ghrelin analogue had no short loop feedback effects on systemic active ghrelin levels. Due to its metabolic role, systemic ghrelin levels may be more dependent on energy homeostasis.