Loss of acyl-ghrelin signalling in male ghrelin-O-acyltransferase knockout mice results in reduced pulsatile growth hormone secretion and a derangement of GH pulse pattern (#121)
Ghrelin is a nutrient-sensing hormone primarily secreted by oxyntic cells of the stomach and gastrointestinal tract. The biological activity of ghrelin is regulated by acylation with an 8-carbon fatty acid, catalysed by the enzyme ghrelin-O-acyltransferase (GOAT). Pharmacologically, acyl-ghrelin augments the release of growth hormone (GH), however speculation remains whether endogenous acyl-ghrelin contributes to peak GH release. To define the role of endogenous acyl-ghrelin in modulating GH secretion, we first assessed pulsatile GH secretion in 16-week old ad libitum fed male germ-line GOAT-/- mice. Starting at 0700h, 36 sequential tail-tip whole blood samples were collected over a 6-h period at 10-min intervals. Analysis of GH was performed using an in-house mouse GH ELISA and quantified by deconvolution analysis. Observations show a reduction in peak GH secretion (total, pulsatile and mean peak per pulse) in GOAT-/- mice. Moreover, we observed a derangement of pulse patterning, characterised by an increase in pulse frequency and a gain of irregularity (increased ApEn). It is thought that an age-associated decline in ghrelin may contribute to the age-associated decline in GH release. Accordingly, we next determined whether changes in altered peak GH secretion were conserved between young (8-week old) and mature (36-week old) GOAT-/- mice. To account for the changes in body composition, GH release was assessed relative to adiposity and circulating leptin. Observations demonstrate a significant reduction in pulsatile GH release in GOAT-/- mice, however this did not reach significance in older mice. Of interest, the derangement of pulse patterning in GOAT-/- mice was conserved regardless of age. Based on these observations, we propose that the stimulatory actions of endogenous acyl-ghrelin on peak GH release occur independent of adiposity, and dissipate with age. Moreover, we propose that acyl-ghrelin is essential for the development and integration of hypothalamic or peripheral networks that facilitate GH pulse patterning.