GROWTH HORMONE: LESSONS FROM CHICKENS

Colin Guy Scanes^*

• University of Wisconsin–Milwaukee, Milwaukee, United States

In chickens, the anterior pituitary gland produces the same palette of hormones seen across the vertebrates:• Adrenocorticotropic hormone (ACTH) and β endorphin • Follicle stimulating hormone (FSH)• Growth hormone (GH)• Luteinizing hormone (LH)• Prolactin • Thyrotropin (TSH)• Neuropeptides e.g. o Met-enkephalin o Relaxin 3 (Lv et al., 2022). This discussion focuses on contributions of the author and his collaborators with comments on what is still not known. Chicken somatotrophs respond to GH releasing hormone (GHRH) and some neuropeptides. Intra-cellular concentrations of calcium ions in somatotrophs are increased by GHRH, thyrotropin-releasing hormone (TRH) (3/4 of somatotrophs), pituitary adenylate cyclaseactivating peptide (85 % of somatotrophs), by leptin (51%), gonadotropin-releasing hormone (GnRH) (40%) and ghrelin (21%) (Scanes et al., 2007). Table 1 summarizes the neuropeptides that influence release of GH (reviewed: Scanes, 2022). Some neuropeptides affect the release of more than one hormone. For instance, neuropeptide W decreases secretion of GH, prolactin and ACTH in chickens (Bu et al., 2016;Liu et al., 2022). What are still unknown are the following:• Why there are multiple stimulatory and inhibitory?• How pituitary cells including influence the functioning of others?• What is the role of folliculo-stellate cells? These produce growth factors/hormones including annexin 1, fibroblast growth factor 2 (FGF2), leptin and vascular endothelial growth factor (VEGF) and these presumably exert paracrine effects (Zhang et al., 2021). There are multiple forms of GH in the chicken pituitary gland:• Monomer (40%)• Glycosylated (16%)• Dimer (14%)• 15-16 KDa sub-monomeric isoform (16%) (Luna et al., 2005). The sub-monomeric isoform of GH predominates in immune tissues (Luna et al., 2005) and retinal ganglion cells in chickens (Baudet et al., 2003). The hypothalamo-pituitary GH -insulin-like growth factor-1 (IGF-1) axis exists in chickens and other birds. GH increases growth in hypophysectomized young chickens (King and Scanes, 1986). Growth is reduced in sex-linked dwarf chickens with a mutation(s) in the GH receptor gene (Burnside et al., 1991). Plasma concentrations of IGF-1 are reduced in hypophysectomized young chickens and restored by GH treatment (Huybrechts et al., 1985). GH increases IGF-1 release from chick hepatocytes (Houston and O'Neill, 1991) and in adult chickens (Radecki et al., 1997). The mechanism for GH's effect on growth are mediated via JAK-2 (Zhou et al., 2005). Studies addressing the question as to whether GH increases growth in intact broilers are at best equivocal (Leung et al., 1986;Vasilatos-Younken et al., 1988;Cogburn et al., 1989;Scanes et al., 1990). GH decreases hepatic deiodination of triiodothyronine (T3) in young chickens (Darras et al., 1992) with optimal circulating concentrations of T3 essential for growth. GH-receptor deficient dwarf chickens have reduced plasma concentrations of T3 (Scanes et al., 1983). Mammalian and avian GH stimulates in vitro lipolysis (glycerol release from adipose tissue explants) (Campbell and Scanes, 1985) and inhibits glucagon induced lipolysis (Campbell and Scanes, 1987). A GH antagonist prevents GH's effect on lipolysis per se but unexpectedly retains full activity in suppressing glucagon induced lipolysis (Campbell et al., 1993). Moreover, reptilian, amphibian and fish GH lack lipolytic activity but inhibit glucagon induced lipolysis (Campbell et al., 1991). What are not known are the following:• Whether the effects of GH are physiologically relevant?• Are these direct effects on the adipocytes or via effects on other cell types present in adipose tissue, such as endothelial cells and macrophage and, subsequently, paracrine effects of cytokines or other neuropeptides? The lipolytic effect is probably mediated by Janus kinase (JAK) 2 based on studies in mice (Shi et al., 2014). However, the mechanism for anti-lipolytic effect is yet to be determined. Administration of GH to laying hens increases in shell thickness (Donoghue et al., 1990); this may be due to effects on the oviduct. This observation was followed by reports of oviductal and ovarian effects of GH. For instance, GH increases progesterone release from large yellow follicles (Hrabia et al., 2014a). GH decreases mucosal apoptosis in the oviduct but increases expression of specific gene (Hrabia et al., 2014b;Socha et al., 2017). Moreover, GH is present in the testes and ovary of chickens (Luna et al., 2014). There are associations between GH polymorphisms and egg production (Su et al., 2014) There are effects of stress on GH in post-hatch chickens. Plasma concentrations of GH were depressed following challenge with ACTH (Davison et al., 1980). Plasma concentrations of GH are also decreased by epinephrine (Harvey and Scanes, 1978) and morphine (Harvey and Scanes, 1987). Heat stress did not affect plasma concentrations of GH in young chickens but did depress hepatic expression of GHR (Uyanga et al., 2022). Corticosterone induces somatotrophs in chick embryos (e.g. Bossis and Porter, 2000). Plasma concentrations of GH are increased by nutritional deprivation such a withholding feed or feeding a protein deficient diet (Buonomo et al., 1982); the latter being presumed to be due to dietary stress depressing negative feedback for T3 and IGF-1. Both GH or prolactin containing neurons are in avian brains (Ramesh et al., 2000). Chick embryo retinal ganglion cells express GH (reviewed: Harvey et al., 2003;Harvey et al., 2012). Moreover, GH exerts a neuroprotective role reducing apoptosis of retinal ganglion cells (Sanders et al., 2005). In vitro, GH depresses apoptosis and expression of caspase-3 and apoptosis inducing factor-1 in neural retina explants from chick embryos (Harvey et al., 2006). Apoptosis in retinal ganglion cells is increased by antisera to GH in ovo supporting locally produced GH regulating retinal apoptosis (Sanders et al., 2005). In an avian model for ischemic stroke, GH exerts a neuroprotective effect in cultured chick embryo hippocampal cells exposed to oxygenglucose deprivation (Olivares-Hernández et al., 2021). Moreover, GH influences neurite development in the inner ear with increases in extension and branching of neurites in chick embryos (Gabrielpillai et al., 2018). Information on the underlying mechanism(s) for neuronal effects of GH is lacking Chick embryo chorio-allantoic membranes (CAM) are useful for examining the effects of hormones and growth factors on angiogenesis. Clapp and colleagues (1993) reported that "the 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis" using chick embryo CAM. In contrast, formation of blood vessels was stimulated by either an anterior pituitary tissue or GH (Gould et al., 1995). The signal transduction mechanism for these effects remains unclear.