Selection for growth rate or against back fat thickness in pigs is associated with changes in growth hormone axis plasma protein concentration and mRNA level.

Selection for increased growth rate or decreased back fat thickness results in concomitant changes in endocrine and metabolic status. Growth hormone (GH) changes in blood plasma concentration related to selection for growth rate and fat deposition were reported in pigs. The molecular mechanisms regulating selection-induced changes in GH plasma concentration remain largely unknown. We investigated selection-associated changes in GH axis parameters in 2 pig lines selected for increased growth rate (F-line), or decreased back fat thickness (L-line), respectively. First, we investigated selection-associated changes in GH pulse parameters. In both selection lines we found each generation a declining GH peak maximum concentration and area under the GH curve. GH pulse width was not associated with generation number. In both lines generation number was associated with a declined pulse interval, indicating that the number of pulses per day increased on average with 1 pulse per 24 h per generation. Second, plasma concentration of GH axis related Insulin-like growth factor-I (IGF-I) and insulin were investigated. Plasma IGF-I concentration was not associated with generation number in the F-line. Mean plasma insulin concentration declined each generation in both lines. Third, we investigated changes in GH and Pit-1 mRNA levels. In both selection lines GH and Pit-1 mRNA levels increased approximately 50% each generation. The high SD of the GH mRNA levels in both lines may suggest that the GH mRNA levels are pulsatile in vivo. We postulate a molecular mechanism that may explain how selection is associated with increased GH mRNA levels and GH pulse numbers, while lowering GH release per pulse.     

The physiological effects of natural variation in growth hormone gene copy number in ram lambs

The effects of natural variation in the number of copies of the growth hormone (GH) gene on growth parameters, plasma GH profiles, and the response to GHRH challenge were compared in Coopworth ram lambs from selection lines differing in body composition and GH levels. Different genotypes at the GH locus carried two, three, or four copies of the GH gene and GH secretion was studied under ad libitum feeding conditions and in the fasted state. There were no significant effects of GH genotype on any parameters of growth or body composition. Basal serum GH concentration, GH pulse frequency, and GH pulse amplitude differed significantly with selection line and fasting, but did not differ significantly between the GH genotypes. Significant differences of subtle nature were found between the GH genotypes in their responsiveness to GHRH. For the ad libitum-fed Lean selection line animals, the first GHRH challenge resulted in a higher mean maximum response for GH1/GH1 than GH2/GH2 (P < 0.05). Between the first and the second challenges there was a decrease in maximum response for the GH1/GH1 genotype and an increase for the GH2/GH2 genotype (P < 0.05 for GH genotype main effect). The differences between GH genotypes in response to GHRH challenge suggest that polymorphism in the number of GH gene copies in sheep may have physiological implications for the function of the GH axis, which may be manifested in growing lambs only under specific genotype-environment combinations.     

Relationship of thyroid status to growth hormone and insulin-like growth factor-I (IGF-I) in plasma and IGF-I mRNA in liver and skeletal muscle of cattle

Steers were made hyperthyroid or hypothyroid to study the effects of physiological alterations in thyroid hormone status on plasma growth hormone (GH) profiles, plasma insulin-like growth factor-I (IGF-I) concentrations, and relative abundance of IGF-I mRNA in skeletal muscle and liver. Eighteen yearling crossbred steers (360 to 420 kg) were randomly allotted to hyperthyroid (subcutaneous injection 0.6 μg/kg BW L-thyroxine for 10 d), hypothyroid (oral thiouracil; 0.25% diet plus 12.5 g capsule/d for 17 d), or control (subcutaneous injection 0.9% NaCl) treatment groups. Blood samples were taken for measurement of GH, IGF-I, thyroxine (T₄) and triiodothyronine (T₃) by RIA. Samples of liver and skeletal muscle were taken by biopsy for measurement of IGF-I mRNA by solution hybridization. Steers receiving thiouracil had 57 and 53% (P<.05) lower T₄ and T₃, respectively, than control steers (84.1 and 1.7 ng/ml). The hyperthyroid steers had 228 and 65% greater (P<.05) T₄ and T₃ than control steers. Neither increased nor decreased thyroid status had any significant effects on plasma GH profiles, liver IGF-I mRNA, or plasma concentration of IGF-I. There was no effect of thyroid hormone alteration on skeletal muscle IGF-I mRNA concentrations. The results of this study suggest that short-term changes in thyroid status of cattle had no major impact on the GH-IGF-I axis or skeletal muscle IGF-I mRNA.     

Influence of nutritional deprivation on insulin-like growth factor I, somatotropin, and metabolic hormones in swine

Although growth hormone (GH) is a primary stimulus for the synthesis of insulin-like growth factor I (IGF-I), other factors such as nutritional status, insulin, and thyroid hormones are important modulators of circulating IGF-I levels. Thus, the effects of feed restriction and subsequent refeeding on plasma levels of IGF-I, GH, insulin, and thyroid hormones were studied in swine. Despite an elevation in plasma GH levels after 48 h of feed restriction, circulating IGF-I levels were decreased by 53% (P less than .05). Plasma triiodothyronine (T3) and insulin were lower (P less than .05) within 24 h after the feed restriction began, whereas thyroxine (T4) did not decrease until 48 h after removal of feed. Blood glucose levels remained unchanged throughout the experiment. Refeeding after the 48-h fast was associated with a decline (P less than .05) in circulating GH levels within 2 h, concomitant with an elevation (P less than .05) in plasma insulin and T3. Refeeding fasted pigs was associated with an increase (P less than .05) in plasma IGF-I; however, levels still had not returned to prefast concentrations within 24 h after refeeding. These data indicate that the GH-IGF-I axis becomes uncoupled during nutritional restriction in swine and that inadequate nutrient supply may limit the expression of the anabolic effects of GH.     

Muscle protein turnover in chickens selected for increased growth rate, food consumption or efficiency of food utilisation: effects of genotype and relationship to plasma IGF-I and growth hormone

1. Rates of muscle protein turnover, growth, and food consumption were determined in 4 lines of chickens selected for either weight gain (line W), food consumption (line F), efficiency of food conversion (line E), or at random (line C) and in two Australian commercial broiler strains (S and H). These measures were related to body composition and the circulating concentrations of plasma growth hormone (GH) and IGF-I. 2. N tau-methylhistidine excretion was 10-14% higher in line F and 7-13% lower in line E compared to line C, showing divergence in the rate of muscle protein breakdown with selection. 3. There were no differences between the 4 experimental lines (W, F, E and C) in muscle protein fractional synthesis rates, whether calculated from N tau-methylhistidine excretion or measured directly by 3H-phenylalanine incorporation. 4. No consistent differences were found between lines in circulating concentrations of either GH or IGF-I but plasma IGF-I concentrations were positively correlated over all lines with protein accretion rates. There was a strong inverse correlation over all lines between the rates of protein degradation and FCR. 5. The correlated responses in protein degradation rates are consistent with the notion of a positive genetic association between the overall efficiency of food utilisation for growth and the efficiency of protein metabolism.     

Mammary growth hormone and tumorigenesis--lessons from the dog

The discovery in the early 1990s that progestin-induced growth hormone (GH) excess in the dog originates in the mammary gland can be seen as a hallmark in the research on the pathogenesis of mammary cancer in the dog. The local biosynthesis and release of GH may provide a highly proliferative environment in the mammary gland, which contributes to the development and/or progression of mammary tumours. Before final goals such as prevention of tumour formation or inhibition of tumour promotion can be achieved it is of eminent importance to elucidate the mechanism of progesterone-induced mammary GH production and the mechanism of local autocrine/paracrine action of GH. These local GH effects may be achieved through direct growth stimulating effects of GH as well as by indirect effects mediated by the stimulation of the biosynthesis of insulin-like growth factor-I (IGF-I). The biological effects of the IGFs largely depend on the presence of IGF binding proteins (IGFBPs) which may both enhance or inhibit the activity of the IGFs. This review concentrates on recent advances in the understanding of the local mammary GH-IGF axis and the lessons which can be drawn from the dog for mammary cancer research in other species.     

Growth hormone and mammary development.

Classic studies in rodents conducted in the 1950s showed that growth hormone (GH) is essential for mammary development both in the pubertal phase and during pregnancy. Since then, a considerable number of experiments have been carried out in ruminants to investigate the role of GH for regulation of normal mammary development and to examine the possibility of enhancing mammary growth by administration of GH. The available evidence demonstrates that GH treatment stimulates mammary growth before puberty, but the data do not convincingly support the idea that the effect is translated into increased milk yield. GH treatment during late pregnancy seems to stimulate both mammary growth and milk yield during lactation. The limited data concerning the effect of GH on mammary growth during lactation indicate that mammary growth is unaffected by GH treatment in early lactation, whereas GH seems to increase the amount of mammary parenchyma in mid-lactation. The mechanism of action of GH remains a puzzle, but the effect of exogenous GH most likely involves insulin-like growth factor-I (IGF-I). Full understanding of the role of endogenous GH for regulation of normal mammary development requires more knowledge about the interaction between GH and IGF-I and the interplay between the GH-IGF-I axis and locally produced factors, including receptors, binding proteins, and growth factors.     

Effect of selection for growth on normal and reduced protein diets on weight gain, feed intake, feed efficiency and body composition in mice

Mice selected for weight gain from 3 to 9 weeks of age on a normal (N) protein diet containing 19.3% protein and a reduced (R) protein diet with 5.1% protein were reared on both diets in generations 7 and 9. The lines NH, NC, NL, RH, RC and RL (H, high; C, control; L, low) were tested for weight gain on diet N and R and for feed intake and feed efficiency on diet N in generation 7. In generation 9, the lines were tested for body composition traits (fat, protein and water percentage) at 3, 6, 9 and 12 weeks of age on both diets. A significant (p < 0.0001) genotype × environment interaction for growth rate was observed in generation 7. Weight gain at both the protein levels was best improved by selection at the protein level itself. Furthermore, the ranking of the lines on diet N was similar for weight gain, feed intake and feed efficiency. In generation 9 at 9 weeks of age, the ranking of the lines for fat percentage was equal to the ranking for weight gain in generation 7 on both test‐diets. The association between weight gain and protein or water percentage was less pronounced, particularly on diet R. These results suggest that the largest genetic improvement in growth rate is obtained when the protein content of the feed is the same in selection and production. However, when selection is carried out in one environment while the animals have to perform under conditions with varying nutrient protein contents, selection in an inferior environment may be advantageous.     

Polymorphisms in genes of the somatotrophic axis are independently associated with milk production, udder health, survival and animal size in Holstein-Friesian dairy cattle

The somatotrophic axis consisting of pituitary-derived growth hormone and circulating insulin-like growth factor 1 has been well established as key regulators of animal health, metabolism, lactation, fertility, body composition and growth rate. The aim of this study was to simultaneously quantify the associations between SNPs in candidate genes of the somatotrophic axis (i.e., IGF-1, GH1 and GHR) with performance traits in Holstein-Friesian (HF) dairy cattle. Both novel SNPs identified previously by this group alongside other published SNPs within these genes were analysed for associations with performance in dairy cattle. Multiple regression analyses regressing genetic merit of up to 848 HF sires on novel SNPs (n = 76) and published SNPs (n = 33) were undertaken using weighted animal mixed linear models. Twenty-three SNPs were significantly associated with at least one of 18 traits analysed and involved in milk production, udder health, fertility and growth. Eight traits including milk fat composition, carcass conformation, stature, chest width, body depth, rump width, carcass and cull cow weight were independently associated with SNPs in two genes. Furthermore, for several traits including milk fat yield, somatic cell count, survival and carcass fat, SNPs in all three genes were independently associated with performance. Milk fat yield and carcass fat showed the highest number of independent associations across all three genes with five SNPs associated with both traits. The cumulative effects of the favourable alleles of all five SNPs across GH1, GHR and IGF-1 result in an increase of 5.9 kg and 28.6 units of milk fat and carcass fat, respectively. Cow survival was associated with a single SNP in each of the three genes with a cumulative allele effect of 1.5%. Independent effects of polymorphisms in GH1, GHR and IGF-1 reinforce the central role of the somatotrophic axis on animal development and performance.     

Use of growth hormone response to growth hormone-releasing hormone to determine growth potential in beef heifers.

The response of GH to GHRH at weaning is known to predict postweaning growth and body composition in beef bulls. The objective of this study was to determine whether GH response to a challenge of GHRH and plasma IGF-I can predict growth rate and body composition in the beef heifer. Growth hormone response to a challenge with two doses of GHRH was measured in 67 Angus heifers averaging 225 d of age (SD = 21) and 217 kg BW (SD = 32). Blood samples were collected at 0 and 10 min relative to an initial "clearance dose" (4.5 micrograms GHRH/100 kg BW) and again, 3 h later, relative to a challenge dose (1.5 or 4.5 micrograms GHRH/100 kg BW). Each animal received each of the two challenge doses, which were randomly assigned across 2 d of blood collection. Serum GH concentration was measured by RIA. Plasma was collected every 28 d during a 140-d growth test and assayed for IGF-I by RIA. Body weight was measured every 28 d and hip height was measured at weaning and at the end of a 140-d growth test. Average daily gain was calculated on d 140 of the growth test and body composition measurements were estimated by ultrasound 2 wk after completion of the growth test. Responses to the two GHRH challenges were dose-dependent (P < 0.05). Average daily gain tended to be related to GH response to the 1.5 micrograms GHRH/100 kg BW dose (R2 = 0.05; P = 0.06), but no relationship was observed at the 4.5 micrograms GHRH/100 kg BW dose (R2 = 0.00; P = 0.93). An inverse relationship (R2 = 0.06; P = 0.02) was observed between response to the 1.5 micrograms GHRH/100 kg BW dose and intramuscular fat percentage. Mean plasma IGF-I concentration was positively associated with ADG (R2 = 0.06; P < 0.01). Growth hormone response to GHRH is modestly related to body composition but not to ADG in weanling beef heifers and likely has limited use in evaluation of growth performance in replacement beef heifers.     

Temporal secretory patterns of growth hormone in male meat-type chickens of lines selected for body weight gain or food conversion.

1. The pronounced episodic release of chicken growth hormone (cGH) in male broiler chicks, as well as its peak interval of about 90 min was confirmed in this study. 2. Lines selected for 6-week body weight (GL line) or for food conversion between 3 and 6 weeks of age (FC line) not only differ in the selection criteria but also in percentage abdominal fat. 3. The overall mean plasma GH concentration was higher in the FC line in both experiments, and this was only caused by peak amplitudes which were almost twice as high as in the FC line. Peak intervals were identical in both selected lines. 4. These observations suggest that decreased abdominal fat and increased protein efficiency may be genetically linked to increased plasma GH peak amplitude. This, and earlier observations on the effectiveness of pulsatile administration of cGH on the growth of broilers suggest that the biological function of GH may depend on its secretory pattern rather than its mean concentration in plasma.     

Efficiency of growth in mice with a major gene for rapid postweaning gain

Previous research in this laboratory demonstrated the existence of a major gene (hg), inherited as a homozygous recessive, which increases postweaning growth by 40 to 50% in C57Bl/6 mice (Ch) compared to the same genetic stock without the major gene (CH). Although its effect has not been previously evaluated, this single recessive allele is also in a line of mice selected for rapid postweaning gain for over 70 generations. Gh represents that line of mice with the major gene for growth (hg) in the growth-selected background and GH the growth-selected background without the major gene. Total body weight, daily weight gain, feed consumption and gain/feed, measured daily from 21 to 42 d of age, were all significantly greater (p less than .01) in the two lines with the hg/hg genotype (Ch and Gh) compared with their respective control lines (CH and GH). Differences in body composition at 42 d of age between CH compared with Ch and GH compared with Gh were accounted for by difference in body weight. Gross and net energetic efficiency, calculated assuming a similar maintenance energy requirement, were improved (P less than .01) in Ch and Gh compared to CH and GH, respectively. The results demonstrated that hg influences growth in growth-neutral and growth-selected backgrounds. The gene also alters energy metabolism by increasing energetic efficiency of growth and(or) decreasing maintenance energy requirement.     

Regulation of protein and energy metabolism by the somatotropic axis.

The somatotropic axis plays a key role in the co-ordination of protein and energy metabolism during postnatal growth. This review discusses the complexity of the regulation of protein and energy metabolism by the somatotropic axis using three main examples: reduced nutrition, growth hormone (GH) treatment and insulin-like growth factor-1 (IGF-1) treatment. Decreased nutrition leads to elevated GH secretion, but it reduces hepatic GH receptor (GHR) number and plasma levels of IGF-1; it also changes the relative concentrations of IGF binding proteins (IGFBPs) in plasma. GH treatment improves the partitioning of nutrients by increasing protein synthesis and decreasing protein degradation and by modifying carbohydrate and lipid metabolism. However, these well-established metabolic responses to GH can change markedly in conditions of reduced nutritional supply or metabolic stress. Short-term infusion of IGF-1 in lambs reduces protein breakdown and increases protein synthesis. However, long-term IGF-1 administration in yearling sheep does not alter body weight gain or carcass composition. The lack of effect of IGF-1 treatment can be explained by activation of feedback mechanisms within the somatotropic axis, which lead to a reduction in GH secretion and hepatic GHR levels. The somatotropic axis has multiple levels of hormone action, with complex feedback and control mechanisms, from gene expression to regulation of mature peptide action. Given that GH has a much wider range of biologic functions than previously recognized, advances in research of the somatotropic axis will improve our understanding of the normal growth process and metabolic disorders.     

Effects of maternal nutrition and porcine growth hormone (pGH) treatment during gestation on endocrine and metabolic factors in sows, fetuses and pigs, skeletal muscle development, and postnatal growth

Prenatal growth is very complex and a highly integrated process. Both maternal nutrition and the maternal somatotropic axis play a significant role in coordinating nutrient partitioning and utilization between maternal, placental and fetal tissues. Maternal nutrition may alter the nutrient concentrations and in turn the expression of growth regulating factors such as IGFs and IGFBPs in the blood and tissues, while GH acts in parallel via changing IGFs/IGFBPs and nutrient availability. The similarity in the target components implies that maternal nutrition and the somatotropic axis are closely related to each other and may induce similar effects on placental and fetal growth. Severe restriction of nutrients throughout gestation has a permanent negative effect on fetal and postnatal growth, whereas the effects of both temporary restriction and feeding above requirements during gestation seem to be of transitional character. Advantages in fetal growth gained by maternal growth hormone treatment during early to mid-gestation are not maintained to term, whereas treatment during late or greatest part of gestation increases progeny size at birth, which could be of advantage for postnatal growth. This review summarizes the available knowledge on the effects of different maternal feeding strategies and maternal GH administration during pregnancy and their interactions on metabolic and hormonal (especially IGFs/IGFBPs) status in the feto-maternal unit, skeletal muscle development and growth of the offspring in pigs.     

Serum growth hormone and insulin-like growth factor-1 concentrations in Japanese black cattle with growth retardation

Serum concentrations of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) were determined in 5 calves in the same lineage with growth retardation. They had normal appetites, activities, body proportion, and laboratory test results. Calves with growth retardation had higher serum GH concentrations and lower serum IGF-I concentrations. These findings suggested defects in the GH-IGF-1 axis, such as in the GH-receptor.     

High body weight gain and reduced bovine mammary growth: physiological basis and implications for milk yield potential

Available evidence concerning the relationship between growth rate, mammary growth and milk yield in heifers leads to these conclusions: 1) Increased growth rate due to high feeding level before puberty onset can lead to reduced pubertal mammary growth and reduced milk yield potential. 2) Increased growth rate due to high feeding level after puberty and during pregnancy have no effect on mammary growth and milk yield. 3) Higher body weight gain due to higher genetic potential for growth is positively related to milk yield. The negative effect of high feeding level before puberty occurs in all breeds, but the level of feeding causing reduced yield varies. Variation in responses between experiments suggests that feeding regimes that support high growth rates without negative effect on yield can be developed. A breakthrough most likely will originate from increased knowledge of the physiological relationship between nutrition and mammary development. Our investigations suggest that blood growth hormone (GH) is important for mammary development, and that the negative effect of high feeding level on mammary development may be due to reduced blood GH. GH, however, does not bind to mammary tissue. Experiments with exogenous GH suggest that GH acts on mammary tissue via IGF-I, but IGF-I is increased by high feeding level - not decreased as GH. This paradoxical relationship cannot be explained by changes in circulating IGF binding proteins. However, the sensitivity of mammary tissue to IGF-I is reduced by high feeding level, probably due to the action of locally produced binding proteins and/or growth factors.     

Hormonal responses to acute exercise, training and overtraining. A review with emphasis on the horse

Overtraining is an imbalance between training and recovery leading to symptoms associated with a neuroendocrine dysbalance called the overtraining syndrome, a disease characterized by behavioral, emotional and physical symptoms similar with depression. Although the prevalence of overtraining is high in human and equine athletes, at present no sensitive and specific test is available to prevent or diagnose overtraining. Nowadays, it is believed that combination of different (hormonal) parameters appear to be the best indicators of overtraining. Therefore, this review provides a summary of previous literature examining the response of the hypothalamic-pituitary-adrenal (HPA) axis and the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis to acute and chronic exercise as well as overtraining in humans and horses. The exercise induced hormonal responses seem to be equal for the equine as well as the human athlete, which makes comparisons possible. Repeated bouts of exercise are suggested to provide a way to detect subtle changes in hormonal responses in the individual athlete, which may make them an important tool in detecting early overtraining. This should be combined with corticotropin releasing hormone (CRH) stimulation tests and basal ACTH and GH pulsatility determination. Further research is needed to establish the correct training intensity and rest period for the exercise test in equines.     

Hormone secretory patterns, pituitary characteristics and selected blood metabolites in feedlot steers implanted with growth stimulants

Twelve Charolais-crossbred steers (256 kg) received one of three treatments: nonimplanted controls (C), implanted initially and at 84 days with 36 mg zeranol (Ralgro, R) and implanted initially and at 84 days with 200 mg of progesterone and 20 mg of estradiol benzoate (Synovex-S,S). All steers were fed a corn-based diet (calculated metabolizable energy 2.89 Mcal/kg dry matter) ad libitum. In a parallel comparative slaughter trial, rates of empty body protein accretion were increased 14% in R and 24% in S steers (P less than .01). R and S steers in the present study had heavier pituitary weights (P less than .001), more pituitary growth hormone content (P less than .04) and more pituitary weight/unit live weight (P less than .05) than did C steers. Cattle implanted with R or S exhibited an increased growth hormone (GH) secretory response to a pituitary challenge with thyrotropin releasing hormone (TRH). Plasma insulin profiles were not significantly altered, but tended to be greater for steers given implants. Overall 9-hr GH secretory profiles were not affected by implantation. Plasma urea N at 94 days post-implantation was decreased (P less than .01) by implantation. Plasma glucose was increased (P less than .04) at both 94 and 199 days in R and S vs C steers. Overall mean and total (integrated area) plasma GH, as well as secretory profile components (baseline mean, amplitude of secretory spikes) were negatively correlated with body weight and size on days 94 and 199. Overall mean, baseline and integrated area of plasma insulin on days 94 and 199 were positively related to body weight and size. Thus positive protein anabolic growth responses from implantation (parallel comparative slaughter trial) were coupled with increased pituitary GH content and little change in circulating plasma GH concentrations between implanted and control steers. This may suggest that changes in tissue sensitivity, an increased plasma clearance rate of GH and/or a direct effect on target tissues may be involved in the improved growth performance of cattle implanted with R or S.