Aside from its general effect in causing growth, growth hormone has multiple specific metabolic effects,
Comparison of weight gain of a rat injected daily with growth hormone with that of a normal littermate.
including (1) increased rate of protein synthesis in most cells of the body; (2) increased mobilization of fatty acids from adipose tissue, increased free fatty acids in the blood, and increased use of fatty acids for energy; and (3) decreased rate of glucose utilization throughout the body. Thus, in effect, growth hormone enhances body protein, uses up fat stores, and conserves carbohydrates.
Growth Hormone Promotes Protein Deposition in Tissues
Although the precise mechanisms by which growth hormone increases protein deposition are not known, a series of different effects are known, all of which could lead to enhanced protein deposition.
Enhancement of Amino Acid Transport Through the Cell Membranes. Growth hormone directly enhances transport of at least some and perhaps most amino acids through the cell membranes to the interior of the cells. This increases the amino acid concentrations in the cells and is presumed to be at least partly responsible for the increased protein synthesis. This control of amino acid transport is similar to the effect of insulin in controlling glucose transport through the membrane, as discussed in Chapters 67 and 78.
Enhancement of RNA Translation to Cause Protein Synthesis by the Ribosomes. Even when the amino acid concentrations are not increased in the cells, growth hormone still increases RNA translation, causing protein to be synthesized in greater amounts by the ribosomes in the cytoplasm.
Increased Nuclear Transcription of DNA to Form RNA. Over more prolonged periods (24 to 48 hours), growth hormone also stimulates the transcription of DNA in the nucleus, causing the formation of increased quantities of RNA. This promotes more protein synthesis and promotes growth if sufficient energy, amino acids, vitamins, and other requisites for growth are available. In the long run, this may be the most important function of growth hormone.
Decreased Catabolism of Protein and Amino Acids. In addition to the increase in protein synthesis, there is a decrease in the breakdown of cell protein. A probable reason for this is that growth hormone also mobilizes large quantities of free fatty acids from the adipose tissue, and these are used to supply most of the energy for the body's cells, thus acting as a potent "protein sparer."
Summary. Growth hormone enhances almost all facets of amino acid uptake and protein synthesis by cells, while at the same time reducing the breakdown of proteins.
Growth hormone has a specific effect in causing the release of fatty acids from adipose tissue and, therefore, increasing the concentration of fatty acids in the body fluids. In addition, in tissues throughout the body, growth hormone enhances the conversion of fatty acids to acetyl coenzyme A (acetyl-CoA) and its subsequent utilization for energy. Therefore, under the influence of growth hormone, fat is used for energy in preference to the use of carbohydrates and proteins.
Growth hormone's ability to promote fat utilization, together with its protein anabolic effect, causes an increase in lean body mass. However, mobilization of fat by growth hormone requires several hours to occur, whereas enhancement of protein synthesis can begin in minutes under the influence of growth hormone.
"Ketogenic" Effect of Growth Hormone. Under the influence of excessive amounts of growth hormone, fat mobilization from adipose tissue sometimes becomes so great that large quantities of acetoacetic acid are formed by the liver and released into the body fluids, thus causing ketosis. This excessive mobilization of fat from the adipose tissue also frequently causes a fatty liver.
Growth hormone causes multiple effects that influence carbohydrate metabolism, including (1) decreased glucose uptake in tissues such as skeletal muscle and fat, (2) increased glucose production by the liver, and (3) increased insulin secretion.
Each of these changes results from growth hormone-induced "insulin resistance," which attenuates insulin's actions to stimulate the uptake and utilization of glucose in skeletal muscle and fat and to inhibit gluconeogenesis (glucose production) by the liver; this leads to increased blood glucose concentration and a compensatory increase in insulin secretion. For these reasons, growth hormone's effects are called diabetogenic, and excess secretion of growth hormone can produce metabolic disturbances very similar to those found in patients with type II (non-insulin-dependent) diabetes, who are also very resistant to the metabolic effects of insulin.
We do not know the precise mechanism by which growth hormone causes insulin resistance and decreased glucose utilization by the cells. However, growth hormone-induced increases in blood concentrations of fatty acids may impair insulin's actions on tissue glucose utilization. Experimental studies indicate that raising blood levels of fatty acids above normal rapidly decreases the sensitivity of the liver and skeletal muscle to insulin's effects on carbohydrate metabolism.
Necessity of Insulin and Carbohydrate for the Growth-Promoting Action of Growth Hormone. Growth hormone fails to cause growth in an animal that lacks a pancreas; it also fails to cause growth if carbohydrates are excluded from the diet. This shows that adequate insulin activity and adequate availability of carbohydrates are necessary for growth hormone to be effec tive. Part of this requirement for carbohydrates and insulin is to provide the energy needed for the metabolism of growth, but there seem to be other effects as well. Especially important is insulin's ability to enhance the transport of some amino acids into cells, in the same way that it stimulates glucose transport.
Although growth hormone stimulates increased deposition of protein and increased growth in almost all tissues of the body, its most obvious effect is to increase growth of the skeletal frame. This results from multiple effects of growth hormone on bone, including
(1) increased deposition of protein by the chondro-cytic and osteogenic cells that cause bone growth,
(2) increased rate of reproduction of these cells, and (3) a specific effect of converting chondrocytes into osteogenic cells, thus causing deposition of new bone.
There are two principal mechanisms of bone growth. First, in response to growth hormone stimulation, the long bones grow in length at the epiphyseal cartilages, where the epiphyses at the ends of the bone are separated from the shaft. This growth first causes deposition of new cartilage, followed by its conversion into new bone, thus elongating the shaft and pushing the epiphyses farther and farther apart. At the same time, the epiphyseal cartilage itself is progressively used up, so that by late adolescence, no additional epi-physeal cartilage remains to provide for further long bone growth. At this time, bony fusion occurs between the shaft and the epiphysis at each end, so that no further lengthening of the long bone can occur.
Second, osteoblasts in the bone periosteum and in some bone cavities deposit new bone on the surfaces of older bone. Simultaneously, osteoclasts in the bone (discussed in detail in Chapter 79) remove old bone. When the rate of deposition is greater than that of resorption, the thickness of the bone increases. Growth hormone strongly stimulates osteoblasts. Therefore, the bones can continue to become thicker throughout life under the influence of growth hormone; this is especially true for the membranous bones. For instance, the jaw bones can be stimulated to grow even after adolescence, causing forward protrusion of the chin and lower teeth. Likewise, the bones of the skull can grow in thickness and give rise to bony protrusions over the eyes.
Growth Hormone Exerts Much of Its Effect Through Intermediate Substances Called "Somatomedins" (Also Called "Insulin-Like Growth Factors")
When growth hormone is supplied directly to cartilage chondrocytes cultured outside the body, proliferation
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