Abstract:
109 Modification and manipulation of nutrient sensitivity in domestic livestock P.B. Cronj�1 and N.R. Adams2 1 2 Depar tment of Animal and Wildlife Sciences, University of Pretoria, Pretoria 0002, South Africa CSIRO Livestock Industries, Private Bag 5, Wembley WA 6913 pierrecronje@hotmail.com Summary This review is concerned with the physiological mechanisms that underpin genetic differences in the way that animals respond to nutrition. The central question is why genetic selection for production traits of economic importance is often associated with changes in the capacity to adapt to low levels of nutrition. Evidence is presented which indicates that genetic increases in the production rates of wool and mohair result in increased tissue sensitivity to insulin, a nutritionally responsive hormone that regulates nutrient partitioning. The hypothesis that is developed here is that this change in nutrient sensitivity is caused by maternal protein insufficiency during pregnancy and that this leads to in utero foetal programming of gene expression. It is proposed that the extent of the protein deficit and hence the magnitude of the change in nutrient sensitivity is dictated by the effects of the maternal and foetal genome on the partitioning of protein between various body tissues. Insulin sensitivity influences the manner in which body reserves are depleted and repleted, and this may affect reproductive fitness in environments subject to large fluctuations in nutrient availability. It is concluded that foetal programming represents an as yet unexploited method for manipulating nutrient sensitivity and possibly hardiness in animals selected for high rates of production. Keywords: ruminant, sheep, wool, nutrition, breeding, insulin, glucose, foetus unknown. This review addresses this issue and, in particular, the question of why selection for fibre production appears to result in altered insulin sensitivity. The rate and extent to which animals change nutrient partitioning between various tissues to accommodate variations in the plane of nutrition is called nutrient sensitivity (Cronj� 2000), and is of particular relevance in regions subject to frequent or protracted periods of sub_optimal nutrient supply. At high levels of nutrition, the effect of a change in the ability to adapt nutrient partitioning may be small, but at low planes of nutrition, disproportionate nutrient partitioning to non_essential functions could deplete body reserves and result in a decrease in reproductive efficiency. On the other hand, disproportionate nutrient partitioning to body reserves during periods of low nutrition could induce greater variation in wool fibre diameter and result in low staple strength, an economically important trait. Despite the obvious importance of nutrient sensitivity for animal production in highly seasonal areas such as the sub_tropics and Mediterranean climatic zones, little is known of how genetic selection affects this characteristic. It is reasonably well established that genetic selection alters the partitioning of available nutrients to favour the tissue or product subject to selection pressure (see Cronj� 2000). Conceptually, these effects can be thought of in terms of nutrient priorities: sheep and goats selected for high rates of fibre production, for example, partition a greater proportion of nitrogen intake to fibre production and less to body protein deposition (Gallagher and Shelton 1972; Cronj� and Smuts 1994; Cronj� 1995; Cronj� 1998). Although these priorities are adapted to accommodate different levels of nutrition, it is not clear why some genotypes adapt to a greater extent than others. Neither is it clear how genetic selection influences the sensitivity of adaptive mechanisms to nutritional cues. The concept of nutrient sensitivity and its potential impact A comprehensive review by Woolaston (1987) established beyond doubt that sheep which differ genetically may react differently to changes in the environment, but the physiological mechanisms responsible for these differences are still largely Recent Advances in Animal Nutrition in Australia, Volume 13 (2001) 110 Cronj�, P.B. and Adams, N.R. Impact of genetic selection for fibre production on nutrient sensitivity The Angora goat has been subject to intense selection pressure for high rates of fibre (mohair) production. The incidence of abortions among this breed is considerably higher than among goats bred for meat production (Wentzel 1986). The Angora goat, therefore, represents a good model for investigating whether selection for fibre production has decreased the ability to adapt nutrient partitioning during pregnancy. In a series of experiments designed to examine nutrient sensitivity and to elucidate the mechanisms responsible for abortions, Cronj� (1992a, b) compared aspects of nitrogen and energy metabolism in the Angora goat to those in the Boer goat, a breed that has been selected for meat production and produces little fibre. In these experiments, the diet used and the five dietary levels fed were formulated to exert pressure on metabolic mechanisms to divert amino acids away from protein synthesis towards gluconeogenesis. Plasma glucose concentration was 7% lower at all dietary levels in the Angora goat. Glucose flux rate was lower and responded more slowly to increments in dietary energy level, and acetate clearance rate was 20% slower (Cronj� 1992a). This, together with a lower urea excretion rate and higher nitrogen retention (Cronj� 1992b) is consistent with a reduced gluconeogenic response to the diets. This lends support to the possibility that selection for fibre production has invoked mechanisms that resist nutrient signals (e.g. low plasma glucose concentrations) that would normally re_direct partitioning of amino acids away from mohair synthesis towards gluconeogenesis. In order to elucidate the mechanisms responsible for these effects and to confirm that they were associated with selection for fibre production per se, Cronj� (1995) compared Angora goats that differed in respect of mohair production rate. Plasma glucose concentrations were measured on two separate occasions, and were found to be 6 and 9% lower in the phenotype that produced high quantities of mohair. In order to confirm the suggestion that low blood glucose concentrations were due to reduced gluconeogenesis from amino acids (Cronj� 1992b), the two lines were subject to a 48 h fast. Plasma glucose concentration in the high producers decreased to a greater extent during the fast than in low producers, confirming that high producers were less able to mobilise amino acids as sources of glucose precursors. In order to subject this hypothesis to further scrutiny, the response of peripheral glucose concentration to an intravenous injection of insulin was studied. At 60 min after the insulin injection, glucose concentrations were 20% lower in the high producers compared to the low producers. This indicates that the high producers are more sensitive to insulin, and supports the hypothesis that high rates of mohair production are associated with a lower rate of conversion of amino acids to glucose. The differences in response to fasting and insulin sensitivity were confirmed in a subsequent experiment, conducted with the same animals when they were two years older (Cronj� 1998). Increased insulin sensitivity would result in accelerated rates of clearance of glucose from the blood into adipose and muscle tissue and inhibit gluconeogenesis, thus providing an explanation for the low plasma glucose concentrations and decreased conversion of amino acids to glucose that had been observed. The consequent inability to sustain an adequate supply of glucose to the foetus would provide a logical explanation for the high frequency of abortions among Angora goats. The situation with the Merino sheep is less clear. Reports on the effects of selection for wool production on reproduction in sheep are highly variable. A review of published estimates of genetic and phenotypic correlations (Fogarty 1995) shows the relationships between fleece weight and various measures of reproduction to be mainly negative, but most correlation coefficients are low. A stronger relationship was reported by Herselman et al. (1998) who observed that wool production per kg body weight was negatively related to the total weight of lamb weaned in a study involving 4500 ewe records for Merino sheep and 609 ewe records for Afrino sheep. At this stage there is insufficient evidence to indicate whether the increase in nutrient sensitivity associated with selection for fibre production in sheep has reached a level that would affect reproductive fitness at levels of nutrition typical of practical farming conditions. Nonetheless, there are several lines of evidence that indicate that selection for an increased rate of wool production does influence nutrient sensitivity. Adams and Briegel (1998) measured the pattern of change in clean wool growth by Merino sheep over different seasons in a Mediterranean environment, and found that the sensitivity of wool growth rate and fibre diameter to nutrition differed between strains. Lobley (1998) compared the fractional synthesis rate (FSR) of skin and muscle protein in the Merino (Liu et al. 1998) to that in Suffolk_cross sheep (Lobley et al. 1992). At the same energy intake, FSR of skin protein in the Merino was nearly two_fold higher than in the Suffolk_ cross. When energy intake was changed from 1.8 x maintenance to 0.6 x maintenance, skin protein FSR in the Merino decreased by 4% while that in the Suffolk_ cross decreased 40%; conversely, muscle protein FSR in the Merino decreased by 40% and in the Suffolk_ cross by 20%. This comparison indicates that genetic selection alters both the absolute rate of protein metabolism and the relative sensitivity of protein synthesis to nutrition. In the case of the Merino, selection for wool growth appears to have made protein synthesis in the skin less sensitive to low planes of nutrition, and protein synthesis in muscle more sensitive. Modification and manipulation of nutrient sensitivity in domestic livestock 111 Increases in fibre production rate in the Merino sheep also appear to be associated with changes in insulin metabolism because wool production rates were found to be positively related to blood insulin concentrations (Oddy and Lindsay 1986). Selection for increased muscle growth rate in the Merino also appears to induce changes in the sensitivity of insulin to changes in nutrient supply. Comparing two lines of Merino sheep that had been selected for and against body mass at weaning for over 30 years, Oddy et al. (1989) showed that the high weaning_weight sheep partitioned more nitrogen to body tissues and less to wool than those subject to selection against weaning mass. In subsequent experiments, it was shown that selection for increased weaning mass had increased the sensitivity of hind_limb amino acid and glucose uptake to insulin (Oddy 1993; Oddy et al. 1995). In summary, it would appear that there are sufficient grounds to substantiate the hypothesis that genetic selection for fibre production influences insulin sensitivity. The link between selection for fibre production and glucose metabolism is, however, not immediately evident as mohair and wool consist mainly of protein and contain little glucose. In addition, it is well known that dietary energy supplementation has little effect on wool synthesis rate in comparison with that of amino acid supply. It would be tempting to conclude that genetic increases in fibre protein production rate are associated with increased insulin sensitivity because of the known positive effect of insulin on whole body protein deposition. Although insulin does appear to be an important regulator of protein turnover at low planes of nutrition, most evidence indicates that the anabolic influence of insulin on muscle protein metabolism in post_pubertal and adult animals is exerted through inhibition of protein breakdown and not by stimulation of protein synthesis (Lobley 1998). Fibre proteins, however, are not subject to protein breakdown and would not be influenced by insulin_mediated effects. It is clear that an alternative explanation for the association between insulin and fibre growth rate must be sought. Possible mechanism for the effect of selection for fibre production on insulin sensitivity An exciting recent development that has received relatively little attention in the context of livestock husbandry is the realisation that nutrient supply and stress in utero can have lifelong effects on the sensitivity of mammals to insulin and glucose. A study of the birth records of 16000 people born in Hertfordshire during 1911_1930 showed that the incidence of Type II diabetes or impaired glucose tolerance in men at the age of 59_70 was three_fold higher in individuals for whom a low birthweight was recorded (2.5 kg or less) than in those who had a birthweight of 3.86 kg or greater (Barker 1998). The association between maternal undernutrition and altered sensitivity to insulin and glucose in humans and other species has since between confirmed in numerous studies (see Barker 1998). There is now a substantial body of evidence that indicates that nutritional and hormonal insults experienced in utero can alter gene expression in the foetus with persistent post_natal and even life_long effects (Godfrey 1998). During foetal growth and development, different tissues grow during differing `critical periods' of rapid cell differentiation and division. Nutrient deprivation at these times may alter expression of the foetal genome, leading to permanent effects on a range of physiological processes. This phenomenon is termed foetal programming. Foetal programming has been shown to affect a range of tissues (skeletal muscle, bone, kidney, liver) and systems (cardiovascular, respiratory, endocrine, immune), and it is thought that programming reflects a general principle of developmental biology (Godfrey 1998). The effects of intra_uterine protein malnutrition on insulin metabolism have been conceptualised in what is now called the 'thrifty phenotype' hypothesis (Ozanne and Hales 1999). Briefly, this hypothesis states that poor nutrition in utero alters the metabolic settings of various foetal tissues in such a way that the offspring is programmed to survive under conditions of poor nutrition. If foetal programming represents 'a general feature of vertebrate adaptability to enhance the survival of species at times when the nutritional circumstances are particularly unfavourable' (Ozanne and Hales 1999), there would be few circumstances where the impact of foetal programming would be more evident than in the case of fibre_producing animals. Several lines of evidence indicate that foetal nutrient supply is likely to be severely constrained in the case of Merino sheep and Angora goats, most of which are held in regions characterised by widely varying availability of feed resources. Firstly, even with high levels of good quality feed, microbial protein production alone is insufficient for maternal and foetal requirements in the sheep (Robinson et al. 1999). This is likely to be exacerbated by selection for high rates of fibre production, as wool and mohair consist mainly of protein, and the associated contribution of skin to whole body protein synthesis (15_20%) is considerable, being similar to that of muscle (Chilliard et al. 1998). Secondly, under practical farming conditions in both the summer and winter rainfall regions of countries such as Australia and South Africa, pregnancy usually coincides with the period of lowest feed availability. The severity of the nutritional restriction experienced under these conditions is illustrated by a survey of 18 farms in the southwest of Western Australia (Kelly 1992) that showed that 41_57 % of lamb mortality could be ascribed to the body mass of ewes during mid_ pregnancy. Ewe mass during mid_pregnancy was also associated with clean fleece mass, fibre diameter and lamb growth rate, leading Kelly (1992) to conclude that 112 Cronj�, P.B. and Adams, N.R. 'ewe mass during mid_pregnancy... is the most important single and practical criterion that can be used by a farmer to set the goals for nutritional management of the flock over pregnancy to improve lamb survival'. The nutrient requirements of sheep during pregnancy have mainly been derived using lamb birth mass or ewe wool growth rate as criteria of nutritional adequacy, and few studies have investigated metabolic effects or extended the measuring period beyond weaning. It is now accepted that mass at birth is 'an inadequate summary measure of foetal growth' (Barker 1998) and that size at birth is only an 'indirect proxy for foetal programming' (Godfrey 1998). The past use of such crude measures of nutritional adequacy calls for a major revision of nutrient requirements during pregnancy because it is now known that foetal programming of major import can take place without any detectable effects on mass or size at birth. Differences in nutrient sensitivity can, to an extent, be inferred from measurements of differences in wool fibre diameter because changes in fibre diameter within a fibre are directly related to nutrition. Kelly et al. (1996) applied a level of undernutrition representative of that experienced by autumn_lambing pregnant ewes in the south_western parts of Western Australia to ewes from day 50 to day 140 of gestation. Lower concentrations of protein and glucose in the blood of foetuses carried by undernourished ewes confirmed that foetal nutrient restriction had been induced. Between the ages of 5 to 17 months, the offspring subject to in utero nutrient restriction exhibited differences in nutrient sensitivity of an economically important wool trait. The fibre diameter of wool from previously restricted animals was less than that of the control group during February (period of low nutrient availability) and greater during June (period of high nutrient availability). This suggests that the plane of nutrition available to the pregnant ewe under practical farming conditions in Western Australia is sufficient to induce foetal programming. Recently, direct experimental evidence has begun to emerge that indicates that foetal programming can be induced in the ovine. Gallaher et al. (1995) found that the sensitivity of the foetus to the insulin_like growth factor (IGF) axis during late gestation was enhanced by a low maternal plane of nutrition from 60 d before until 30 d after conception. Brameld et al. (2000) recently reported that maternal nutrition from day 28_80 of gestation altered the expression of several primary nutritionally responsive genes (IGF_I, IGF_II, growth hormone receptor) in the foetus at 140 d of gestation. Sheep quite often give birth to twins, and mass differences between twins are an indication that foetal growth retardation has occurred. Clarke et al. (2000) examined glucose metabolism within sets of twin lambs and found that glucose sensitivity to insulin as well as glucose tolerance was increased at the ages of one and six months in the lighter of the twins. Gatford et al. (2000) exposed foetal sheep to the synthetic glucocorticoid, dexamethasone, for just 48 h at day 27 of pregnancy. Although there were no differences in birth mass, these animals were hypertensive at 3_4 months of age and as adults. Insulin and glucose sensitivity was measured when the animals were 4.8 years of age. Although there were no effects of dexamethasone exposure on the sensitivity of net whole body glucose or amino acids to insulin, lipolysis was more sensitive to insulin. Non_esterified fatty acids were suppressed to a greater extent during a hyperinsulinaemic euglycaemic clamp in the dexamethasone group than in control animals. This suggests that sheep that have been exposed to stress in utero during early gestation will take up more glucose into adipose tissue and break down fewer lipids resulting in increased lipid accumulation. Although data on the body composition of these animals is yet to be published, a predisposition for increased deposition of lipid energy reserves in animals subject to stress or nutrient deprivation in utero would be consistent with the `thrifty phenotype' hypothesis. Manipulation of nutrient sensitivity It is evident that nutrient sensitivity can be influenced by genetic selection pressure and also by nutrition in utero. The evidence reviewed here indicates that selection for high rates of protein deposition, either as fibre or muscle deposition, increases insulin sensitivity. The fact that increased insulin sensitivity is also a well_ documented consequence of protein restriction during pregnancy in several species may not be coincidental. Genetic selection for high protein production rates will increase maternal dietary protein requirements and thus the potential for foetal amino acid restriction in utero. This, in turn, will increase the probability of foetal programming of gene expression and birth of `thrifty' phenotypes. Under such circumstances the resulting increase in insulin sensitivity is probably aimed at conserving proteins by inhibiting gluconeogenesis, but would also have the effect of conserving glucose energy for deposition as adipose tissue. In humans, the latter effect results in a greater susceptibility to diabetes and hypertension when high_fat diets are consumed; in the Angora goat, the former effect results in a greater susceptibility to abortions when low glucose precursor diets are consumed. This hypothesis suggests that nutrient sensitivity can be manipulated by nutritional or genetic means but the outcome of manipulation of one will be influenced by the state of the other. In essence, this represents a framework for conceptualising the physiological basis of genotype x environment interactions. Support for the idea that changes in insulin sensitivity result from reduced availability of amino acids for the foetus comes from an experiment (Greef et al. 1997), in which nutrient sensitivity was changed without any apparent changes in insulin sensitivity. Lines of sheep were selected to differ in wool staple strength Modification and manipulation of nutrient sensitivity in domestic livestock 113 but not clean fleece weight, but because the rate of wool growth was not altered, presumably the availability of amino acids for the foetus did not differ between the lines. The reduced nutritional sensitivity in the high staple strength line (Adams et al. 1997) appears to have been caused by reduced sensitivity of skin and muscle protein synthesis to nutrition, particularly with feeding below maintenance (Adams et al. 2000a). The overall result was a very even growth of wool throughout the year, and appeared to be mediated by IGF_I (Adams et al. 2000b). The concentration of insulin did not differ between the lines; this may be because wool growth rate and hence availability of amino acids to the foetus did not differ between lines. If so, this implies that it would be possible to manipulate nutritional sensitivity independently of insulin sensitivity and its associated negative effects on reproduction. BBSRC (1998). Biotechnology and Biological Sciences Research Council Technical Committee on Responses to Nutrients, Report no. 11. Responses in the yield of milk constituents to intake of nutrients by dairy cows. CAB International, Wallingford, UK. Brameld, J.M., Mostyn, A., Dandrea, J., Stephenson, T.J., Dawson, J.M., Buttery, P.J. and Symonds, M.E. (2000). Maternal nutrition alters the expression of insulin_like growth factors in fetal sheep liver and skeletal muscle. Journal of Endocrinology 167, 429_437. 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