Growth, Body Composition, and Endocrine Responses to Chronic ...

Growth, Body Composition, and Endocrine Responses to Chronic Administration of Insulin-Like Growth Factor I and(or) Porcine Growth Hormone in Pigs1,2,3 John Klindt*,4, J. T. Yen*, F. C. Buonomo†, A. J. Roberts*, and T. Wise* *Roman L. Hruska U.S. Meat Animal Research Center, ARS, USDA, Clay Center, NE 68933 and †Protiva-Monsanto, St. Louis, MO 63198

ABSTRACT: The actions of IGF-I, alone and in combination with porcine growth hormone (pGH), on growth and circulating endocrines and metabolites important in growth were investigated in peripubertal-age Meishan barrows. Pigs were assigned to four treatments: control, buffer; IGF-I, 33 mg rhIGF-I/kg BW injected twice daily; pGH, 33 mg rpGH/kg BW injected once daily; and IGF-I+pGH, 33 mg rhIGF-I/kg BW injected twice daily plus 33 mg rpGH/kg BW injected once daily. Treatments were administered for 28 d. Feed intake, BW, and backfat were recorded and blood samples were collected weekly. At slaughter, organ and primal cut weights were recorded. Offal and half the carcass were ground for chemical analysis. Serum concentrations of IGF-I on d 7, 14, 21, and 28 in the IGF-I, pGH, and IGF-I+pGH groups were increased 60, 107, and 131%, respectively, compared with those of the control group. Administration of pGH

increased gain 43%, feed efficiency 60%, carcass protein accretion 88%, and trimmed lean cuts 16%, whereas IGF-I administration increased gain 22%, carcass protein accretion 33%, and trimmed lean cuts 5%. There was little difference in responses to administration of IGF-I+pGH and pGH alone except that coadministration of IGF-I with pGH reduced the ability of pGH to suppress backfat gain ( P < .02). Even though administration of IGF-I resulted in a 60% increase in chronic nadir serum concentrations of IGF-I, only a few growth and carcass measures were changed when compared with control pigs. These included increased ( P < .05) weight of body, leaf fat, kidneys, and belly. The actions of pGH on growth of pigs were not mimicked, and some were countermanded by administration of IGF-I at a dose that produces significantly increased serum concentrations of IGF-I.

Key Words: Pigs, Insulin-like Growth Factor, Somatotropin, Growth, Carcass Composition 1998 American Society of Animal Science. All rights reserved.

J. Anim. Sci. 1998. 76:2368–2381

Introduction 1Presented in part at the 88th Annual Meeting of the American Society of Animal Science, July 24−26, 1996, Rapid City, SD, abstr. 156, and at the 10th International congress of Endocrinology, June 12−15, 1996, San Francisco, CA, abstr. P2-192. 2Mention of trade names or companies does not constitute an implied warranty or endorsement by the USDA or the authors. 3The authors acknowledge the secretarial assistance of Jan Watts; the technical assistance of Pat Nuss, Shelia Schemm, and Sandy Cummins; the MARC swine crew for husbandry of the animals; the MARC abattoir crew for assistance with slaughter of the animals and collection of carcass data; A. F. Parlow, Harbor General Hospital, for providing the reagents for RIA of pGH; R. G. Clark and Mike Cronin, Genentech, for providing the IGF-I that was administered to the animals; and P. A. Schoknecht and P. E. Walton for constructive criticism during preparation of the manuscript for submission. 4To whom correspondence should be addressed: P.O. Box 166, Clay Center, NE 68933-0166; Phone: 402/762-4224; fax: 402/ 762-4148; E-mail: [email protected]. Received December 22, 1997. Accepted May 18, 1998.

The ability of exogenously administered porcine growth hormone ( pGH) to reduce feed consumption, maintain or increase rate of gain, improve efficiency of feed utilization for gain, reduce the accretion of adipose tissue, and increase accretion of lean tissues has been convincingly demonstrated (Klindt et al., 1992; Etherton et al., 1994). Accompanying the pGHinduced changes in growth performance are changes in circulating levels of endocrine factors and metabolites. Glucose, insulin, and IGF-I, and sometimes IGFII are increased, and serum urea nitrogen and IGF binding protein-2 ( IGFBP-2) are decreased following GH administration (Cohick and Clemmons, 1993). Even though increased circulating concentrations of IGF-I have been suggested to be the mediators of many of the actions of pGH on growth, it may be that local, paracrine and(or) autocrine, production, rather

2368

2369

CHRONIC ADMINISTRATION OF IGF-I AND(OR) GH

than circulating concentrations, is the determinant of the growth responses. Additionally, pGH has direct effects on feed intake and adipose tissue (Etherton et al., 1994). However, if increased circulating concentrations of IGF-I mediate actions of pGH on growth, then administration of IGF-I should produce effects similar to those observed with pGH administration. Evidence from rodent and human studies indicates that there may be a direct action of IGF-I and(or) synergism of GH and IGF-I on measures of growth and growth regulation (Guler et al., 1988; Elahi et al., 1993; Clark et al., 1994). However, infusion of IGF-I into growing hogs for 15 d, a short period, failed to have a positive effect on growth (Walton et al., 1995). The objective of the current study was to quantify the effect of administration of exogenous IGF-I, alone or in combination with pGH, for 4 wk on rate, efficiency, and composition of growth and circulating concentrations of pGH, IGF-I, IGF-II, insulin, and IGFBP in growing swine.

Materials and Methods Male pigs ( n = 24; barrows) of the Meishan breed were used in the study. The animals were 96.9 ± 11.3 d of age (mean ± SD), weighed 33.5 ± 7.4 kg (mean ± SD), and backfat thickness at start of the trial averaged 15.3 ± 1.2 mm (mean ± SD). Meishan barrows were used because of their small size and because their rate of adipose tissue accretion is significant at this peripubertal age. Detection of a shift in nutrient partitioning from adipose to lean requires the presence of significant initial adipose accretion. The small size of the pigs reduced the quantity of hormone required for each animal in the study. Pigs were stratified by dam and sire and randomly assigned to four treatment groups ( 6 pigs/ treatment group): control, administered the buffer (10 mM acetic acid, 160 mM sodium chloride) for preparation of IGF-I at a dose of .033 mL/kg BW at 0800 and 2000 daily and the buffer (25 mM sodium bicarbonate) for preparation of pGH at .033 mL/kg BW at 0800 daily; IGF-I, administered 33 mg rhIGF-I/ kg BW at 0800 and 2000 daily for a total daily dose of 66 mg rhIGF-I/kg BW−1 and the bicarbonate buffer at .033 mL/kg BW at 0800 daily; pGH, administered 33 mg rpGH/kg BW at 0800 daily and the acetic acid buffer at a dose of .033 mL/kg BW at 0800 and 2000 daily; and IGF-I+pGH, administered 33 mg rhIGF-I/kg BW at 0800 and 2000 daily and 33 mg rpGH/kg BW at 0800 daily for a total daily dose of 66 mg rhIGFI·kg−1·d−1 plus 33 mg rpGH·kg−1·d−1. Treatments were administered through 2000 of d 28. Solutions of IGF-I and pGH for injection were prepared daily at a concentration of 1.0 mg/mL. Recombinant pGH was provided by Protiva-Monsanto, St. Louis, MO, and recombinant human IGF-I was provided by Genentech, South San Francisco, CA. Dose of pGH ad-

Table 1. Composition of the diet fed during the 4 wk of the trial Item

Unit

Ingredients Yellow dent corn grain, % Solvent-extracted soybean meal, % Dicalcium phosphate, % Limestone, % Iodized NaCl, % Trace mineral premix, %a Vitamin premix, %b Choline chloride, %c

64.5 31.6 2.4 .5 .4 .2 .2 .2

Calculated composition (as fed) Crude protein, %d Lysine, %e

19.5 1.08

Analyzed composition (as fed) f Dry matter, % Gross energy, cal/g Crude protein, %

87.95 3,756 22.05

aSupplied the following in milligrams per kilogram of diet: Fe (as ferrous sulfate heptahydrate), 160; Cu (as cupric oxide), 10; Mn (as manganese oxide), 20; and Zn (as zinc oxide), 100. The carrier was CaCO3. bSupplied the following per kilogram of diet: retinyl acetate, 5,280 IU; cholecalciferol, 704 IU; dl-alpha-tocopheryl acetate, 70.4 IU; menadione sodium bisulfite complex, 3.35 mg; vitamin B12, 26.4 mg; riboflavin, 5.3 mg; niacin, 28.2 mg; d-pantothenic acid, 21.1 mg. cSupplied 868 mg choline per kilogram of diet. dAssuming the crude protein content is 8.5% for corn and 44% for soybean meal (NRC, 1988). eAssuming the lysine content is .25% for corn and 2.9% for soybean meal (NRC, 1988). fAOAC (1984).

ministered was considered to be a moderate dose, a dose that would produce less than maximal response based on previous results (Evock et al., 1988; Klindt et al., 1995). The dose of IGF-I was derived primarily from rat and human studies (Elahi et al., 1993; Clark et al., 1994). All treatments were administered by i.m. injection (Klindt et al., 1995) for 28 d. All animal procedures were reviewed and approved by the U.S. Meat Animal Research Center Animal Care and Use committee. During the study, the pigs were individually housed in slotted floor pens (1.2 × 1.2 m ) in an enclosed, temperature-controlled building ( ∼21°C ) with free access to water and feed. Feed was a corn-soybean meal diet containing 22.05% CP and 3.756 Mcal/kg (as-fed) that met or exceeded the National Research Council (NRC, 1988) nutrient requirements (Table 1). At each weighing, backfat thickness was determined ultrasonically (Lean-Meater, Renco, Minneapolis, MN) approximately 35 mm off the midline at three sites: 1st rib, last rib, and last lumbar vertebra. These three values were averaged to obtain average backfat thickness. Blood samples (10 mL) were collected by jugular venipuncture at 0, 3, 6, and 24 h and at 7, 14, 21, and 28 d. Samples obtained at time of injections were collected immediately before injection (i.e., 12 h after

2370

KLINDT ET AL.

last IGF-I injection and 24 h after last pGH injection). Blood samples were immediately placed in ice, and serum was harvested and aliquoted within 4 h after collection. Serum was stored at −15°C until it was assayed to determine serum concentrations of pGH (Klindt et al., 1983), insulin (Buonomo and Baile, 1991), IGF-I (Buonomo et al., 1987), and IGF-II (Buonomo et al., 1988) with RIA. Estimates of intraassay CV, interassay CV, and least detectable concentrations, respectively, for the pGH RIA were 5.1%, 12.4%, and .87 ng/mL; for the insulin RIA, they were 15.1%, 8.7%, and 1.45 mIU/mL; for the IGF-I RIA, they were 11.0%, 3.4%, and .2 ng/mL; and for the IGF-II RIA, they were 12.0%, 4.3%, and .37 ng/mL. Serum concentrations of glucose and urea nitrogen were determined using a clinical analyzer. Serum concentrations of the insulin-like growth factor binding proteins (IGFBP) were quantified with ligand blot analysis (Echternkamp et al., 1994; Funston et al., 1995). Ligand blot analyses of IGFBP were performed on serum of samples collected at 0, 6, and 24 h and at 7 and 28 d. Briefly, serum proteins were separated on a 12% one-dimensional SDS-PAGE gel, proteins were transferred to nitrocellulose membranes, membranes were probed overnight with [125I]IGF-I, and they were subsequently exposed to xray film at −70°C for 24 and 72 h. Identity of the bands was determined by size and immunoprecipitation analysis (Funston et al., 1996; Figure 1). All samples for an individual pig were analyzed on a single gel, and the three treatments were represented on each gel in order to preclude gel × treatment confounding. On the morning of d 29, the pigs were weighed prior to slaughter. Following exsanguination, the pigs were skinned, and hot carcass weight and weights of the offal components were recorded. Gastrointestinal components were emptied of contents before weighing. The head and hocks were removed and weighed. Organs from the abdominal and thoracic cavities, the internal offal, and hide plus head plus hocks were frozen separately for subsequent grinding and determination of chemical composition (AOAC, 1984). Approximately 24 h after slaughter, chilled carcass weight was determined. The right half of each carcass was frozen for subsequent grinding and sampling for determination of chemical composition (AOAC, 1984). The left side was retained for dissection into primal cuts (NAMP, 1988). The primal cuts were weighed and, with the exception of the belly, trimmed to approximately 6 mm of fat cover and again weighed. The trimmed weights of the picnic, Boston butt, loin, and ham were summed to obtain the value for trimmed lean cuts ( TLC) . The left ham was dissected into lean tissue, bone, and fat. The cross section of the loin between ribs 10 and 11 was traced, and area of the longissimus muscle (loin eye) was measured using computerized planimetry (Bioquant IV System, R & M Biometrics, Nashville, TN).

Figure 1. Representative ligand blot of IGF binding proteins (BP) detected in porcine serum either before (Raw) or after immunoprecipitation with an antiserum against IGFBP-3 (BP-3), IGFBP-2 (BP-2), IGFBP-4 (BP-4), or IGFBP-5 (BP-5). Volume of serum run on the gel was 2 mL- for Raw and 5-mL equivalents for immunoprecipitated samples. The antiserum against IGFBP-3 exhibited significant cross-reaction with IGFBP-2.

The data were analyzed using the General Linear Models procedure of SAS (1989). Average daily gain and average change in backfat thickness throughout the trial were determined by regression. Growth performance (i.e., feed intake, daily gain, efficiency of gain, and daily change in average backfat thickness) and tissue weights and accretion rates of chemical components were analyzed by one-way analysis of variance with initial weight included as a covariant. Sums of squares were partitioned into single degree of freedom contrasts to examine specific a priori nonorthogonal comparisons (i.e., control vs IGF-I, control vs pGH, IGF-I vs pGH, and IGF-I+pGH vs pGH). Temporal concentrations of serum constituents were examined by split-plot analysis of variance. For analysis of serum constituents other than IGFBP, the responses were classified as acute (i.e., samples collected at 0, 3, 6, and 24 h ) and chronic (i.e., samples collected at 7, 14, 21, 24 d ) and analyzed separately. The model consisted of the effects of treatment group tested with pig within treatment group and effects of time (hour or day) and the interaction of time × treatment tested with the remaining variation. Sums of squares were partitioned


2371

into single degree of freedom contrasts to examine the specific a priori nonorthogonal comparisons listed above. The IGFBP were analyzed using a similar splitplot model, and all times (0, 6, and 24 h and 7 and 28 d ) were included in the model. For all analyses, individual pig was considered the experimental unit. Least squares means are presented.

Results None of the exogenous hormone treatments resulted in feed intake that was different ( P > .10) from those of control animals (Figure 2). However, feed intake of animals administered IGF-I was greater ( P < .05) than that of pigs administered pGH. Gains of pigs administered IGF-I and(or) pGH were greater ( P < .05) than those of control pigs. Administration of IGFI+pGH did not produce greater gains than administration of pGH alone. Efficiency of conversion of feed to live weight gain was increased ( P < .03) with pGH administration, and IGF-I+pGH did not further improve feed efficiency. Rate of backfat deposition was not influenced by administration of IGF-I alone; it was decreased ( P < .01) to near zero with pGH, and this pGH-induced reduction was partially reversed with administration of IGF-I+pGH (i.e., greater rate of backfat deposition was obtained with the combination than with pGH alone [P < .02]). Weight at slaughter was increased by all exogenous hormone treatments (Table 2). The increase in slaughter weight was greater ( P < .03) with pGH administration than with IGF-I administration, and there was no advantage of IGF-I+pGH over administration of pGH alone. Treatment had no significant effect on weight of head, hocks, or hide at slaughter. Weight of perirenal or leaf fat was greater ( P < .05) in IGF-I treated animals than in controls or animals administered pGH. Administration of the combination of IGF-I+pGH reduced the weight of leaf fat to a quantity less than that in control pigs. Among the vital organs, only the weights of the kidneys and pancreas were influenced ( P ≤ .10) by IGF-I administration; weights of these were increased about 20% with IGF-I treatment. All vital organ weights were increased ( P ≤ .10) with pGH treatment. The weight of the small intestine was the only gastrointestinal component that was influenced ( P < .05) by IGF-I treatment. Weights of stomach, small intestine, and large intestine were increased ( P < .04) in pigs administered pGH. Coadministration of IGF-I and pGH resulted in greater ( P < .05) stomach weights and reduced ( P < .10) lung weights as compared with those of pGH-treated animals. Administration of IGF-I alone had little influence on carcass measures (Table 3). Only cold carcass weight and weight of the belly were changed by the IGF-I treatment ( P ≤ .08). Belly weight was increased

Figure 2. Live measures of growth performance, daily feed intake, daily gain, efficiency of conversion of feed to live weight gain, and daily rate of change in backfat thickness of control (Cont) pigs and pigs administered IGF-I and(or) pGH. Vertical bars are standard errors of the mean. Values above horizontal lines are probability, determined by nonorthogonal contrasts, that the difference between the groups compared is not different from zero.

2372

KLINDT ET AL.

Table 2. Least squares means for weights of offal components at end of the trial adjusted to constant initial weight Nonorthogonal contrastsb Variable

Control

Slaughter wt, kg

49.7

Head, kg Hocks, kg Hide, kg

4.52 1.03 6.54

Leaf fat, g

IGF-I

pGH

IGF-I + pGH

52.7

56.7

56.9

4.54 1.01 6.67

4.85 1.13 7.47

4.96 1.14 7.74

PSEMa

IGF-I pGH vs Control vs Control

IGF-I vs pGH

IGF-I+pGH vs pGH

.7

.05

.01

.03

.87

.11 .04 .22

.93 .75 .79

.23 .27 .11

.25 .17 .15

.65 .90 .61

674

803

617

524

28

.05

.42

.02

.18

Lungs, g Heart, g Liver, g Kidneys, g Spleen, g Pancreas, g

293 165 1,071 184 76 69

347 177 1,094 220 83 83

496 218 1,443 269 90 90

377 222 1,434 292 95 95

27 4 29 8 3 4

.34 .14 .70 .05 .33 .10

.01 .01 .01 .01 .10 .04

.04 .01 .01 .03 .36 .40

.08 .63 .90 .25 .47 .56

Stomach, g Small intestine, g Cecum, g Large intestine, g

371 1,138 116 1,214

378 1,283 109 1,255

415 1,396 120 1,493

463 1,436 126 1,507

7 32 4 49

.66 .05 .40 .68

.02 .01 .63 .04

.04 .16 .24 .06

.01 .60 .48 .90

aPooled standard bProbability that

error of the mean. the difference between the means contrasted is not different from zero.

( P < .01) with exogenous hormone administration. The increases were similar with administration of IGF-I or pGH; however, the increase was reduced with IGF-I+pGH treatment. Most carcass measures were increased with pGH administration. Weights of the belly and the trimmed picnic were different ( P < .09)

with administration of IGF-I+pGH than with administration of pGH. Chemical composition determined for body components and rates of accretion of the chemical components were calculated (Table 4). Administration of IGF-I alone increased ( P ≤ .10) accretion of weight by

Table 3. Least squares means for weights of carcass components at end of the trial adjusted to constant initial weight Nonorthogonal contrastsb Control

IGF-I

pGH

IGF-I + pGH

PSEMa

Slaughter wt, kg

49.0

52.7

56.7

56.9

.7

.05

Cold carcass wt, kg Carcass length, cm Longissimus muscle area, cm2

23.0 61.2 11.2

24.4 61.4 11.9

25.8 61.5 32.6

25.4 61.5 13.6

.4 1.1 .5

.08 .92 .49

Variable

IGF-I pGH vs Control vs Control

IGF-I vs pGH

IGF-I+pGH vs pGH

.01

.03

.87

.01 .16 .02

.11 .17 .04

.64 .16 .32

Boston butt, kg Trimmed Boston butt, kg

2.81 2.26

2.85 2.28

3.04 2.48

3.06 2.62

.08 .07

.82 .85

.26 .20

.33 .24

.94 .36

Picnic, kg Trimmed picnic, kg Loin, kg Trimmed loin, kg

2.62 2.34 5.33 4.03

2.70 2.37 5.74 4.37

2.95 2.64 6.21 4.84

3.06 2.83 6.35 4.93

.04 .04 .20 .14

.30 .72 .36 .23

.01 .01 .13 .03

.02 .02 .41 .15

.22 .09 .73 .79

Ham, kg Trimmed ham, kg

5.55 4.38

5.74 4.53

6.21 5.18

6.35 5.23

.11 .12

.39 .55

.02 .02

.08 .04

.59 .87

Belly, kg

5.66

Lean cuts, kg Trimmed lean cuts, kg Ham, lean, kg Ham, fat, kg Ham, bone, kg aPooled standard bProbability that

16.3 13.0 3.46 .95 1.12

6.32 17.0 13.6 3.68 .96 1.08

6.45 18.3 15.1 4.27 .79 1.18

5.97 18.4 15.6 4.25 .80 1.26

.08

.01

.01

.46

.02

.3 .3

.27 .38

.02 .01

.09 .05

.88 .52

.11 .04 .04

.34 .88 .64

.01 .11 .56

.04 .08 .33

.94 .91 .41

error of the mean. the difference between the means contrasted is not different from zero.

2373


the carcass and internal offal and thus empty body. Accretion of head, hocks, and hide chemical component weights were not influenced by IGF-I administration. Accretion of empty body fat, empty body energy, empty body protein, carcass protein, carcass ash, and internal offal were increased ( P ≤ .09) with administration of IGF-I alone. However, these changes were due to increased weight of the body components. When

the chemical composition data were analyzed on a per unit of body weight basis, these changes were not significant ( P = .33). In general, administration of pGH increased accretion of water, protein, and ash and decreased accretion of fat. Administration of IGFI+pGH did not result in accretion rates of chemical components that were different from those in animals given pGH alone.

Table 4. Least squares means for accretion rates of chemical components of the empty body and its components in Meishan barrows administered IGF-I and(or) pGH Component wt, g/d Empty bodya Control IGF-I pGH IGF-I+pGH PSEMb

406 504 586 594 23

Water, g/d 152 188 311 333 17

Fat, g/d 184 227 150 135 10

Control vs IGF-I Control vs pGH IGF-I vs pGH pGH vs IGF+pGH

.10 .01 .17 .90

Carcass Control IGF-I pGH IGF-I+pGH PSEM

248 313 336 336 12

.41 .01 .01 .62 85 110 178 184 8

.09 .19 .01 .55

.25 .01 .03 .87

118 144 79 72 6

Energy, kcal/d

17.8 21.9 27.2 26.8 1.3

1,959 2,444 1,910 1,791 88

30.9 41.1 58.1 57.2 2.1

.20 .01 .11 .91 13.9 17.6 20.2 20.5 .8

.04 .83 .03 .59 1,239 1,530 1,040 987 58

Pc

Contrasts Control vs IGF-I Control vs pGH IGF-I vs pGH pGH vs IGF+pGH

.04 .01 .45 .99

Internal offal Control IGF-I pGH IGF-I+pGH PSEM

57 86 109 108 6

.24 .01 .01 .79 19 33 54 61 4

.13 .02 .01 .68

.07 .01 .01 .86

29 41 38 29 4

4.7 8.2 11.3 12.2 .9

.07 .01 .20 .90 .27 .49 .72 .77 .05

.06 .19 .01 .72 294 417 419 343 32

Pc

Contrasts Control vs IGF-I Control vs pGH IGF-I vs pGH pGH vs IGF+pGH

.06 .01 .12 .98

Head, hide, and hocks Control IGF-I pGH IGF-I+pGH PSEM

101 106 142 150 13

.20 .01 .06 .46 44 41 75 83 8

.22 .33 .81 .30

.12 .01 .18 .70

34 42 32 33 2

22 22 32 30 3

.09 .01 .10 .66 3.3 3.5 5.9 5.2 .7

.14 .14 .98 .35 402 473 428 438 28

Pc

Contrasts

aSum of carcass; bPooled standard cProbability that

59 73 103 101 5

Ash, g/d

Pc

Contrasts

Control vs IGF-I Control vs pGH IGF-I vs pGH pGH vs IGF+pGH

Protein, g/d

.88 .21 .26 .80

.92 .15 .12 .70

.22 .63 .09 .86

.95 .22 .24 .80

.92 .13 .16 .68

internal offal; and hide, head, and hocks. error of the mean. the difference between the means contrasted is not different from zero.

.32 .72 .52 .88

2374

KLINDT ET AL.

Blood samples were collected at 0, 3, 6, and 24 h and on d 7, 14, 21, and 28. With the exception of the h 3 and h 6 samples, samples were collected immediately before the morning injections. Nevertheless, mean serum concentrations of IGF-I in pigs administered exogenous hormone were chronically elevated above those of the control pigs (Figure 3). The acute response to administered IGF-I produced maximal concentrations at 3 and 6 h after injection, and, chronically, at 12 h after previous injection, serum concentrations were still greater in IGF-I treated pigs than in controls (Figure 3). With administration of exogenous pGH, the mean concentrations of pGH were increased owing to the acute elevation measured at 3 and 6 h after (Figure 4). Animals chronically administered IGF-I had lower concentrations of IGF-II than control- ( P < .01) or pGH-treated animals (Figure 5). Serum insulin and glucose concentrations were not altered by administration of IGF-I alone (Figures 6 and 7). Serum concentrations of insulin and glucose were increased ( P < .01) with administration of pGH or IGF-I+pGH. Acute increases in insulin were noted in animals in the pGH treatment group. There was an acute increase in serum glucose in all pigs given pGH; however, this acute response in glucose was reduced in animals administered IGF-I+pGH. In general, serum concentrations of urea nitrogen were unaffected by administration of IGF-I and reduced ( P < .01) with pGH or IGF-I+pGH administration (Figure 8). All IGFBP except the 36-kDa band were influenced ( P < .10) by time or the interaction of time × treatment (Table 5). Little influence of treatment was noted for the 44-kDa band of IGFBP-3. The 40-kDa band of IGFBP-3 was increased with administration of pGH and IGF-I+pGH. The 36-kDa band, which seems to be a form of IGFBP-3, was acutely stimulated with administration of IGF-I+pGH; increased levels were evident 24 h after the first injections. In pigs administered pGH alone, the abundance of the 36-kDa band tended to increase gradually from d 1 to d 28 of the study. The IGFBP-2, the 34-kDa band, was decreased with administration of pGH, either alone or with IGF-I. Levels of IGFBP-2 tended to increase in serum of animals in the IGF-I group. There were few responses to treatment in the 22-kDa band of IGFBP-4. Level of the 28-kDa band of IGFBP-4 was increased with administration of pGH, but was not affected by IGF-I administration.

Discussion Even though increased circulating concentrations of IGF-I seem to be an absolute consequence of pGH administration, exogenous IGF-I did not mimic the actions of pGH on growth or circulating moieties. In general, IGF-I at the dosage used had little effect on

Figure 3. Acute, 0 to 24 h, and chronic, 7 to 28 d, responses in serum concentrations of IGF-I to administration of IGF-I and(or) pGH. In the acute responses, concentrations were influenced (P < .01) by the interaction of treatment and time. All nonorthogonal contrasts among the treatment groups described in the Materials and Methods section were significant (P < .01). In the chronic responses, concentrations were influenced (P < .01) only by treatment. Vertical bars are standard errors of the mean. Values above horizontal bars are the probability, determined by nonorthogonal contrasts, that the difference is not different from zero.


2375

Figure 4. Acute, 0 to 24 h, and chronic, 7 to 28 d, responses in serum concentrations of pGH in control (Cont) pigs and in pigs administered IGF-I and(or) pGH. Acute and chronic responses were influenced (P < .03) by the interaction of treatment × time. During the acute phase, nonorthogonal contrasts revealed differences among control and pGH (P < .01) and IGF-I and pGH (P < .01) treatment groups. During the chronic phase, nonorthogonal contrasts revealed differences among control and IGF-I (P < .06) and control and pGH (P < .05) treatment groups.

feed intake, efficiency of live weight gain, backfat deposition, and carcass composition. A striking effect of IGF-I administration, and a demonstration of the efficacy of the dosage, was increased adiposity: greater weight of leaf fat, empty body fat, and carcass and empty body energy. The effect of IGF-I treatment on adiposity is in contrast to the effect of pGH treatment, which decreased weight of leaf fat and carcass fat. Even though IGF-I administration resulted in increased circulating concentrations of IGF-I, the results in growth performance and composition were different

Figure 5. Acute, 0 to 24 h, and chronic, 7 to 28 d, responses in serum concentrations of IGF-II in control (Cont) pigs and in pigs administered IGF-I and(or) pGH. The acute responses were not influenced by treatment, time, or their interaction. Chronic responses were influenced by treatment, but not by time. Vertical bars are standard errors of the mean. Values above horizontal bars are the probability, determined by nonorthogonal contrasts, that the difference is not different from zero.

2376

KLINDT ET AL.

than those in pigs administered pGH. Administration of IGF-I, as herein, does not produce large advantageous alterations in growth performance of pigs. Admittedly, the carcass and growth responses might have been different with a greater dose of exogenous IGF-I and(or) more frequent administration. The amount and administration schedule of IGFI used in the present study were empirically derived

Figure 7. Acute, 0 to 24 h, and chronic, 7 to 28 d, responses in serum concentrations of glucose to administration of IGF-I and(or) pGH. The acute and chronic responses were influenced by the main effects of treatment and time. Nonorthogonal contrasts revealed differences (P < .01) that were due to treatment between control and pGH, and IGF-I and pGH treatments in the acute responses. Differences in the chronic responses (P < .01) between control and pGH, IGF-I and pGH, and pGH and pGH+IGF-I treatments were detected by nonorthogonal contrasts.

Figure 6. Acute, 0 to 24 h, and chronic, 7 to 28 d, responses in serum concentrations of insulin in control (Cont) pigs and in pigs administered IGF-I and(or) pGH. During each response phase, insulin concentrations were influenced (P < .04) only by treatment. Values above horizontal bars are the probability, determined by nonorthogonal contrasts, that the treatment difference is not different from zero.

from the results of rat and human studies (Elahi et al., 1993; Clark et al., 1994), the size of the pigs, and the quantity of IGF-I available for the study. The dose and administration schedule was anticipated to produce circulating concentrations of IGF-I over 24 h that would be equitable to those obtained with exogenous pGH treatment. The hypothesis was predicated on the observation that IGF-I concentrations are maintained at a nearly constant level during an


8-h postinjection period in pigs chronically treated with pGH (Klindt et al., 1994) and on the assumption that concentrations of IGF-I would rise and then fall following each administration of exogenous IGF-I. The chronic concentrations of IGF-I presented in Figure 3 are nadir values. Unfortunately, circulating concentra-

Figure 8. Acute, 0 to 24 h, and chronic, 7 to 28 d, responses in serum concentrations of urea nitrogen in pigs administered IGF-I and(or) pGH. Acute responses were influenced (P < .02) by interaction of treatment × time. Mean of concentrations at 0, 6, 12, and 24 h were different (P < .02) by nonorthogonal contrasts between control and pGH, IGF-I and pGH, and pGH and IGFI+pGH treatment groups. Chronic responses were influenced (P < .01) by treatment. Nonorthogonal contrasts revealed differences (P < .01) between control and pGH and IGF-I and pGH treatment groups.

2377

tions over a 24-h period were not monitored in chronically treated pigs (e.g., 14 to 27 d of treatment). As has been well-established, administration of pGH, either by daily injection or sustained-release implant, results in decreased feed intake, increased rate and efficiency of gain, and reduced rate of backfat deposition (Evock et al., 1988; Klindt et al., 1992; Etherton et al., 1994). Administration of IGF-I+pGH resulted in feed intakes and rates and efficiencies of gain similar to those measured with administration of pGH alone. With pGH administration, rate of backfat deposition was decreased; however, the rate of backfat deposition in pigs given IGF-I+pGH was about half of that of the control pigs but was considerably greater than that of pigs given pGH alone. This action of exogenous IGF-I coadministered with pGH is additional evidence of the trophic effect of IGF-I on adiposity. The action of IGF-I on leaf fat is equivocal; quantity of leaf fat at slaughter was increased ( P < .05) 19% by IGF-I treatment, unchanged ( P < .42) by pGH treatment, and decreased 22% by the combination treatment, IGF-I+pGH, as compared with that in the control pigs. These results demonstrate that the endocrine actions of IGF-I on adipose tissue may be modulated by the pGH status of the animal. As well, Brameld et al. (1996) presented evidence that both genotype or breed and adipose tissue depot influence quantity of IGF-I mRNA measured. Other workers have investigated the growth responses of animals to exogenous IGF-I. Many of these studies have involved rodents that have been genetically, surgically, or pharmacologically compromised and have utilized doses considerably greater than that used in the current study. Insulin-like growth factor-I or analogs of IGF-I that bind poorly to the IGFBP have been administered to hypophysectomized rats (Guler et al., 1988; Cox, 1994), dwarf mice (Pell and Bates, 1992) and rats (Ambler et al., 1993), diabetic rats (Ballard et al., 1991), dexamethasone-treated rats (Ballard et al., 1991), and gut-resected rats (Ballard et al., 1991), and increased weight gains were among the observed effects. Additive effects of GH and IGF-I were investigated with administration of bGH (1.5 or 20 mg/d) and(or) IGF-I (20 mg/d or ~2,000 mg·kg BW−1·d−1) to Snell dwarf mice (Pell and Bates, 1992). Even though weight gains were increased with all treatments, an additive effect of bGH+IGF-I was evident only with the lower dose of bGH. Cottam et al. (1992) treated wethers with 150 mg IGF-I·kg BW−1·d−1 for 56 d. During the first 28 d, IGF-I treatment had no effect on gain; however, during the last half of the trial, feed intake and thus gains were reduced in the treated sheep. In the current study, the gain responses to the IGF-I treatment were small compared with those induced with the pGH treatment during the 28-d trial. More recently, administration of 150 mg IGF-I·kg BW−1·d−1 to lambs fed 110% of maintenance did not change the

2378

KLINDT ET AL.

meager weight gains, which indicated that exogenous IGF-I cannot alter the use or digestibility of nutrients when the excess, above maintenance, is small (Min et al., 1996). Walton et al. (1995) infused IGF-I or IGF analogs with minipumps to pigs at doses up to 180 mg·kg BW−1·d−1 for 15 d. In that study, treatment with IGF-I induced no changes in feed intake or gain. In contrast to rodent studies and in agreement with results from lambs, exogenous IGF-I at a moderate dose, a dose that chronically increased serum IGF-I concentrations to 60% greater than those in control pigs, has minimal effect on growth rate in pigs. In contrast, administration of pGH at a dose that resulted in serum concentrations of IGF-I 30% greater than those in IGF-I-treated pigs produced considerable increases in growth performance.

As expected, treatment with pGH increased the weight of trimmed and untrimmed lean cuts. Weight of lean cuts, trimmed or untrimmed, was not affected by administration of IGF-I, nor was empty body protein accretion. However, carcass protein accretion tended to be greater in IGF-I treated pigs, as was carcass and energy accretion, but, when the percentage composition of carcass was analyzed, there were no differences resulting from the IGF-I treatment and thus no preferential promotion of lean tissue growth. Nitrogen retention was unaffected in lambs administered IGF-I (Min et al., 1996). Exogenous IGF-I administered for the period evaluated in this study does not seem to alter the partitioning of nutrients to carcass lean and carcass adipose.

Table 5. Mean estimates of serum concentrations of IGFBP in Meishan barrows administered IGF-I and(or) pGH for 28 da Binding protein-2

Binding protein-3 Treatment and time

Binding protein-4

44 kDa

40 kDa

36 kDa

34 kDa

28 kDa

22 kDa

Control 0 h 6 h 24 h 7 d 28 d

7.2 6.8 5.5 6.9 6.6

6.4 5.6 4.3 6.2 5.7

NDb ND .05 .22 ND

3.63 3.28 2.67 3.71 3.35

.33 .38 .32 .49 .22

.77 1.07 1.02 .87 .87

IGF-I 0 h 6 h 24 h 7 d 28 d

7.3 6.8 6.8 6.8 6.8

7.1 6.5 6.4 5.5 5.8

ND ND ND ND ND

3.36 3.35 3.70 3.91 4.17

.40 .36 .59 .45 .27

1.00 .93 .95 .82 .74

pGH 0 h 6 h 24 h 7 d 28 d

6.2 6.4 6.0 7.0 7.6

5.3 5.8 5.3 7.7 8.6

ND ND ND .30 .64

2.58 2.53 1.83 1.76 1.56

.20 .23 .28 .29 .33

.73 .90 1.09 .76 1.06

IGF-I+pGH 0 h 6 h 24 h 7 d 28 d

5.4 5.8 5.7 6.7 7.8

5.1 5.9 5.6 6.8 8.4

ND ND 1.03 .83 .38

2.44 2.46 1.96 1.61 1.35

.26 .42 .33 .36 .44

.76 1.10 .90 1.04 .86

PSEMc

.19

.22

.09

.10

.03

.04

ANOVA Treatment Time Treatment × time

.95 .02 .12

.84 .01 .01

.04 .11 .21

.02 .09 .01

.62 .14 .03

.99 .08 .21

.04 .01 .01 .60

.10 .05 .03 .02

.66 .91 .74 .74

Pd

Contrasts Control vs IGF-I Control vs pGH IGF-I vs pGH pGH vs IGF-I+pGH

.30 .82 .41 .22

.10 .02 .49 .66

.73 .35 .20 .08

aLeast squares means of concentration in densimetric units. bND = not detectable. cPooled standard error of the mean. dProbability that the difference between the means contrasted

is not different from zero.


As seen in previous studies, administration of pGH resulted in increased weights of lungs, heart, liver, kidneys, spleen, pancreas, stomach, and small and large intestine. Only a few organs, kidneys, pancreas, and small intestine, weighed more as a result of IGF-I treatment. A positive additive effect of IGF-I+pGH was evident only in the weight of the stomach. The pGH-induced increase in stomach weight was doubled with the combination treatment. Similarly, only minor changes occurred in weights of organs of wethers administered a dose of IGF-I more than two times greater than the dose administered to the pigs herein (Cottam et al., 1992). Variation in mass and energy expenditure of the internal organs are major sources of the variation in rate and composition of gain (Leymaster and Jenkins, 1985; Ferrell, 1988). The ability of pGH to improve rate and composition of gain may be dependent on its ability to increase the mass of the internal organs (Klindt et al., 1992). The increased mass of, and thus energy expenditure by, the internal organs, the offal, support the ability to increase utilization of nutrients such that there is increased rate of gain and lean tissue accretion. Failure of exogenous IGF-I to increase mass of most of the internal organs may explain the inability of administered IGF-I to improve rate and composition of gain of the pigs. Administration of IGF-I chronically increased serum concentrations of IGF-I and decreased serum concentrations of pGH and IGF-II. Similarly, infusion of long R3IGF-I resulted in decreased plasma concentrations of IGF-II, possibly owing to negative feedback by IGF-I on IGF-II production or displacement of IGFII from carrier proteins, resulting in greater clearance (Walton et al., 1995). Exogenous IGF-I did not change chronic circulating concentrations of insulin, glucose, and urea nitrogen, which indicates minor influence of IGF-I on these moieties important in growth. Serum concentrations of IGF-II were less than those reported by others (Buonomo and Klindt, 1993; Owens et al., 1994). Buonomo and Klindt (1993) reported higher concentrations of IGF-II in genetically obese than in genetically lean pigs, and they reported higher concentrations in boars than in gilts. The lower concentrations of IGF-II reported herein may reflect the Meishan breeding of the barrows. During the first 24 h of the study when blood samples were collected at 0, 3, 6, and 24 h, there was a general decline in IGF-I serum concentrations. There is no ready explanation for this. The pigs were acclimated to the feed and the facilities for 2 wk prior to initiation of the study. The only changes at time zero were initiation of injections and blood sampling. Increases in IGF-I, independent of increased GH, may not be involved as an endocrine regulator of body growth, particularly of lean tissue accretion, in swine. In the present study, administration of IGF-I was relatively ineffective, as compared with pGH, in

2379

promoting lean tissue accretion, even though IGF-I administration increased circulating concentrations of IGF-I 60% compared with controls and achieved levels within 75% of those seen with pGH administration. Elevated circulating concentrations of IGF-I are an absolute consequence of pGH treatment, but the source of these elevated concentrations has not been definitively determined. Even though the liver is often implicated as a major source of circulating IGF-I, substantial expression of IGF-I mRNA also occurs in many other tissues and cell types (Cohick and Clemmons, 1993). In swine adipose and hepatic tissues, the expression of IGF-I mRNA is increased with pGH administration (Grant et al., 1991; Wolverton et al., 1992; Coleman et al., 1994). The quantity of IGF-I mRNA in longissimus muscle of untreated pigs was similar to that in hepatic tissue. Even though hepatic IGF-I mRNA expression was responsive to pGH administration, no such response to pGH was detected in longissimus muscle (Grant et al., 1991; Coleman et al., 1994). Therefore, the elevated circulating concentrations of IGF-I induced by pGH may be of adipose and(or) hepatic origin. Additionally, a small increase in IGF-I production by muscle, not detectable in the aforementioned studies, could be reflected in significant changes in serum concentrations because of the large mass of muscle (carcass lean is 31% of BW; Whittemore and Elsley, 1976). Hua et al. (1993) measured the concentrations of IGF-I in plasma, liver, kidneys, and muscle of lambs. Examination of those data reveals that 70% of the total IGF-I measured was in muscle and only 4% was in the liver. These data provide evidence that production of IGF-I in muscle may be considerable. This local production may be a greater determinant of muscle growth than circulating concentrations. Thus, IGF-I alone may not be an endocrine for muscle growth as evidenced by the failure of a 60% increase in circulating IGF-I concentrations to induce increased muscle or trimmed lean cut accretion. The action of IGF-I on muscle growth may be of a paracrine or autocrine nature. Actions of the IGF are modulated by their binding to IGFBP. Initially, it was thought that the role of the IGFBP was to bind IGF-I in order to prevent its binding to IGF-I receptors and initiation of signaling pathways (Rechler, 1997). Subsequent results now show that the IGFBP can potentiate the actions of IGF-I (Jones and Clemmons, 1995), and recent results indicate that IGFBP-3 has the ability to inhibit cell proliferation through a direct action on the cell independent of sequestration and blocking of IGF-I actions on the cell (Rechler, 1997). These findings befog elucidation of the biological consequences of the changes in circulating levels of the IGFBP induced by the treatments in the present study. Over the course of the trial, IGF-I treatment decreased ( P < .10) serum concentrations of the 40-kDa band of IGFBP-3

2380

KLINDT ET AL.

and the 28-kDa band of IGFBP-4 and increased ( P < .10) serum IGFBP-2 (34 kDa). In addition, coadministration of IGF-I with pGH increased serum concentrations of the 36-kDa band, thought to be a less-glycosylated form of IGFBP-3, above those measured in pGH treated pigs and prevented the pGHinduced decrease in the 28-kDa band of IGFBP-4. It is not possible with the information available to ascertain whether these observed increases in the IGFBP prevented IGF-I from exerting positive effects on growth. A suggestion that these increases in IGFBP did not prevent exogenous IGF-I from exerting a positive influence on growth and composition can be derived from the failure of long R3IGF-I and R3IGF-I to increase rate of gain in pigs (Walton et al., 1994, 1995). It should be noted that administration of pGH resulted in increased serum concentrations of the 40-kDa band of IGFBP-3, the predominant IGFBP. These increased concentrations of the 40-kDa band may prolong the half-life of IGF and enhance the response to the pGH-stimulated concentrations of IGF-I. However, these changes in the IGFBP might have had direct physiological actions, independent of binding IGF-I.

Implications Administration of insulin-like growth factor (IGF)I altered circulating concentrations IGF-I, IGF-II, and porcine growth hormone (pGH), and it increased the rate of gain without affecting feed intake or efficiency of gain. Administration of IGF-I increased serum IGFI 60% and accretion of carcass protein 33%, and pGH administration resulted in a 107% increase in serum IGF-I and an 88% increase in carcass protein accretion. Administration of pGH reduced carcass fat accretion, but IGF-I administration increased empty body fat and energy accretion and carcass energy. Elevation of circulating IGF-I by administration of IGF-I did not approximate the actions of pGH on growth and composition. Additionally, there was little augmentation of the responses to pGH with administration of IGF-I. Exogenously IGF-I may have to be administered in greater doses and(or) more frequently to have potential as a growth modifier for use in pork production.

Literature Cited Ambler, G. R., B. H. Breier, S. N. McCutcheon, and P. D. Gluckman. 1993. Effects of intermittent growth hormone or insulin-like growth factor 1 administration in the neonatal dwarf rat. Horm. Res. 40:178. AOAC. 1984. Official Methods of Analysis (14th Ed.). Association of Official Analytical Chemists, Washington, DC. Ballard, J. F., F. M. Tomas, L. C. Read, S. E. Knowles, P. C. Owens, A. B. Lemmey, A. A. Martin, J.R.E. Wells, J. C. Wallace, and G. L. Francis. 1991. Effects of IGF-I and IGF analogs on growth

during catabolic states in rats. In: E. M. Spencer (Ed.) Modern Concepts of Insulin-Like Growth Factors. pp 617−627. Elsevier Science Publishing, Inc., New York. Brameld, J. M., J. L. Atkinson, T. J. Budd, J. C. Saunders, J. M. Pell, A. M. Salter, R. S. Gilmour, and P. J. Buttery. 1996. Expression of insulin-like growth factor-1 (IGF-1) and growth hormone-receptor (GHR) mRNA in liver, skeletal muscle and adipose tissue of different breeds of pig. Anim. Sci. 62:555−559. Buonomo, F. C., and C. A. Baile. 1991. Influence of nutritional deprivation on insulin-like growth factor I, somatotropin, and metabolic hormones in swine. J. Anim. Sci.69:755−760. Buonomo, F. C., D. L. Grohs, C. A. Baile, and D. R. Campion. 1988. Determination of circulating levels of insulin-like growth factor II (IGF-II) in swine. Domest. Anim. Endocrinol. 10:323−329. Buonomo, F. C., and J. Klindt. 1993. Ontogeny of growth hormone (GH), insulin-like growth factors (IGF-I and IGF-II) and IGF binding protein-2 (IGFBP-2) in genetically lean and obese swine. Domest. Anim. Endocrinol. 10:257−265. Buonomo, F. C., T. L. Lauterio, C. A. Baile, and D. R. Campion. 1987. Determination of insulin-like growth factor I (IGF-I) and IGF binding protein levels in swine. Domest. Anim. Endocrinol. 10:23−31. Clark, R. G., L.M.S. Carlsson, D. Mortensen, and M. J. Cronin. 1994. Additive effects on body growth of insulin-like growth factor-I and growth hormone in hypophysectomized rats. Endocrinol. Metab. 1:49. Cohick, W. S., and D. R. Clemmons. 1993. The insulin-like growth factors. Annu. Rev. Physiol. 55:131−153. Coleman, M. E., L. Russell, and T. D. Etherton. 1994. Porcine somatotropin (pST) increases IGF-I mRNA abundance in liver and subcutaneous adipose tissue but not in skeletal muscle of growing pigs. J. Anim. Sci. 72:918−924. Cottom, Y. H., H. T. Blair, B. W. Gallaher, R. W. Purchas, B. H. Breier, S. N. McCutcheon, and P. D. Gluckman. 1992. Body growth, carcass composition, and endocrine changes in lambs chronically treated with recombinantly derived insulin-like growth factor-I. Endocrinology 130:2924−2930. Cox, G. N., M. J. McDermott, E. Merkel, C. A. Stroh, C. S. Ko, C. H. Squires, T. M. Gleason, and D. Russell. 1994. Recombinant human insulin-like growth factor (IGF)-binding protein-1 inhibits somatic growth stimulated by IGF-I and growth hormone in hypophysectomized rats. Endocrinology 135:1913−1920. Echternkamp, S. E., J. J. Howard, A. J. Roberts, J. Grizzle, and T. Wise. 1994. Relationships among concentrations of steroids, insulin-like growth factor-I, and insulin-like growth factor binding proteins in ovarian follicular fluid of beef cattle. Biol. Reprod. 51:971−981. Elahi, D., M. McAloon-Dyke, N. K. Fukagawa, A. L. Sclater, G. A. Wong, R. P. Shannon, K. L. Minaker, J. M. Miles, A. H. Rubenstein, C. J. Vandepol, H.-P. Guler, W. R. Good, J. J. Seaman, and R. R. Wolf. 1993. Effects of recombinant human IGF-I on glucose and leucine kinetics in men. Am. J. Physiol. 265:E831. Etherton, T. D., D. E. Bauman, D. H. Beerman, R. D. Boyd, P. J. Buttery, R. B. Campbell, W. V. Chalupa, K. Klasing, G. T. Schelling, and N. C. Steele. 1994. Metabolic Modifiers. National Academy of Sciences, Washington, DC. Evock, C. M., T. D. Etherton, C. S. Chung, and R. E. Ivy. 1988. Pituitary porcine growth hormone (pGH) and a recombinant pGH analog stimulate pig growth performance in a similar manner. J. Anim. Sci. 66:1928−1941. Ferrell, C. L. 1988. Contribution of visceral organs to animal energy expenditures. J. Anim. Sci. 66(Suppl. 3):23−34. Funston, R. N., G. E. Moss, and A. J. Roberts. 1995. Insulin-like growth factor-I (IGF-I) and IGF-binding proteins in bovine sera and pituitaries at different stages of the estrous cycle. Endocrinology 136:62−68. Funston, R. N., G. E. Seidel, Jr., J. Klindt, and A. J. Roberts. 1996. Insulin-like growth factor I and insulin-like growth factorbinding proteins in bovine serum and follicular fluid before and

CHRONIC ADMINISTRATION OF IGF-I AND(OR) GH after preovulatory surge of luteinizing hormone. Biol. Reprod. 55:1390−1396. Grant, A. L., W. G. Helferich, S. A. Kramer, R. A. Merkel, and W. G. Bergen. 1991. Administration of growth hormone to pigs alters the relative amount of insulin-like growth factor-I mRNA in liver and skeletal muscle. J. Endocrinol. 130:331−338. Guler, H. P., J. Zapf, E. Scheiwiller, and E. R. Froesch. 1988. Recombinant human insulin-like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc. Natl. Acad. Sci. 85:4889. Hua, K. M., R. Ord, S. Kirk, Q. J. Li, S. C. Hodgkinson, G.S.G. Spencer, P. C. Molan, and J. J. Bass. 1993. Regulation of plasma and tissue levels of insulin-like growth factor-I by nutrition and treatment with growth hormone in sheep. J. Endocrinol. 136:217−224. Jones, J. L., and D. R. Clemmons. 1995. Insulin-like growth factors and their binding proteins: Biological actions. Endocr. Rev. 16: 3−34. Klindt, J., F. C. Buonomo, and J. T. Yen. 1992. Administration of porcine somatotropin by sustained-release implant: Growth and endocrine responses in genetically lean and obese barrows and gilts. J. Anim. Sci. 70:3721−3733. Klindt, J., F. C. Buonomo, and J. T. Yen. 1994. Influence of porcine somatotropin administration and sex on glucose and endocrine responses in obese pigs. Proc. Soc. Exp. Biol. Med. 207:48−56. Klindt, J., F. C. Buonomo, J. T. Yen, W. G. Pond, and H. J. Mersmann. 1995. Administration of porcine somatotropin by daily injection: Growth and endocrine responses in genetically lean and obese barrows and gilts. J. Anim. Sci. 73:3294−3303. Klindt, J., J. J. Ford, J. G. Berardinelli, and L. L. Anderson. 1983. Growth hormone secretion after hypophyseal stalk transection in pigs. Proc. Soc. Exp. Biol. Med. 172:508−513. Leymaster, K. A., and T. G. Jenkins. 1985. Characterization of accretive rates for growth constituents in male Suffolk sheep. J. Anim. Sci. 61:430−435.

2381

Min, S. H., D.D.S. MacKenzie, B. H. Breier, S. N. McCutcheon, and P. D. Gluckman. 1996. Responses of young energy-restricted sheep to chronically administered insulin-like growth factor I (IGF-I): Evidence that IGF-I suppresses the hepatic growth hormone receptor. Endocrinology 137:1129−1137. NAMP. 1997. The Meat Buyers Guide. North American Meat Processors Association, Reston, VA. NRC. 1988. Nutrient Requirements of Swine (9th Ed.). National Academic Press, Washington, DC. Owens, P. C., R. G. Campbell, G. L. Francis, and K. J. Quinn. 1994. Growth hormone, gender and insulin-like growth factors: Relationship to growth performance in pigs. J. Anim. Sci. 72(Suppl. 1):253. Pell, J. M., and P. C. Bates. 1992. Differential actions of growth hormone and insulin-like growth factor-I on tissue protein metabolism in dwarf mice. Endocrinology 130:1942−1950. Rechler, M. M. 1997. Editorial: Growth inhibition by insulin-like growth factor (IGF) binding protein-3—what’s IGF got to do with it. Endocrinology 138:2645−2647. SAS. 1989. SAS/STAT User’s Guide (Version 6, 4th Ed.). SAS Inst. Inc., Cary, NC. Walton, P. E., F. R. Dunshea, and F. J. Ballard. 1995. In vivo actions of IGF analogues with poor affinities for IGFBPs: Metabolic and growth effects in pigs of different ages and GH responsiveness. Prog. Growth Factor Res. 6:385−395. Walton, P. E., P. C. Owens, S. E. Knowles, and V. Dunaiski. 1994. Metabolic actions and roles of IGF-I and IGF-I analogs in growth regulation in pigs. J. Anim. Sci. 72(Suppl. 1):253. Whittemore, C. T., and F.W.H. Elsley. 1976. Practical Swine Nutrition. Farming Press Limited. Ipswich, Suffolk. Wolverton, C. K., M. J. Azain, J. Y. Duffy, M. E. White, and T. G. Ramsay. 1992. Influence of somatotropin on lipid metabolism and IGF gene expression in porcine adipose tissue. Am. J. Physiol. 263:E637−E645.