126 I
. Louveau et al. Livestock Production Science 66 2000 121 –131
5. Interactions between nutrition, hormones and Thus, plasma T concentrations, hepatic 59-deiodin-
3
development ase activity and nuclear TR levels in liver and
muscle can all be modified by the amount of food 5.1. Effect of milk intake
eaten and the ambient temperature during the first 48 to 54 h after birth. Skeletal muscle nuclear TR
5.1.1. Immediate effects binding capacity is also lower in intrauterine growth-
Nutritional status during the period immediately restricted IUGR piglets compared with control
after birth can markedly affect the GH–IGF axis. littermates, and this may explain their reduced
Fasting for the first 24 h results in a decrease in metabolic rate and lower respiratory enzyme ac-
serum IGF-I concentration Campion et al., 1986. It tivities Dauncey and Geers, 1990. Our recent
also causes a decline in serum IGFBP-3, IGFBP-2 results also show that TR isoform mRNA expression
and the M 24 000 IGFBP-4 McCusker et al., 1985. is profoundly affected by IUGR in all four striated
r
Energy and fat intake also have a profound influence muscles investigated White and Dauncey, unpub-
on the tissue-specific mRNA expression of IGF-I, lished data. The extent to which these isoforms can
IGF-II and GHR Dauncey, Burton and Le Dividich, also be affected by nutrition in the period immedi-
unpublished data. Piglets were fed every hour a low ately after birth remains to be investigated.
or high food intake 5 or 15 g colostrum kg body weight feed with 4 or 8 fat content during the
5.1.2. Medium-term effects first 36 h postnatally. In liver, muscle and heart, the
Both moderate
and severe
food restriction
increase in IGF-I mRNA expression levels which Dauncey et al., 1994a; Louveau, 1998 decrease
occurred in all animals was greatest in those on the plasma IGF-I and IGFBP-3 concentrations. As ob-
high food intake, and in liver this response was even served in older animals, there is increasing evidence
greater in animals on the high fat intake. For IGF-II, that circulating IGF-I is directly related to energy
the inverse response was seen, for example, with the intake in neonatal pigs. At 14 days of age, plasma
decrease in hepatic IGF-II mRNA being greatest in IGF-I concentrations do not differ between IUGR
animals on the high food intake and with 8 fat and control littermate piglets that were pair fed
content. For GHR, the pattern of response was Dauncey et al., 1994a; Ritacco et al., 1997. Plasma
similar to that observed in pigs aged 3 to 7 weeks IGF-I concentrations increase with energy intake in
Dauncey et al., 1994b, in that the highest nutrition 7-day-old pigs Louveau and Le Dividich, unpub-
high food and 8 fat intake resulted in higher lished data. Piglets that were bottle-fed isoenergetic
hepatic mRNA levels and lower muscle mRNA amounts of maternal milk or milk replacer for 7 days
levels compared with animals on the lowest nutrition after birth have similar plasma IGF-I concentrations.
low food and 4 fat diet. This resulted, for However, they have lower plasma IGF-I concen-
example, in the high food intake preventing the fall trations than their littermates that were reared by the
in hepatic GHR which otherwise occurred during the sow and that consumed 28 more milk Louveau
neonatal period. Thus, these results clearly demon- and Le Dividich, unpublished data.
strate that nutrition in the period immediately after The effects on IGF and GH receptor levels have
birth can markedly alter the potential for optimal been studied less extensively, although our recent
postnatal growth. investigations are starting to elucidate some of the
Serum concentrations of insulin and T were non- responses involved. For example, whereas moderate
4
detectable or lower in non-suckled piglets when food restriction induced by a larger litter size does
compared with suckled piglets, while serum GH not significantly affect GHR, it decreases IGF-IR in
concentrations were higher in the non-suckled piglets liver but not in skeletal muscle Louveau, 1998.
and serum T was not influenced by nutritional status Severe food restriction from birth to 7 days of age
3
Campion et al., 1986. However, more recent decreases GHR in liver but not in skeletal muscle,
studies have shown that energy intake, especially in and increases IGF-IR in skeletal muscle but not in
relation to energy demand, can influence THs in the liver Louveau and Le Dividich, unpublished data.
neonate Herpin et al., 1995; Berthon et al., 1996. The results from these studies clearly indicate that
I . Louveau et al. Livestock Production Science 66 2000 121 –131
127
the regulation of the receptors is tissue specific and in several recent studies of newborn animals fed
dependent on the type of undernutrition. Moreover, various combinations of colostrum, mature milk or
age and stage of development are also likely to be milk formula supplemented with IGF-I.
important because a low food intake in pigs aged between 3 and 7 weeks results in down-regulation of
5.2.1. Intestinal absorption of milk-borne IGF-I hepatic but an upregulation of muscle GHR mRNA
The basic question regarding the possible action of Dauncey et al., 1994b, which is reflected in a
milk-borne IGF-I on growth and development is marked decrease in hepatic IGF-I mRNA and growth
whether it survives digestion and is absorbed into the rate Weller et al., 1994.
peripheral circulation in a biologically active form. There are marked effects of food intake on the
Two studies have assessed absorption of milk-borne
125
thyroid axis postnatally: a low intake reduces thyroid IGF-I by direct measurements of
I-IGF-I adminis- gland activity, circulating TH concentrations and
tered orally to colostrum-fed Xu and Wang, 1996 nuclear TR abundance in muscle Dauncey, 1990;
or formula-fed Donovan et al., 1997 neonatal pigs Morovat and Dauncey, 1995. Moreover, a major
Table 3. Although these two studies indicate that
125
effect of undernutrition on expression of cardiac orally-administered
I-IGF-I can be absorbed into TRa isoforms during the first 1–2 months after birth
the wall of the gastrointestinal tract and into the has been reported White and Dauncey, 1998.
circulation, it is not clear whether absorbed IGF-I Considerable attention now needs to be focussed on
contributes significantly to circulating IGF-I con- the first 1–2 weeks postnatally because this period
centration. Other studies indicate that colostrum- may be especially important for long-term develop-
deprived piglets that were fed sow’s milk replacer ment Dauncey, 1997.
alone or supplemented with recombinant human IGF-I for 4 Burrin et al., 1996 or 14 days Houle et
5.2. Possible role of milk-borne growth factors in al., 1997 had similar serum IGF-I concentrations.
neonatal development Similarly, plasma IGF-I concentrations did not differ
between piglets that were fed isoenergetically for 7 The physiological role of milk-borne growth fac-
days either maternal milk or milk replacer which tors is not yet fully understood. Whether they are
contained no IGF-I Louveau and Le Dividich, absorbed by the gastrointestinal tract and subsequent-
unpublished data. In contrast to these studies, it has ly affect growth and development has been evaluated
been shown that neonatal pigs fed colostrum for 18 h
Table 3 Summary of studies investigating the possible absorption of milk-borne insulin-like growth factor-I IGF-I in the neonatal pig
Animal model diet Duration of the study
Plasma IGF-I Ref.
125
Newborn unsuckled or 1 day
I-IGF-I detected Xu and Wang 1996
3-day-old suckled
125
1 I-IGF-I 3 mg kg BW in colostrum
125
Newborn unsuckled 1 day
I-IGF-I detected Donovan et al. 1997
125
1 I-IGF-I 100 ng in formula
Formula or Birth to 4 days
↔ Burrin et al. 1996
formula 1 IGF-I 3.5 mg kg day Formula or
Birth to 14 days ↔
Houle et al. 1997 formula 1 IGF-I 200 mg kg day
Colostrum vs. formula Birth to 1 day
↑ Wester et al. 1998b
Maternal milk or formula Birth to 7 days
↔ Louveau and Le Dividich unpublished data
128 I
. Louveau et al. Livestock Production Science 66 2000 121 –131
have higher plasma IGF-I concentrations than pigs 5.2.3. Role in protein synthesis
fed milk replacer Wester et al., 1998b. Taken Colostrum has specific effects on protein synthesis
together, the available data indicate that the physio- in gastrointestinal and peripheral tissues. In neonates,
logical significance of intestinal absorption of IGF-I the rate of protein synthesis is 50 higher in skeletal
remains unclear. The studies that have investigated muscle of pigs given colostrum compared with
the role of IGF-I by adding it to a milk replacer that mature milk during the first 6 h of feeding Burrin et
is devoid of bioactive components represent a sim- al., 1992. Protein synthesis rates in the jejunum, and
plified picture since the interactions between IGF and the longissimus dorsi and gastrocnemius muscles
IGFBP are omitted. Therefore, further studies are were higher in colostrum-fed pigs than those fed
needed to determine whether pigs fed colostrum have either mature milk or formula with a nutrient com-
higher plasma IGF-I concentrations than those fed position similar to that of colostrum but essentially
mature milk. devoid of growth factors Burrin et al., 1995. There
were no differences in the protein synthesis rates of 5.2.2. Role in growth and development
the ileum, stomach and pancreas between the three When piglets were fed IGF-I at a pharmacological
treatment groups. level 3.5 mg kg day for 4 days postpartum, they
tended to gain more weight and have heavier livers 5.2.4. Role in the gastrointestinal tract
and spleens than did control animals Burrin et al., Recent studies in neonatal pigs provide increasing
1996. By contrast, piglets that were pair fed milk evidence that milk-borne growth factors significantly
formula with or without a physiological supplement affect gastrointestinal growth and development. The
of IGF-I 200 mg kg day for 7 or 14 days post- apical membranes of the small intestine contain
partum had similar final body and organ weights functional receptors for IGF-I, suggesting that the
Houle et al., 1997. Similarly, piglets isoenergetical- developing intestine is a major target of these growth
ly fed maternal milk colostrum followed by mature factors Schober et al., 1990. Several studies in
milk or formula milk for 7 days had similar final which IGF-I or IGF-II were administered orally have
body weight and growth rate Louveau and Le been reported. Oral administration of a pharmaco-
Dividich, unpublished data. In that experiment, logical dose of IGF-I 3.5 mg kg day to formula-
formula milk increased the pool of stromal-vascular fed pigs from birth to 4 days of age resulted in an
cells and their proliferative capacity while it de- increase in the small intestinal weight, and protein
creased their potential of differentiation in primary and DNA contents, but no significant differences
culture, compared with maternal milk Gerfault et within the other digestive organs Burrin et al.,
al., 2000. This suggests that the type of neonatal 1996. In contrast, no significant differences in
feeding may influence subsequent development of intestinal weight, length or protein content occurred
adipose tissue. Moreover, our recent evidence sug- when piglets consumed formula supplemented with
gests that it may also influence muscle development IGF-I at a dose of 200 mg kg day, which was
Dauncey, Burton and Le Dividich, unpublished approximately twice that found in colostrum Houle
data. Tissue levels of GHR and IGF mRNA were et al., 1997. Although this lower dose of IGF-I does
determined in neonates isoenergetically fed during not increase total intestinal weight, significant differ-
the next 36 h on colostrum, mature milk which has a ences in villus height and digestive enzyme activities
very low IGF-I content or mature milk sup- were observed in comparison with controls fed
plemented with IGF-I to the same level or twice the formula without an IGF-I supplement. Lactase and
level of that in colostrum. There were no clear-cut sucrase activities were higher in IGF-I-treated than in
effects on hepatic mRNA levels. However, the IGF control animals. Newborn colostrum-deprived piglets
mRNA levels in muscle tended to be greater in that were fed formula supplemented with IGF-I 440
animals fed either colostrum or milk supplemented mg kg day for the first 24 h postpartum have
with IGF-I, compared with those fed mature milk similar digestive organ weights to control formula-
alone. Whether these differences in muscle IGF gene fed piglets, with the exception of the pancreas which
expression affect its cellular differentiation and was heavier in animals given the formula sup-
proliferation now needs to be determined. plemented with IGF-I Xu et al., 1994. This IGF-I
I . Louveau et al. Livestock Production Science 66 2000 121 –131
129 nutrient dependent factors stimulate protein synthesis in colos-
treatment also stimulated cell proliferation in the
trum-fed newborn pigs. Pediatr. Res. 37, 593–599.
small intestinal crypts Xu et al., 1994 and in the
Burrin, D.G., Wester, T.J., Davis, T.A., Amick, S., Heath, J.P.,
oesophagus Xu et al., 1996.
1996. Orally administered IGF-I increases intestinal mucosal growth in formula-fed neonatal pigs. Am. J. Physiol. 270,
R1085–1091. Campion, D.R., McCusker, R.H., Buonomo, F.C., Jones, Jr. W.K.,
6. Conclusions
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