title: An early reduction in GH peak amplitude in preproghrelin-deficient male mice has a minor impact on linear growth.
abstract: Ghrelin is a gut hormone processed from the proghrelin peptide acting as the endogenous ligand of the GH secretagogue receptor 1a. The regulatory role of endogenous ghrelin on pulsatile GH secretion and linear growth had to be established. The aim of the present study was to delineate the endogenous actions of preproghrelin on peripheral and central components of the GH axis. Accordingly, the ultradian pattern of GH secretion was measured in young and old preproghrelin-deficient males. Blood samples were collected by tail bleeding every 10 minutes over a period of 6 hours. Analysis of the GH pulsatile pattern by deconvolution showed that GH was secreted in an ultradian manner in all genotypes, with major secretory peaks occurring at about 3-hour intervals. In older mice, the peak number was reduced and secretion was less irregular compared with younger animals. Remarkably, in young Ghrl(-/-) mice, the amplitude of GH secretory bursts was significantly reduced. In older mice, however, genotype differences were less significant. Changes in GH pulsatility in young Ghrl(-/-) mice were associated with a tendency for reduced GH pituitary contents and plasma IGF-I concentrations, but with only a minor impact on linear growth. In Ghrl(+/-) mice, despite reduced Acyl ghrelin to des-acyl ghrelin ratio, GH secretion was not impaired. Ghrelin deficiency was not associated with a reduction in hypothalamic GHRH content or altered response to GHRH stimulation. Therefore, reduction in GHRH production and/or sensitivity do not primarily account for the altered GH pulsatile secretion of young Ghrl(-/-) mice. Instead, GHRH expression was elevated in young but not old Ghrl(-/-) mice, suggesting that differential compensatory responses resulting from the absence of endogenous ghrelin is occurring according to age. These results show that endogenous ghrelin is a regulator of GH pulse amplitude in growing mice but does not significantly modulate linear growth.
authors.affiliation: Unité Mixte de Recherche en Santé 894 (R.H., P.Z., O.F., A.L., J.C., J.E., V.T.), INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France; School of Biomedical Sciences (F.S., C.C.), University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia; Unité Mixte de Recherche 7104 (C.T.), Centre National de la Recherche Scientifique/ Unité 596, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, 67404 Illkirch, France; and Department of Medicine (J.D.V.), Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Rim
authors.initials: R
authors.lastname: Hassouna
authors.forename: Philippe
authors.initials: P
authors.lastname: Zizzari
authors.forename: Catherine
authors.initials: C
authors.lastname: Tomasetto
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.forename: Oriane
authors.initials: O
authors.lastname: Fiquet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Labarthe
authors.forename: Julie
authors.initials: J
authors.lastname: Cognet
authors.forename: Frederik
authors.initials: F
authors.lastname: Steyn
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Jacques
authors.initials: J
authors.lastname: Epelbaum
authors.forename: Virginie
authors.initials: V
authors.lastname: Tolle
mesh_terms: D000818:Animals; D054439:Ghrelin / Q000172:deficiency* / Q000235:genetics; D013006:Growth Hormone / Q000378:metabolism*; D008297:Male; D051379:Mice / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*
chemical_list: D054439:Ghrelin; D011498:Protein Precursors; D013006:Growth Hormone