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Department of Animal and Grassland Research, National Agricultural Research Centre for Kyushu Okinawa Region, Kumamoto 861-1192, Japan and * The Babraham Institute, Cambridge CB2 4AT, UK
3To whom correspondence should be addressed. E-mail: masaya{at}affrc.go.jp.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • dietary lysine • insulin-like growth factor-I • insulin-like growth factor-binding protein-3 • mRNA expression • pigs
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3
) and IGF-I (1
,3
–5
); consequently, circulating IGF-I is also reduced.
Nutritional protein status also exerts strong effects on the GH-IGF axis. Feeding a protein-free or low protein diet to rats reduces body weight gain, hepatic IGF-I mRNA expression and circulating levels of IGF-I (6
–9
). Similarly, a low protein diet reduces IGF-I mRNA expression and plasma IGF-I level in larger animals such as sheep (4
). Moreover, protein quality also affects IGF-I expression. Both plasma IGF-I concentration and IGF-I mRNA expression in the liver of rats fed a gluten-based diet (120 g gluten/kg diet) are lower than those of rats fed a casein-based diet (120 g casein/kg diet) (9
).
Many previous studies of the influence of food intake in regulating the GH-IGF axis provided no information about the role of specific nutrients. Moreover, previous studies of the influence of protein status on the GH-IGF axis did not control food intake. Dietary protein deprivation can result in either an increase or decrease in food intake (8
,9
). Thus, it is impossible to determine whether impaired activity of the GH-IGF axis due to dietary protein deprivation results from different levels of dietary protein, differences in quality of dietary protein or differences in food intake.
In cultured hepatocytes, amino acid concentration affects GHR and IGF-I expression (10
–14
). Primary cultures of ovine hepatocytes in a medium containing free amino acids at a fivefold higher concentration than in venous blood of fed sheep exhibited significantly greater IGF-I release than did hepatocytes grown in a medium containing one fifth, or levels of amino acids identical to those in vivo (13
). Moreover, removal of glucose or some specific amino acids from the culture medium reduced GHR mRNA and IGF-I mRNA expression in cultured porcine hepatocytes (14
). Although these observations were obtained in experiments using cultured hepatocytes, they suggest that specific nutrients such as glucose or amino acids may individually affect the activity of the GH-IGF-I axis in vivo.
The aim of the present study was therefore to elucidate the influence of lysine, a major limiting amino acid in animal and human diets, in isoenergetic and isoprotein diets on the activity of GH-IGF-I axis, and specifically on hepatic GHR and IGF-I gene expression and plasma IGF-I level. In addition, the influence of dietary lysine level on plasma IGF binding protein (IGFBP) profiles was also determined, and discussed in relation to its influence on plasma IGF-I.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Six litters of pigs, Duroc x (Large White x Landrace), were investigated. Pigs were weaned at 4 wk of age, and two males of similar body weight were then selected from each litter. They were transferred to an air-conditioned room 1 wk before the study, housed in pairs for the first 1–2 d and then kept in separate pens to allow careful control of food intake and ambient temperature. At 6 wk of age, each littermate was assigned to one of two diets, control or low lysine (LL; Table 1
). A basal diet containing 180 g protein/kg diet was first formulated. For the control diet, additional lysine was then added to give a level of 5.8 g/kg diet to meet the requirement for lysine. This added lysine was replaced by added cornstarch in the LL diet. Thus, the crude protein contents were 185and 180 g/kg for the control and LL diets, respectively. The control diet contained all essential amino acids in the recommended amounts (15
) as follows (g/kg): arginine, 8.2; histidine, 4.6; isoleucine, 7.4; leucine, 16.3; methionine, 4.5; cystine, 3.1; phenylalanine, 9.0; tyrosine, 6.6; threonine, 8.3; tryptophan, 2.2; valine, 8.8; and lysine, 11.5. The LL diet was similar to the control diet but contained only 7 g lysine/kg. The diets were isoenergetic, providing 14.3 MJ digestible energy, 73 g crude fat, and 25 g acid detergent fiber per kg diet. The pigs were housed at an ambient temperature of 26°C, which is close to thermal neutrality, for the 3-wk experiment. A pair-feeding protocol was used. The amount of food was increased as the pigs grew, and the final daily intake was 900 g. The food was provided as two meals per day, at 0900 and 1600 h, and water was freely available.
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Assessment of plasma IGF-I and IGFBP concentrations.
Plasma IGF-I concentration was measured by RIA with an IGF-I reagent pack (Amersham Pharmacia Biotech, Little Chalfont, UK) consisting of rabbit anti-hIGF-I and 125I-iodotyrosyl-hIGF-I. Recombinant hIGF-I (PeproTech, Rocky Hill, NJ) was used as standard. Before the assay, IGF-I was extracted by acid-ethanol cryoprecipitation (16
). IGFBP profiles were quantified by densitometry (Densitograph, Atto, Tokyo, Japan) after SDS-PAGE separation, Western blot analysis and probing with 125I-IGF-I, as described previously (17
). Due to hemolysis of a blood sample from one pig in the LL group, analysis of plasma IGFBP profiles was undertaken in five littermate pairs of pigs.
Assessment of GHR and IGF-I mRNA expression.
The methods for total RNA extraction and RNase protection assay have been described in detail previously (18
–20
). Total RNA was extracted from 0.5-g samples of frozen tissue using the guanidine thiocyanate method (21
) and quantified by measuring absorbance at 260 nm. The integrity of total RNA was routinely checked by agarose gel electrophoresis and ethidium bromide staining of the two ribosomal RNA bands. RNase protection assays were carried out in duplicate with 50 µg total RNA extracted from each tissue. Samples were hybridized with a small molar excess of the radiolabeled antisense GHR or class 2 IGF-I riboprobes (3
,18
,22
) to ensure linearity of the assay with respect to RNA. After 16 h of hybridization at 45°C, excess nonprotected RNA was digested with RNase A (50 mg/L, 
1 U/sample) and RNase T1 (30 x 104 U/L, 80 U/sample). The protected hybridization products were purified by extraction in phenol/chloroform/isoamyl alcohol (25:24:1) and separated on 6% polyacrylamide sequencing gels. The dried gels were exposed to X-ray film at -80°C, and relative intensities of the protected bands were quantified by densitometry (Densitograph, Atto).
Statistical analysis.
Statistical significances between the two treatment groups were assessed by paired t test using the UNIVARIATE procedure of SAS (23
). Results are presented as means ± SD. Differences with probabilities of < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Despite equal total energy and protein intakes, growth rates were slower in pigs fed the LL compared with the control diet (P < 0.001; Table 2
). Furthermore, feed efficiency was also lower in pigs fed the LL diet (P < 0.01).
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Consistent with the lower growth rates and efficiencies of growth, plasma IGF-I levels were lower in pigs fed the LL diet (P < 0.01) A representative autoradiograph of plasma IGFBP profiles obtained from two littermate pairs of pigs is presented in Figure 1
. Distinct bands were observed with molecular weights of 26, 33 and a doublet at 45–50 kDa, corresponding to IGFBP1, IGFBP2 and IGFBP3, respectively; IGFBP3 was quantified as the sum of the doublet (17
). No clear-cut effects due to dietary lysine were observed in plasma levels of IGFBP1 and IGFBP2. However, pigs fed the LL diet had lower plasma IGFBP3 levels (P < 0.05) than their littermates fed the control diet (Fig. 2
).
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Figure 3
presents results from RNase protection analysis of GHR mRNA in liver and l. dorsi muscle. The abundance of hepatic GHR mRNA in pigs on the LL diet tended to be lower than in controls (P = 0.099). By contrast, the LL diet elevated GHR mRNA in l. dorsi muscle (P < 0.05). Figure 4
presents an autoradiograph obtained using the class 2–specific riboprobe for porcine IGF-I, showing protected bands of 190 and 147 bp. Transcription of the IGF-I gene yields two distinct IGF-I mRNA classes: exons 1 and 2 encode leader sequence and are differentially spliced to exon 3 to produce class 1 and 2 transcripts, respectively. Essentially all of the IGF-I mRNA in both liver and muscle is accounted for by these two transcripts. We have shown previously that, when using the class 2–specific probe, the bands at 147 and 190 bp represent class 1 and 2 transcripts, respectively (3
,18
). Figure 5
presents results for the effects of dietary lysine levels on hepatic class 1, class 2 and total IGF-I mRNA expression in liver. Dietary lysine level did not affect any of these estimates of IGF-I mRNA abundance. Moreover, IGF-I mRNA expression in l. dorsi muscle did not differ between the two dietary treatment groups (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Regulation of the IGF-I axis by nutrition.
Potential mechanisms underlying the reduction in plasma IGF-I with no change in IGF-I mRNA by low dietary lysine include suppression of post-transcriptional events in IGF-I expression and differences in IGF-I clearance from plasma. Injections of pharmacologic doses of GH to intact rats restricted in dietary protein for 1 wk restored hepatic IGF-I mRNA without normalization of serum IGF-I concentration (24
). Furthermore, a single injection of GH to hypophysectomized rats fed a 50 g/kg casein low protein diet increased IGF-I mRNA but did not restore the lowered serum IGF-I level. This suggested that the mechanism involved in transcription of the hepatic IGF-I gene was not affected in the protein-restricted rats, because they had a normal IGF-I mRNA response to high doses of GH. It was suggested that delayed translation of IGF-I mRNA or enhanced serum IGF-I clearance could explain the low serum IGF-I concentrations during dietary protein restriction. Such mechanisms may also underlie the reduction in plasma IGF-I concentrations in young pigs fed the LL diet despite normal hepatic IGF-I mRNA levels. Although no direct evidence supporting a reduction in translation rate is available, Western ligand blotting showed that the principal binding protein of IGF-I in blood, IGFBP3, was significantly reduced in pigs fed the LL diet. The IGF-IGFBP3-acid labile subunit complex functions as a storage pool for circulating IGF and prolongs the half-life of IGF-I from <10 min in the free, unbound state to 15 h for the complex (25
). Not only does a low protein diet decrease serum IGFBP3 level (26
), but clearance rates of radiolabeled IGF-I are greater in pigs fed a low protein diet (27
). Although it is not known whether specific amino acids can affect the clearance rate of IGF-I, this likely was higher in pigs fed the LL diet as a result of a decrease in plasma IGFBP3, and this greater clearance rate probably induced the reduction in plasma IGF-I. The mechanisms underlying the reduction in plasma IGFBP3 are not known. Total energy restriction decreased hepatic IGFBP3 mRNA in neonatal rats (28
) but no studies have determined whether specific dietary amino acids can affect IGFBP3 gene expression. Furthermore, IGF-I is itself an important regulator of IGFBP3 (29
). Therefore, whether the decreased circulating IGF-I level itself had a role in reducing plasma IGFBP3 in pigs fed the LL diet remains to be investigated.
In cultured porcine hepatocytes, only very low concentrations of lysine are necessary for maximum expression of IGF-I mRNA (14
). This observation in vitro may help in interpreting our in vivo findings. The lysine concentration of 7 g/kg in the LL diet was 0.6 of the recommended lysine level of 11.5 g/kg for pigs of body weight similar to those in the present study (15
). This moderate restriction of dietary lysine may be adequate for maintaining normal levels of hepatic IGF-I mRNA. Furthermore, in contrast with previous studies of the effects of undernutrition or dietary protein restriction, intakes of energy and all essential amino acids other than lysine of the LL and control pigs were the same. Thus, the magnitude of dietary restriction in the present study seemed to be great enough to impair growth and suppress plasma IGF-I, but not severe enough to affect hepatic IGF-I mRNA expression. This in turn suggests that the mechanisms regulating plasma IGF-I level are more sensitive to dietary amino acids than those regulating hepatic IGF-I mRNA expression.
Extrahepatic tissues express high levels of IGF-I mRNA, suggesting that the reduction in plasma IGF-I concentrations in pigs fed the LL diet may have been due to reduced IGF-I mRNA expression in tissues other than liver. To test this possibility, levels of IGF-I mRNA expression were determined in l. dorsi muscle. However, IGF-I expression in the muscle did not differ between the two dietary treatment groups (data not shown). There remains the possibility that IGF-I mRNA expression in tissues other than liver and l. dorsi muscle were affected by the LL diet. Thus, the effects of a single amino acid deficiency on IGF-I gene expression in other tissues such as adipose remain to be investigated.
Regulation of GHR by nutrition: implications for glucose homeostasis.
We showed previously that undernutrition induces tissue-specific changes in GHR mRNA, i.e., hepatic levels are down-regulated, whereas in muscle, they are up-regulated (2
,20
). This observation has now been extended by the present finding that a reduction in a single dietary amino acid tends to decrease GHR mRNA in liver but increase its abundance in muscle. This tissue-specific regulation of GHR mRNA expression in response to nutritional status is consistent with the distinct physiologic roles of GHR in these two tissues. In liver, GHR has a major somatogenic role via induction of IGF-I gene expression, whereas in muscle it has an important metabolic role and enhances oxidative capacity. In general, the metabolic actions of muscle GH are anti-insulin and act to divert energy from muscle; up-regulation of GHR mRNA expression in response to low food intake can be viewed as an adaptation that spares neural and bone growth at the expense of muscle growth (20
). Moreover, in food-restricted animals, there is an increase in gene expression of the insulin-dependent glucose transporter, GLUT4, but a reduction in insulin-stimulated glucose uptake in muscle (30
). We recently found that low dietary lysine also up-regulates muscle GLUT4 mRNA expression (31
). Taken together, these results suggest an underlying coordinated mechanism that controls glucose homeostasis by regulating gene expression of GHR and GLUT4 during undernutrition or dietary essential amino acid deficiency.
Although GHR mRNA expression in liver tended to be reduced in pigs fed the LL diet, this diet did not also down-regulate hepatic IGF-I mRNA expression. This apparent paradox may be related to the multiple functions of GH. In addition to its somatogenic role, GH also is involved in controlling glucose metabolism in the liver by regulating gluconeogenesis and glycogen accumulation (32
,33
). Thus, we propose that although the somatogenic function of GH in the liver was not impaired by a reduction in dietary lysine, amino acid intake may affect the metabolic functions of GH.
The present findings suggest that the appropriate dietary intake of even a single amino acid is extremely important for maintenance of normal circulating levels of plasma IGF-I and optimal growth. The reduction in plasma IGF-I levels caused by reduced dietary lysine level may have been due in part to suppression of post-transcriptional events in IGF-I expression. Moreover, increased clearance rates of circulating IGF-I may also have been involved. Finally, the present study suggests that plasma IGF-I level is a more sensitive indicator than hepatic IGF-I mRNA expression of the potential influence of nutritional status on postnatal development.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Funded by National Agricultural Research Centre for Kyushu Okinawa Region, National Agricultural Research Organization; Japan Science and Technology Cooperation (S.K.); and Biotechnology and Biological Sciences Research Council (The Babraham Institute, M.J.D). This work was also supported by a research grant from Bio-design Project of the Ministry of Agriculture, Fisheries and Forestry, Japan .
4 Present address: National Institute of Livestock and Grassland Sciences, National Agricultural Research Organization Tsukuba 305, Japan.
5 Abbreviations used: GH, growth hormone; GHR, growth hormone receptor; GLUT, glucose transporter; IGF-I, insulin-like growth factor-I; IGFBP, insulin-like growth factor binding protein; l. dorsi, longissimus dorsi; LL, low lysine.
Manuscript received 13 August 2001. Initial review completed 17 November 2001. Revision accepted 11 January 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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