Actions of GH

GH promotes transport and incorporation of amino acids in skeletal muscle, cardiac muscle, adipose tissue, 

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Hepatic transcription of IGF-1, in particular, is initiated upon binding of growth hormone (GH) to its hepatic receptors and, indeed, most of the growth-promoting actions of GH are directly mediated by IGF-1. 

Somatomedin C probably mediates many of the actions of GH. The hormone also has specific effects on the proliferation or differentiation of many cells, including fibroblasts and chondrocytes. 

Actions of GH on somatomedin C production in vitro have also been demonstrated, using various different tissues. Thus the hormone has been shown to stimulate somatomedin C production by perfused rat liver [16], cultured rat hepatocytes [60,61], human fibroblasts [62] and human lymphoid cells [63] in vitro. 

GH stimulates incorporation of labelled amino acids into protein in skeletal muscle (diaphragm) from hypophysectomized rats in vitro [41,84], The effect is a consequence of stimulation of protein biosynthesis, although amino acid transport is also affected. Insulin and somatomedins also stimulate protein synthesis in diaphragm [44], but there are clear-cut differences between the actions of these hormones and of GH. Thus a 30 min lag period is characteristic of the action of GH, as is a refractory. period after 2-3 h of stimulation. 

GH administered to hypophysectomized rats in vivo causes a drop in the level of plasma non-esterified fatty acids (NEFA), followed by a prolonged increase in this level [89]. This appears to be due to increased utilization of lipids - increased uptake of NEFA by muscle preceding increased output by adipose tissue. As a consequence GH diverts the energy metabolism of the organism from carbohydrate utilization to lipid utilization, and acts to oppose the effects of insulin. Actions of GH on lipid metabolism are particularly marked in man, where GH levels become elevated on fasting and presumably serve to help stimulate the increased lipid utilization seen in this condition. In contrast, in the rat, GH levels fall on fasting. 

Some of the effects of GH may be a consequence of its stimulation of synthesis and secretion of insulin by the pancreas. Such effects have been demonstrated in various systems [93], as have actions on cell growth in islets of Langerhans. The pancreas is a site of production of somatomedin C, and the possibility that this factor may mediate the actions of GH on insulin production has not been excluded. 

As has been discussed, some of the actions of GH involve the induction of expression of specific proteins, but the effect is reversed on removal of the hormone. In a few cases, however, GH appears to induce a more permanent differentiation. 

The mechanisms involved in mediating the direct actions of GH on cell proliferation are not well understood, but recent work on the induction of the c-myc protooncogene by GH has important implications [105]. Expression of this gene has been shown to follow mitogenic stimulation of various cell lines by a number of dif-... 

The spectacular development of recombinant DNA techniques during the past decade has had a major impact on the study of GH. As yet this impact has been concerned mainly with the nature of the hormone itself, and of the genes that direct its production, and their regulation, though such techniques have also made a major contribution to studies of the actions of GH on transcription of specific genes, as discussed above. At least two additional lines of work are likely to contribute to our understanding of the action of GH and will be summarized here. 

The mechanism of this potentiation of the action of GH is not clear. It does not appear to be due to the bivalent nature of the antibodies, since monovalent (Fab)... 

Fig. 6. Potentiation of the actions of GH by monoclonal antibodies. Increasing doses of human GH injected into hypophysectomized rats induced an increase in serum somatomedin concentration and growth in hypophysectomized rats after 24 h. Monoclonal antibody EB2 (right-hand column) markedly enhanced growth and somatomedin levels induced by 125 /u.g GH (centre column).

It will be clear from what has been presented in this chapter that there is no clear consensus as to the mechanism of action of GH. The hormone has a large number of different actions, affecting most of the tissues of the body, and it is difficult to identify any one, or even a few, of these as of key importance. In the past 10-15 years emphasis has been placed on the role of somatomedin C as a mediator of the actions of GH, whereas previously direct actions of the hormone on protein synthesis and other metabolic processes received particular attention however, the change of emphasis seems to have been determined by technical advances rather than any altered recognition of biological importance. 

Expression of the cDNA for the rabbit GH receptor and of the extracellular domain of the human receptor was obtained in transfected monkey COS-7 cells. The proteins so obtained bound 125I-labelled human GH, and showed a specificity similar to that of the receptors obtained from normal tissues. Thus, the rabbit receptor could bind human GH, bovine GH and to a lesser extent ovine prolactin, while the human receptor bound human GH but not bovine GH or ovine prolactin. This provides strong evidence that these receptors mediate the growth-promoting actions of GH, since biological responses show a similar specificity. 

The major biological action of GH is to promote overall somatic growth. Deticiency in the secretion of this hormone can cause dwarfism, and an overproduction of this hormone can cause acromegaly and giantism. Secretion of this hormone is stimulated by growth hormone-releasing hormone (GH-RH). a 44-iesiduc polypeptide. secreted by the hypothalamus. Secretion of GH is inhibited by. somatostatin. 

The protein-anabolic and protein-sparing actions of GH require the metabolic effects of insulin, glucagon, cortisol, and thyroid hormone in the unstressed individual. These actions depend on fine-tuned control of GH release, which is achieved mainly by substrate feedback to the hypothalamus (Figure 31-5). 

The actions of GH can be classified as those that occur as a consequence of the hormone s direct effect on target cells and those that occur indirectly through the ability of GH to generate other factors, particularly IGF-I. 

The IGF-I-independent actions of GH are exerted primarily in hepatocytes. GH administration is followed by an early increase in the synthesis of 8 to 10 proteins, among which are IGF-I, a2-macroglobulin, and the serine protease inhibitors Spi 2.1 and Spi 2.3. Expression of the gene for ornithine decarboxylase, an enzyme active in polyamine synthesis (and, therefore, in the regulation of cell proliferation), is also significantly increased by GH. 

Conversely, GH secretion is suppressed by growth hormone release-inhibiting hormone (GHRIH, also called somatostatin, which has already been discussed). In addition, IGF-I, produced primarily in the liver in response to the action of GH on hepatocytes, feeds back negatively on the somatotrophs to limit GH secretion. Other physiologic factors (e.g., exercise and sleep) and many pathologic factors conuol its release (Table 43.2). 

The effects on plasma insulin and glucagon result from a direct action of GH-RIH on the alpha and beta cells of the pancreas since they have been demonstrated by direct perfusion experiments with the isolated canine pancreas (Al, 12). 

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