Neuroendocrine Regulation of Growth Hormone Secretion

Park, Seungjoon

Abstract

The regulation of growth hormone (GH) secretion is, to a larger extent, controlled by three hypothalamic hormones: GH-releasing hormone (GHRH), somatostatin, and ghrelin. Each binds to G protein-linked membrane receptors through which signaling occurs. We used a series of genetic and transgenic animal models with perturbations of individual compounds of the GH regulatory system to study somatotrope signaling. Impaired GH signaling is present in the lit mouse, which has a GHRH receptor (GHRH-R) mutation, and the dw rat, which has a post-receptor signaling defect. Both models also have impaired response to GH secretagogues (GHS), implying an interaction between the two signaling systems. The spontaneous dwarf rat (SDR), in which a mutation of the GH gene results in total absence of the hormone, shows characteristic changes in the hypothalamic regulatory hormones due to an absence of GH feedback and alterations in the expression of each of their pituitary receptors. Treatment of SDRs with GHRH and a GHS has allowed demonstration of a stimulatory effect GHRH on GHRH-R and GHS-R, and somatostatin receptor type 2 (sst2) expression and an inhibitory effect on sst5 expression. GH also modifies the expression of these receptors, though its effects are seen at later time periods and appear to be indirect. In the absence of GH negative feedback, both hypothalamic and pituitary expression is altered to favor stimulation of GH synthesis and release. However, in the presence of GH negative feedback, both hypothalamic and pituitary expression is altered to favor suppression of GH synthesis and release. Loss of liver insulin-like growth factor I (IGF-I) feedback on the hypothalamic-pituitary system increases GH secretion, which, in turn, stimulates liver growth. Depletion of liver-derived IGF-I increases the expression and sensitivity of pituitary GHRH-R and GHS-R. The major site of action of liver-derived IGF-I in the regulation of GH secretion is at the pituitary level. Neuropeptide Y (NPY) is not required for basal regulation of the GH axis. NPY is required for fasting-induced suppression of GHRH and SRIH expression. NPY is also required for fasting-induced augmentation of pituitary GHS-R mRNA. Overall, the results indicate a complex regulation of GH secretion in which somatotrope receptor, as well as ligand expression, exerts an important physiological role.