Oral Presentation The International Congress of Neuroendocrinology 2014

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)

Teresa Xie 1 , Shyuan Ngo 1 , Johannes Veldhuis 2 , Penny Jeffery 3 , Lisa Chopin 3 , Virginie Tolle 4 , Jacques Epelbaum 4 , Matthias Tschöp 5 , Frederik Steyn 1 , Chen Chen 1
  1. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia
  2. Department of Medicine, Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical TranslScience Center, Mayo Clinicational , Rochester, Minnesota , USA
  3. Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
  4. UMR-S 894 INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité Paris, France
  5. Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

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.