I . Louveau et al. Livestock Production Science 66 2000 121 –131
123 Table 2
1991. The GHR was first purified, sequenced and
Proximate composition of suckled piglets from birth to 21 days of
cloned from rabbit liver Leung et al., 1987. Sub-
age
sequently, the cDNA for the GHR has been cloned in
Age days
several other species including pigs Cioffi et al.,
a a
b c
Birth 1
7 21
1990. GHR is a transmembrane protein encoded by nine exons. Receptors are highly expressed in liver
Moisture, 80.5
79.2 74.6
68.2
but are also found in many other tissues Louveau
Crude protein N 3 6.25, 10.7
12.4 15.9
14.9 Fat,
1.7 2.3
4.6 11.3
and Etherton, 1992; S¢rensen et al., 1992; Lee et al.,
Gross energy kcal g 0.84
0.93 1.36
2.06
1993. The GHR is able to associate with and
a
Le Dividich et al. 1997a.
activate the tyrosine kinase JAK2 that in turn
b
Marion and Le Dividich unpublished data.
activates a number of intracellular pathways Wojcik
c
Noblet and Etienne 1987.
and Postel-Vinay, 1999. In addition to the membrane-bound GHR, a
GHBP, which essentially corresponds to the extracel- Major body composition changes begin early in
lular domain of the GHR Leung et al., 1987, has the neonatal period Table 2. At 24 h postpartum,
been identified in the serum of many species includ- fat and protein percentages have both increased
ing pigs Davis et al., 1992. GHBP is derived from significantly, with the increase in body fat being
the same gene as GHR and is generated by mecha- especially marked. Fat percentage continues to in-
nisms that differ between species Bauman, 1995. crease throughout the first 3 weeks whereas protein
Little is known about the physiological role of this content remains nearly constant after 2 weeks of age.
GHBP. It has been shown to enhance the growth- Body fat is derived primarily from dietary fat and
promoting effects of GH in vivo probably by increas- hence accretion of both fat and protein are highly
ing the half-life of GH in the circulation. dependent on the intake of milk fat and protein.
Between birth and 7 days of age, the regression 4.1.2. IGF, IGF receptors IGFRs and IGF
equations relating accreted protein aP and fat aF binding proteins
IGFBPs to protein Pi and fat intake Fi are as follows: aP
IGF-I and IGF-II are M | 7500 single-chain poly-
r 2
g day 5 0.96Pi g day 2 0.48 R 5 0.99; and aF peptides that retain 70 amino acid homology with
2
g day 5 0.58Fi g day 2 6.8 R 5 0.93 Marion each other and 50 homology with proinsulin. The
and Le Dividich, 1999, unpublished data. During the IGF amino acid sequence is highly conserved across
3-week suckling period, Noblet and Etienne 1987 species, showing 100 identity between human,
found that 88 and 54 of milk protein and fat intake, porcine and bovine IGF-I Tavakkol et al., 1988.
respectively, was retained in the body. While the growth-promoting properties of IGF-I are
well established, the biological significance of IGF-II postnatally is less clear. However, primary cultures
4. Hormonal control of neonatal growth of skeletal muscle satellite cells, the postnatal
myogenic precursor cells, can be induced to prolifer- 4.1. The GH–IGF axis
ate by exposure to physiological levels of IGF-II Dodson et al., 1985, suggesting an important role
4.1.1. GH, GH receptor GHR and GH binding for IGF-II in the control of postnatal muscle growth.
protein GHBP
IGF-I is predominantly synthesised by the liver GH is a molecular mass M 22 000 polypeptide
under the influence of GH. Local production of both
r
hormone released from the anterior pituitary gland. IGF-I and IGF-II has also been demonstrated in
Both the synthesis and release of GH are pulsatile. numerous other tissues and organs.
The first step in GH action is binding to a specific IGF-I and IGF-II interact with two types of
cell surface receptor GHR that belongs to the receptors, type I and type II, that differ in their
superfamily of cytokine receptors Kelly et al., amino acid sequence, secondary structure, ligand-
124 I
. Louveau et al. Livestock Production Science 66 2000 121 –131
binding specificity and signalling mechanism Re- and early postnatal periods, with the extent of the
chler and Nissley, 1985; Jones and Clemmons, change being dependent on diet. For example, during
1995. The type I receptor has a heterotetrameric the first 36 h, IGF-I mRNA levels increase whereas
structure which is homologous to that of the insulin IGF-II mRNA levels decline after birth in liver,
receptor. The type II receptor is a monomeric skeletal muscle and heart Kampman et al., 1993;
protein. IGF-I receptors IGF-IR are expressed in a Dauncey, Burton and Le Dividich, unpublished data.
wide variety of cell types Jones and Clemmons, The IGFBP profile of newborn pig serum is
1995. similar to that of 110-day foetal serum in which the
The IGFs are present in all biological fluids, M 34 000 IGFBP-2 predominates. After 24 h of
r
almost entirely 95 to 99 bound to a family of feeding, the IGFBP profile changes towards a pattern
structurally-related binding proteins IGFBPs. To that is more similar to a peripubertal animal
date, six genetically distinct IGFBPs IGFBP-1 to McCusker et al., 1985. The abundance of plasma
IGFBP-6 have been cloned and sequenced Jones IGFBP-3 increases with increasing plasma IGF-I
and Clemmons, 1995; Rajaram et al., 1997; Hwa et concentration Lee et al., 1991. IGFBP-2 is two- to
al., 1999, and five of them have been identified in three-fold more abundant in foetal than in postnatal
pigs McCusker et al., 1985; Coleman et al., 1991. serum McCusker et al., 1991; Lee et al., 1993, and
In adults, most of the bound serum IGFs are present hepatic IGFBP-2 mRNA levels decline postnatally
in an M 150 000 complex that contains IGFBP-3 Kampman et al., 1993; Lee et al., 1993.
r
and an additional M 85 000 protein known as the The postnatal rise in plasma IGF-I concentration is
r
acid-labile subunit ALS. Marked changes in the associated with a developmental increase in hepatic
relative proportions of circulating IGFBP occur with GHR Breier et al., 1989; Schnoebelen-Combes et
age and, in 2-month-old pigs, both IGFBP-3 and al., 1996 and plasma GHBP concentrations Mullins
IGFBP-2 contribute the major portion of plasma IGF and Davis, 1992, Schnoebelen-Combes et al., 1996.
binding activity Dauncey et al., 1993; changes The expression of GHR is tissue- and perhaps cell-
during the perinatal period are discussed in the next specific. The GHR is expressed at a much earlier
section. The IGFBP differ in their regulation and stage of development in muscle than in liver and,
their affinities for IGF-I and IGF-II. In addition to postnatally, the ontogenic profiles differ between
serving as carrier proteins M 150 000 complex, these
two tissues
Duchamp et
al., 1996;
r
they modulate the interactions of IGF with their Schnoebelen-Combes et al., 1996. IGF-IR in liver,
target tissues. kidney and skeletal muscle decline markedly after
birth Lee et al., 1993; Louveau et al., 1996; Peng et 4.1.3. GH, IGF and their binding proteins and
al., 1996. In the small intestine, IGF-I binding is receptors during foetal and neonatal development
highest at birth, declines by day 3 and increases by Numerous changes occur during the neonatal
day 21 Schober et al., 1990. period at many levels of the somatotrophic axis.
During the first 2–3 days postnatally, plasma GH 4.1.4. Function of the somatotrophic axis in the
concentrations decrease
sharply Klindt,
1986; neonate
Scanes et al., 1987; Carrol et al., 1998. Plasma Although the somatotrophic axis is considered to
IGF-I concentration increases significantly during the be essential for postnatal growth, it is widely
first 3 weeks of postnatal life in pigs Lee et al., believed that its role in neonatal growth is relatively
1991,1993; Louveau et al., 1996, as in other species. limited. This concept is based on relatively low
Compared with plasma IGF-I concentration, plasma hepatic GH binding and circulating IGF-I concen-
IGF-II remains high throughout the prenatal period trations in the neonate. Recent studies, however,
Lee et al., 1991. It also increases postnatally, but indicate that neonatal pigs exhibit a significant
the change is not as pronounced as that of IGF-I biological response to porcine GH pGH adminis-
Lee et al., 1991. Marked changes in GHR and IGF tration Matteri et al., 1997; Lewis et al., 1998;
gene expression can also occur during the neonatal Wester et al., 1998a. The stimulatory effect of pGH
I . Louveau et al. Livestock Production Science 66 2000 121 –131
125
on blood IGF-I, which is well documented in grow- human, and then sheep, sequences. The focus of
ing pigs, also occurs in the piglet. The effect on these recent investigations was on cardiac and skelet-
weight gain is less clear. Whereas Matteri et al. al muscles, in which it was found that TRa are
1997 report no effect, Wester et al. 1998a indicate expressed at a much higher level than TRb isoforms.
that body weight is 10 greater in pGH-treated than Distinct muscle-specific differential expression pat-
in control pigs. The lack of response in body weight terns of the TR isoforms were observed, suggesting
in some studies should not be interpreted as a key roles for these isoforms in acquisition and
complete lack of growth response; the possibility of maintenance of optimal muscle function postnatally.
an effect of pGH on body composition cannot be excluded. It has been shown recently that pGH
4.2.2. T , T and receptors during early
3 4
decreases fatty acid synthesis from glucose in cul- development
tured adipose tissue from 7-day-old piglets Wang et Plasma concentrations of both total and free TH,
al., 1999. Taken together, these recent studies thyroid gland weights and hepatic 59-deiodinase
indicate that the somatotrophic axis is functional and activity all increase during late gestation; the change
responsive to exogenous pGH in neonatal pigs, in deiodinase activity between 80 and 110 days of
although the responsiveness is probably lower than gestation is particularly striking Berthon et al.,
in older pigs. 1993. During the first 6 h after birth, there is a surge
in TH concentrations and this is much greater for T
3
4.2. Thyroid hormones than for T . Apart from a transient decline at 12 h,
4
TH concentrations remain elevated during the first 2 4.2.1. Thyroid axis
days and then decline slightly over the next 2 weeks Thyroid hormones THs: 3,5,39,59-tetra-iodo-
L
- Slebodzinski
et al.,
1981; Berthon
et al.,
thyronine or thyroxine, T ; 3,5,39-triiodo-
L
-thyronine 1993,1996. The postnatal surge in TH may be
4
or triiodothyronine, T play central roles in the explained in part by depletion of preformed hormon-
3
control of growth, development and metabolism. al stores from the thyroid gland or release from
They are synthesised in the thyroid gland under the peripheral reservoirs such as the liver. Supply of
influence of thyroid-stimulating hormone TSH maternal hormones and iodine via colostrum inges-
from the anterior pituitary gland, which is itself in tion may also be involved, although provision of
part regulated by the hypothalamic thyrotropin-re- THs in the colostrum is suggested to be of marginal
leasing hormone TRH Ribeiro et al., 1998. The importance to the newborn pig Slebodzinski, 1986.
more metabolically active T is also produced in
The fall in ambient temperature at birth may also
3
extrathyroidal tissues by enzymatic deiodination of play a role in inducing the surge in plasma THs,
the less active T . In the blood, THs are predomi- either directly by stimulation of the thyroid gland or
4
nantly bound to plasma proteins. indirectly via stimulation of the hypothalamic–pitui-
The action of THs are mediated primarily through tary–thyroid axis.
interactions with nuclear TH receptors TRs which Although nuclear TRs in liver are undetectable
occur as a series of isoforms controlling the tran- until 110 days of gestation, those in skeletal muscle
scription of TH-responsive genes Lazar, 1993. The are already high at 80 days of gestation birth 5 114
TRa1, TRb1 and TRb2 isoforms can bind TH and 115 days, suggesting that porcine muscle can poten-
transactivate response elements on target genes. tially respond to THs much earlier in development
However, TRa2 cannot bind TH because of structur- than can liver Duchamp et al., 1994. Moreover, we
al changes in the ligand-binding domain and it acts have recently found marked tissue-specific differ-
as a dominant negative regulator of TH activity. The ences in the ontogeny of TRa and TRb isoform
porcine TR isoforms have recently been cloned and expression White, Burton, Fowden and Dauncey,
sequenced, and a quantitative analysis undertaken of unpublished data, indicating a further mechanism by
their tissue-specific expression White and Dauncey, which given blood concentrations of TH can have
1999. They have extremely high homology with very different effects in a wide variety of cell types.
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-
