ENDOCRINE MECHANISMS UNDERLYING GENETIC VARIATION IN GROWTH IN RUMINANTS

Transcription

1 ENDOCRINE MECHANISMS UNDERLYING GENETIC VARIATION IN GROWTH IN RUMINANTS K. SEJRSEK National Institute of Animal Science Foulum Research Centre, P.0. Box 39 DK rum Sdrl., DENMARK SUMMARY The biochemical pathways contributing to growth of body tissues are regulated and coordinated by hormones. It is therefore likely that inherited variation in the endocrine system is a major factor in the physiological basis for genetic variation in growth. The endocrine system is subject to genetic variation at all levels. A complete understanding of the endocrine basis for genetic variation therefore cannot be obtained alone from correlations between growth and circulating levels of hormones. However, profound effects on productivity have been obtained by a simple change in the circulating level of a single hormone. Important relationships may therefore be found even if the mechanisms behind the observed correlations are not completely understood. Relationships between growth and circulating levels of hormones have been studied in numerous experiments, but the results have often been conflicting. The reasons for the discrepancies are likely to be confounding effects of environmental factors, physiological state of animal or sampling technique. The influence of these factors should be taken into account in the interpretation of experimental results. With the influence of these factors in mind the existing data suggest that animals with high genetic growth capacity have elevated circulating levels of growth hormone, somatomedin, thyroid hormones and possibly insulin. The influence of the confounding factors should be considered when new experiments are planned and their influence should be known and taken into account when and if the knowledge of the endocrine basis for genetic variation in growth capacity is used in breeding programs. INTRODUCTION Genetic progress in economic beef traits has been based mainly on use of superior bulls selected directly for merit, but without any consideration for the physiological basis for the obtained effect. Breeding programs may, however, in several ways benefit from knowledge of physiological mechanisms underlying genetic variation. Knowledge of the physiological factors contributing to variation in merit may lead to identification of limiting factors and may suggest which factors that are likely to contribute to continued improvement (Smith, 1982; Bauman et al., 1985). Knowledge of the physiological basis for variation may also help to avoid unforseen and unwanted effects of selection programs and the knowledge is important for choosing the best conditions for estimation of genetic merit (Smith, 1982). Finally better understanding of physiological mechanism underlying genetic merit is the basis for attemps to find indirect predictors of merit (Land, 1985). This is especially im- 261

2 portant in sex- and age-limited traits as milk yield and reproduction. However, attemps have also been made to find physiological predictors of carcass composition of bulls (Miles, 1982), although ultrasonic measures are more likely to be of practical use. Physiological mechanisms underlying genetic variation in quantitative traits like growth probably include inherited variation in the endocrine system, because the biochemical pathways - in which food is transformed into body tissues - are regulated and coordinated by the endocrine system. The individual biochemical processes contributing to growth are controlled by individual enzymes, that are regulated by individual genes. It is, however, unlikely that genetic variation in the activity of a single enzyme will have significant influence on a quantitative trait as growth, because a change in one enzyme in a biochemical pathway is likely to be couteracted by a change in the activities of the other enzymes in the pathway (Kascer & Burns, 1979 cit. from Land, 1981). The endocrine system, in contrast, regulates the whole pathway and coordinates the pathways in all the tissues and organs of the body. On this background it is the objective of this paper to review the possible endocrine basis for genetic variation in growth. PRINCIPLES OF ENDOCRINE REGULATION The keystone in the endocrine regulation of biological processes - including growth - is a biological need (Roth & Grunfeld, 1981). The need is sensed by the secretory cells in an endocrine gland and the release and synthesis of the hormone (or hormones) of the gland is either stimulated or inhibited. The hormone is transported via the blood stream to the target tissue and acts as an intercellular messenger between the cells of the endocrine gland and the target tissue. The hormone interacts with the target tissue to modify its activities in order to meet the biological need. A feed-back signal originating from the target tissue is sensed by the endocrine gland and the hormone secretion returns to normal when the biological need is fulfilled. An obvious exapmple is the involvement of insulin released from the pancreas in returning blood glucose levels to normal after a glucose load. The interaction of the circulating hormone with the target tissue is a very important aspect of endocrine regulation. It occurs via interaction of the hormone with its target tissue receptor, that is specific for the hormone. Protein hormone receptors are bound to the cell membrane and the hormone-receptor complex act via a second messenger in the cell. Steroid hormone receptors are present in the cell, where they form a complex with the hormone entering the cell. The steroid hormone-receptor complex interact directly with the DNA in the nucleus of the cell. It is important to realize that the endocrine system functions as an integrated unit. A hormone usually act on several processes to fulfil the biological need that caused its release. Insulin, for instance, lower blood glucose after a glucose load by increasing glucose uptake of the peripheral tissues, while it at the same time inhibit glucose release from the liver. Most biological processes are similarly regulated by several hormones. Gluconeogenesis, for example, is inhibited by insulin and stimulated by glucagon. 262

3 Furthermore, the endocrine system is involved in short term (homeostatic) as well as long term (homeorhetic) regulation of biological processes including growth (Bauman et al., 1982). The short term regulation usually involves changes in circulating levels of hormones. Changed hormones levels may also be involved in long term regulation, but changes in receptor concentration and competence may also play a role. HORMONES INVOLVED IN REGULATION OF GROWTH This brief overview of endocrine regulation of growth is of course in no way comprehensive (see reviews by Spencer, 1985 and Florini, 1985) and does not consider regulation of appetite and feed utilization. It is the intention to emphasize the complex nature of the endocrine regulation of growth and stress the importance of interrelations between hormones and the interaction of hormones with their receptors. The endocrine regulation of growth involves many hormones including thyroid hormones, insulin, glucocorticoids, sex steriods and possibly prolactin, but growth hormone - also called somatotropin - is considered the principal hormone regulating growth. The importance of growth hormone (GH) for body growth has been known for many years and several studies have shown that administration of GH improve growth and/or carcass composition in sheep and cattle (for references see Bauman & McCuteheon, 1985). In a recent experiment we found that GH caused increased gain of carcass lean meat and bone, whereas carcass fat gain was unchanged (Sejrsen, Foldager, Klastrup & Bauman, unpublished). The endogenous secretion of GH from the pituitary, where it is synthesized, is regulated by the hypothalamic hormones somatostatin and GRF (Growth hormone Releasing Factor). Administration of GRF stimulates GH secretion and has resulted in increased milk yield in cows (Enright et al., 1985; Lapierre et al., 1985). It is therefore also likely to stimulate growth. Somatostatin inhibits GH release and immunization against somatostatin has resulted in higher growth rate in sheep (Spencer et al., 1983). It is now well established that the effct of GH on protein and muscle growth is mediated via its effect on somatomedin secretion (Van Wyk, 1984). We (Sejrsen et al., unpublished) found, in agreement, higher circulating levels of somatomedins in heifers receiving GH than in controls and somatomedin receptors are present in muscle as well as in bone cartilage (for ref. see Spencer, 1985). The central role of the growth hormone - somatomedin axis for control of growth is underlined by the fact that most of the other hormones affecting growth may act at least partly via interaction with this axis. The effect of insulin on muscle growth may be due to its involvement in regulation of GH stimulation of somatomedin secretion. Insulin is necessary for GH binding to its liver receptors (Baxter et a l., 1980), so the effect of GH on growth is inhibited when insulin is low. The role of insulin on fat deposition and carcass composition, in contrast, is a well documented direct effect on fat tissue (Martin et al., 1984). Thyroid hormones have a dose - dependent direct effect on muscle growth, but they may also act via interaction with the growth hormone - somatomedin axis (Spencer, 1985). Thyroids hor

4 mones seem to stimulate growth hormone and possibly somatomedin secretion. They also seem to stimulate somatomedin target tissue receptors (Spencer, 1985). The anabolic steroids may also act in concert with the growth hormone - somatomedin axis (Buttery & Sinnett-Smith, 1984). It has been suggested that the steroids stimulate growth hormone as well as somatomedin secretion. Glucocorticoids and prolactin has also been suggested to affect somatomedin secretion. GENETIC VARIATION OF THE ENDOCRINE SYSTEM That inherited variation in the endocrine system is an important factor in the physiological basis for genetic differences in growth capacity is supported by several findings showing a relationship between circulating levels of hormones and growth capacity. However, the endocrine system is subject to genetic variation at all levels (Shire, 1976, 1979; Kiddy, 1979). Genetic variation can determine the presence or absence of an endocrine gland and affect its rate of growth and final size. Genes determine the structure of protein hormones and their effectiveness - that depend on their specific activity, rate of synthesis and stability - is also subject to genetic variation. So is the biological response of a hormone. It depends on the number, specificity and competence of its receptors; all properties that are affected by genetic variation. Genetic variation also affect the system that stimulate the release of a hormone from its gland, and the type of response of differentiated cells depend on which genes that are activated and on which genes that can be activated. Because the endocrine system is affected by genetic variation at all levels and due to the complexity of the endocrine regulation of growth it is clear that a thorough understanding of the endocrine basis for genetic variation cannot be obtained alone from relationships between circulating levels of individual hormones and growth. However, it should not be forgotten that a simple increase in the circulating level of single hormone (i.e. growth hormone) can have very profound effect on productivity. This suggest that important relationship may be found even if the mechanisms behind the relationships are not completely understood. RELATIONSHIP BETWEEN CIRCULATING HORMONE LEVELS AND GENETIC GROWTH CAPACITY The relationships between circulating levels of hormones and growth have been investigated in many experiments, but many of the results are conflicting. There are a number of possible reasons for the discrepancies, but the most important is probably lack of control over or knowledge of the influences of confounding environmental factors. The relationship between growth and individual hormones may also be affected by interactions with other hormones and the choice of experimental animals may also affect the results. Influences of environmental factors It is now known that environmental factors as daylength, ambient temperature, feeding level and meal pattern affect the level 2 6 4

5 of hormones in the blood. In many experiments these factors have not been controlled or their influences have not been considered in the interpretation of the data. The importance of controlling these factors can be illustrated with data from an experiment with heifers fed two different feeding levels (Sejrsen et. al., 1983). In agreement with earlier results the circulating levels of growth hormones were highest in the heifers on low feeding level. These heifers naturally had the lowest growth rate. Therefore there was a highly significant negative correlation between growth hormone and growth when the effect of feeding level was not taken into account. In contrast, there was a positive although not significant, correlation between growth hormone and growth rate when the relationship was calculated within feeding level. Another possible reason for the observed conflicting results is the fact that the hormone levels in many studies are based on single acute samples. This is not sufficient because many hormones are released episodically. The stress connected with the sampling also affect the circulating level of some hormones. Single samples or sampling over a short period of time may furthermore miss possible interactions with diurnal variation or variation related to meal pattern. In the experiment mentioned above there was no difference between treatments in growth hormones levels in a period after feeding, even if the overall means were different. Sampling only in this period would therefore have been misleading. It is therefore very important that the experimental conditions and the experimental conditions are planned very carefully in studies on relationships between genetic capacity and hormone levels. This problem has been discussed in detail in a review article by Trenkle (1978). One way to avoid the effect of environmental variation may be to apply relevant physiological challenges (Land et al., 1983; Sejrsen & L0vendahl, 1985). Influences of interrelationships between hormones It also has to be kept in mind that growth is regulated by many hormones. They act together and many have opposing actions. Unexpected relationships between circulating levels of a hormone and growth may therefore be caused by differences in another hormone, that perhaps were not measured. It is therefore important that as many of the hormones known to affect growth as possible are measured. This is illustrated in results by Sejrsen et al. (1984) and Klindt et al. (1985). Influences of experimental animals chosen The conclusions that can be drawn from experiments on the relationship between the endocrine system and genetic growth are greatly influenced by the experimental animals used in the experiments. This problem has been discussed in detail by Poliak et al. (1984). From results of experiments with randomly selected animals and/or animals selected on their own performance it is difficult to separate the environmental influence from the genetic. This is possible when different breeds are compared. However, breed comparisons have other drawbacks. First of all, it has to be assumed that 265

6 the variation between breeds is similar to the variation within breeds. This may not always be the case. Secondly, the results may be affected by confounding influences of the physiological state, because many hormones are affected by stage of development. Two breeds, as for instance Hereford and Charolais, are at different physiological states at the same body weight due to different mature sizes, but they are also at different states at the same age because they reach maturity at different ages. They might even reach a given physiological state at different times in relationship to maturity. A thorough comparison of breeds without bias therefore would require sampling at several stages of development. The choice of feeding level is another problem in experiments aimed at comparing hormone levels in animals from different breeds. This can best be illustrated by results from the experiment reported by Hart et al. (1978). They compared hormone levels in Friesians and Hereford cows fed the same daily amount of energy. The circulating levels of growth hormone were highest in the Friesians and the levels of insulin were lower. The Friesian cows had higher milk yield than the Herefords and they lost weight whereas the Herefords gained weight. It is therefore not possible to conclude whether the differences in hormone levels are due difference between breeds or a consequence of the different energy balances. The factors that may confound comparisons between breeds may also to some extent influence comparisons of selected lines within breed. However, the problems are likely to be less dramatic and the value of selected lines for research on physiological basis of genetic differences has been strongly emphasized by Land (1985). Hormones related to growth capacity There are a number of reports on endocrine difference between cattle selected for high and low milk yield (Land et al., 1983; Flux et al., 1984; Sejrsen et al., 1984; Barnes et al., 1985), but to my knowledge there are no reports on endocrine differences between cattle from lines selected for high and low growth capacity. In sheep data have been reported by Dodson et al. (1984). They found that the animals selected for high growth capacity had higher circulating levels of growth hormone and thyroid stimulating hormone. The results support finding in selected lines of pigs (Lund- Larsen & Bakke, 1975; Althen & Gerrits, 1976). Due to the many conflicting results that exist it is very difficult to draw a conclusion on the relationship between circulating levels of hormones and growth. However, with the influences of all the confounding factors in mind the data indicate that high genetic capacity for growth is related to increased circulating levels of growth hormone, somatomedin, thyroid hormones and possibly insulin (Lund-Larsen et al., 1977; Keller et a l., 1977; Ohlson et al., 1981; Falconer et al., 1981; S0rensen et al., 1981; Verde & Trenkle, 1982; Land et al., 1983; Dobson et al., 1984). CONCLUDING REMARKS Physiological mechanisms underlying genetic variation in growth capacity no doubt involve inherited variation in the endocrine system. A careful evaluation of many conflicting results in- 266

7 dicate that animals with high genetic growth capacity have elevated circulating levels of growth hormone, somatomedin, thyroid hormones and possibly insulin. One of the likely reasons for the conflicting results is probably uncontrolled variation due to environmental factors such as feeding level, feeding regime, days length, ambient temperature and sampling technique. Another possible reason for the many conflicting results may be related to the experimental animals used. Use of animals that are selected based on their own performance makes it difficult to separate environmental factors from genetic. Comparing different breeds may also lead to misleading results due to confounding effects of physiological state and feeding level. These effects may also be present in results on animals from selected lines, but the effects are likely to be less dramatic. All these factors should be taken into account in the interpretation of existing results and they should be considered when new experiments are planned. The influences of the confounding factors affecting circulating levels of hormones should be known and taken into account when and if knowledge of the endocrine basis for genetic variation in growth capacity is used in breeding programs. Important and useful relationships between growth capacity and circulating levels of hormones are likely to exist. However, it should be emphasized that a complete understanding of the endocrine basis for genetic variation in growth require knowledge of genetic variation at all levels of the endocrine system. REFERENCES ALTHEN, T. G. and GERRITS, R. J Pituitary and serum growth hormone levels in Duroc and Yorkshire swine genetically selected for high and low backfat. J. Anim. Sci. 42, BARNES, M. A., KAZMER, G. W., AKERS, R. M. and PEARSON, R. E Influence of selection for milk yield on endegenous hormones and metabolites in Holstein heifers and cows. J. Anim. Sci. 60, BAUMAN, D. E. and CURRIE, W. B Partitioning of nutrients during pregnancy and lactation: A review of mechanisms involving homeostasis. J, Dairy Sci. 63, BAUMAN, D. E., EISEMANN, J. H. and CURRIE, W. B Hormonal effects on partitioning of nutrients for tissue growth: Role of growth hormone and prolactin. Fed. Proc. 41, BAUMAN, D. E. and McCUTCHEON, S. N The effects of growth hormone and prolactin on metabolism. In: Proc IV Int Symp Rum Phys: Control of digestion and metabolism in ruminants. Ed. L. P. Milligan, W. L. Grovum and A. Dobson. Reston Publ Co, Inc. Reston UA. BAUMAN, D. E., McCUTCHEON, S. N., STEINHOUR, W. D., EPPARD, P. J. and SECHEN, S. J Sources of variation and prospects for improvement of productive efficiency in the dairy cow: A review. J. Anim. Sci. 60,

8 BAXTER, R. C., BRYSON, J. M. and TURTLE, J. R Somatogenic receptors of rat liver: regulation by insulin. Endocr. 107, BUTTERY, P. J. and SINNETT-SMITH, P. A The mode of action of anabolic agents with special reference to their effects on protein metabolism - some speculations. In: Manipulation of growth in farm animals. Ed. J. F. Roche and P. o'callaghan. M. Nijhoff, Boston DODSON, M. V., DAVIS, S. L., OHLSON, P. L. and ERCANBRACK, S. K Temporal patterns of growth hormone, prolactin and thyroprotein secretion in Targhee rams selected for rate and efficiency of gain. J. Anim. Sci. 57, ENRIGHT, W. J., CHAPIN, L. T., MOSELEY, W. M. and TUCKER, H. A Growth hormone-releasing-factor (GRF) stimulates milk production in Holstein cows. Fed. Proc. 44, FALCONER, J., FORBES, J. M., BINES, J. A., ROY, J. H. B. and HART, I. C Somatomedin - like activity in cattle: The effect of breed, lactation and time of day. J. Endocr. 86, FLORINI, J. R Hormonal control of muscle cell growth. J. Anim. Sci. 61, Suppl. 2, FLUX, D. S., MacKENZIE, D. D. S. and WILSON, G. F Plasma metabolite and hormone concentrations in Friesian cows of differing genetic merit measured at two feeding levels. Anim. Prod. 38, HART, I. C Recent investigations into the physiology of beef and dairy cattle. Presented at EEC scientific workshop Edinburgh. HART, I. C., BINES, J. A., MORANT, S. V. and RIDLEY, J. L Endocrine control of energy metabolism in the cow: Comparison of the levels of hormones (prolactin, growth hormone, insulin and thyroxine) and metabolites in the plasma of high and low yielding cattle at various stages of lactation. J. Endocr. 77, KIDDY, C. A A review of research on genetic variation in physiological characteristics related to performance in dairy cattle. J. Dairy Sci. 62, KLINDT, J., JENKINS, T. G. and LEYMASTER, K. A Relationship between some estimates of growth hormone and prolactin secretion and rates of accretion of constitnents of body gain in rams. Anim. Prod. 41, LAND, R. B Physiological criteria and genetic selection. Livest. Prod, Sci LAND, R. B Knowledge for animal breeding. Phil. Trans. R. Soc. Lond. B310,

9 LAND, R. B., CARR, W. R., HART, I. C., OSMOND, T. J., THOMPSON, R. and TILAKARATNE, N Physiological attributes as possible selection criteria for milk production. 3. Plasma hormone concentrations and metabolite and hormonal responses to changes in energy equilibrium. Anim. Prod. 37, LAPIERRE, H., PELLETIER, G., PETITCLERC, D., MORRISSET, J., COU TURE, Y. and BRAZEAU, P Effects of human growth hormone-releasing-factor-44-nh2 (hgrf) on bovine growth hormone (bgh) release and milk production in lactating dairy cows. Fed. Proc. 44, LUND-LARSEN, T. R. and BAKKE, H Growth hormone and somatomedin activities in lines of pigs selected for rate of gain and thickness of backfat. Acta Agric. Scand. 25, LUND-LARSEN, T. R., SUNDBY, A., KRUSE, V. and VELLE, W Relationship between growth rate, serum somatomedin and plasma testosterone in young bulls. J. Anim. Sci. 44, MARTIN, R. J., RAMSEY, T. G. and HARRIS, R. B. S Central role of insulin in growth and development. Dom. Anim. Endocr. 1, MILES, C. A Other techniques and future possibilities. In: In vivo estimation of body composition in beef. Ed. B. B. Andersen. 524th report National Institute of Animal Science, Denmark OHLSON, D. C., DAVIS, S. L., FERREL, C. C. and JENKINS, T. G Plasma growth hormone, prolactin and thyrotropin secretory patterns in Hereford and Simmental calves. J. Anim. Sci. 53, POLLAK, E. J., LANE, S. F. and SNIFFEN, G. J The use of genetic concepts and variation in the study of metabolism. J. Anim. Sci. 59, ROTH, J. and GRUNFELD, C Endocrine systems: Mechanisms of disease, target cells and receptors. In: Textbook of endocrinology. Ed. R. H. Williams. Saunders, London. SEJRSEN, K., HUBER, J. T. and TUCKER, H. A Influence of amount fed on hormone concentrations and their relationship to mammary growth in heifers. J. Dairy Sci. 66, SEJRSEN, K., LARSEN, F. and ANDERSEN, B. B Use of plasma hormone and metabolite levels to predict breeding value of young bulls for butterfat production. Anim. Prod. 39, SEJRSEN, K. and L0VENDAHL, P Criteria identifying genetic merit for milk production. CEC-seminar, Edinburgh. SHIRE, J. G. M The forms, uses and significance of genetic variation in endocrine systems. Biol. Rev. 51,

10 SHIRE, J. G. M The uses and consequences of genetic variation in hormone systems. In: Genetic variation in hormone systems. Vol 1. Ed. J. G. M. Shire, CRC. Press, Fla. SMITH, C Genetical and statistical aspects of physiological predictors of merit. CEC-scientific workshop, Edinburgh. SPENCER, G. S. G Hormonal systems regulating growth: A review. Livest. Prod. Sci. 12, SPENCER, G. S. G., GARSSEN, G. J. and HART, I. C A novel approach to growth promotion using auto-immunisation against somatostatin. I. Effects on growth and hormone levels in lambs. Livest. Prod. Sci. 10, S0RENSEN, M. T., KRUSE, V. and ANDERSEN, B. B Thyroxine degradation rate in young bulls of Danish dual-purpose breeds. Genetic relationship to weight gain, feed conversion and breeding value for butterfat production. Livest. Prod. Sci. 3, TRENKLE, A Relation of hormonal variations to nutritional studies and metabolism of ruminants. J. Dairy Sci. 61, Van WYK, J. J The somatomedins: Biological actions and physiological control mechanisms. In: Hormonal proteins and peptides. Ed. C. H. Li. Acudenric Press, New York. VERDE, L. S. and TRENKLE, A Concentrations of hormones in plasma from cattle with different growth potential. J. Anim. Sci. 55, Suppl. 2,