A Comparative Update on the Neuroendocrine Regulation of Growth Hormone in Vertebrates

Abstract

Growth hormone (GH), mainly produced from the pituitary somatotrophs is a key endocrine regulator of somatic growth. GH, a pleiotropic hormone, is also involved in regulating vital processes, including nutrition, reproduction, physical activity, neuroprotection, immunity, and osmotic pressure in vertebrates. The dysregulation of the pituitary GH and hepatic insulin-like growth factors (IGFs) affects many cellular processes associated with growth promotion, including protein synthesis, cell proliferation and metabolism, leading to growth disorders. The metabolic and growth effects of GH have interesting applications in different fields, including the livestock industry and aquaculture. The latest discoveries on new regulators of pituitary GH synthesis and secretion deserve our attention. These novel regulators include the stimulators adropin, klotho, and the fibroblast growth factors, as well as the inhibitors, nucleobindin-encoded peptides (nesfatin-1 and nesfatin-1-like peptide) and irisin. This review aims for a comparative analysis of our current understanding of the endocrine regulation of GH from the pituitary of vertebrates. In addition, we will consider useful pharmacological molecules (i.e. stimulators and inhibitors of the GH signaling pathways) that are important in studying GH and somatotroph biology. The main goal of this review is to provide an overview and update on GH regulators in 2020. While an extensive review of each of the GH regulators and an in-depth analysis of specifics are beyond its scope, we have compiled information on the main endogenous and pharmacological regulators to facilitate an easy access. Overall, this review aims to serve as a resource on GH endocrinology for a beginner to intermediate level knowledge seeker on this topic.

Keywords: cell signaling; growth hormone; hormones; neuropeptides; pituitary; somatotrophs cells; vertebrates.

Figure 1

Schematic representation of the neuroendocrine (GHRH/Somatostatin–GH–IGF) axis and its main hormonal regulators. The hypothalamic stimulator GHRH and the inhibitor somatostatin mainly control GH synthesis and secretion by the pituitary somatotrophs. GH stimulates, mostly in the liver, the secretion of IGF–1, which acts in autocrine, paracrine, and endocrine manners in different somatic tissues to control diverse physiological processes, including protein synthesis, cell proliferation and metabolism. Both GH and IGF–1 could regulate its levels through the long–loop and short–loop feedback mechanisms, while GH and GHRH and somatostatin could regulate their levels via an ultra–short–loop feedback mechanism. Endogenous factors arising outside (shown in two boxes on the right side) of the hypothalamo–pituitary–liver axis could elicit stimulatory (green font), inhibitory (red font) or dual roles (orange font) to regulate pituitary GH. Figure created with BioRender.com tools.

Figure 2

Simplified overview of the cAMP/PKA/CREB pathway in the control of GH synthesis and secretion in somatotrophs. The modulation of GH synthesis starts with the activation of GPCRs and the control of the activity of the adenylyl cyclase (AC) enzyme by the action of either stimulatory Gα (Gαs) or inhibitory (Gαi) subunits. The activation of AC increases cAMP levels, which activates the protein kinase A (PKA). CREB is one of its targets, and phosphorylated CREB can stimulate the expression of the transcription factor pit–1, which upregulates GH mRNAs. The stimulation of phosphodiesterases (PDE) by PKA could elicit a negative feedback, limiting cAMP levels. The activation of adenylyl cyclase and the protein lipase C (PLC) induced by GHRH causes the rise in either cAMP or IP3, respectively, stimulating the calcium (Ca²⁺) influx, which in turn potentiates the exocytosis and release of GH. This mechanism involves the activation of Na⁺ channels to depolarize the plasma membrane to regulate Ca²⁺ influx by Ca²⁺–channels, and the mobilization of Ca²⁺ from the endoplasmic reticulum. It was reported that cGMP could stimulate GH release independently of cAMP. Otherwise, the limitation of cAMP levels and the activation of K⁺ channels reduce the secretion of GH. Figure created with BioRender.com tools.