Effect of Deletion of Ghrelin‐O‐Acyltransferase on the Pulsatile Release of Growth Hormone in Mice

Abstract

Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat(-/-) mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat(-/-) mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat(-/-) mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat(-/-) mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat(-/-) mice.

Rising maternal circulating GH during murine pregnancy suggests placental regulation

“…The recent study of Trivedi and coworkers, in which a single sample of maternal blood was collected from each mouse 18 days after mating, at 0930 h, 4 h after lights on, showed normal increases in maternal circulating GH during pregnancy in the Mboat4 -knockout mouse (11), although it is possible that the circulating pattern is perturbed. This contrasts with decreased GH secretion in young male Mboat4 -knockout mice (40) and suggests that acyl-ghrelin is not the driver of pregnancy-associated GH increases in the pregnant mouse. Placenta-derived GHRH may therefore be the more plausible candidate to explain the increasing pituitary GH secretion during murine pregnancy but further studies are required to test this hypothesis, including measures of circulating GHRH.…”

“…The absence of GHRH induces profound GH deficiency and reduces postnatal growth in mice, leading to a reduction in adult weight of 40–45% (38). Loss of total or acyl-ghrelin also reduces GH secretion in mice, albeit to a lesser extent (39, 40). Intriguingly, litter size is more than halved in homozygous females lacking GHRH, and neonatal mortality is also higher in these pregnancies (38).…”

Unacylated ghrelin promotes adipogenesis in rodent bone marrow via ghrelin O-acyl transferase and GHS-R1a activity: evidence for target cell-induced acylation

“…In this context it should be noted that while GHS-R-null mice show relatively normal circulating IGF-1 32 , GOAT-KO mice show elevated circulating IGF-1 in conjunction with reduced GH secretion 33 . Since marrow adipocytes are exquisitely sensitive to GH 34 , a modest reduction in GH could explain the increase in adipocyte number in both of these models.…”

Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice

“…Though we cannot exclude more subtle changes in hormone timing, such as changes in the pulsatile release of growth hormone, we believe that these more subtle changes would be unlikely to lead to the severe growth restriction observed in these mice, which is much less severe in mice with specific deficiencies in pulsatile release[ 34 ]. In addition, while we did not assay cortisol directly, the similar levels of ACTH in Trls2 +/+ and Trls2 -/- mice suggests normal HPA axis function.…”