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www.elsevier.com / locate / livprodsci

Regulation of development by nutrition and by the

somatotrophic and thyroid axes in the neonatal pig

a ,

_*

b a

I. Louveau

, M.J. Dauncey , J. Le Dividich

INRA, Unite Mixte de Recherches sur le Veau et le Porc, 35590 Saint Gilles, France b

The Babraham Institute, Cambridge CB2 4AT, UK

Abstract

The neonatal period is a particularly critical stage during which the long-term development of the individual can be affected. The rapid somatic growth is accompanied by tremendous anatomical, physiological and chemical composition changes. This period is also associated with dramatic changes in the endocrine system which plays a central role in the control of metabolism and growth. The review focuses primarily on the somatotrophic and thyroid axes. Changes in hormone and binding protein concentrations in plasma, as well as receptor expression in target tissues, are considered. After birth, the ability of the neonate to express its growth potential is related to milk intake and milk quality. There are interactions between nutrition, endocrine parameters and development. In addition to nutrients, colostrum and milk contain a large group of biologically active components such as enzymes, hormones, growth factors and immunological agents that may be involved in the neonatal development. The possible role of milk-borne insulin-like growth factor-I (IGF-I) on body growth, the gastrointestinal tract and protein synthesis in neonates has been the subject of considerable investigation in the past ten years. There is increasing evidence that milk-borne IGF-I significantly affects gastrointestinal growth and development. The effects of this factor on development of other tissues and / organs are not so clear.  2000 Elsevier Science B.V. All rights reserved.

Keywords: Nutrition; Hormone; Development; Pig; Neonate

1. Introduction hormonal regulation of growth and development in

the neonatal pig. The review concentrates on the

Development of the neonate involves complex roles played by the growth hormone

(GH)–insulin-interactions between genetics, environment, nutrition like growth factor (IGF) axis and thyroid hormones and hormone status. The aim of the present paper is (THs). The influence of nutrition on growth and to review the data concerning the nutritional and development will also be considered. There is con-siderable interest in the function of milk-borne growth factors, and it has often been hypothesised that they affect neonatal growth and development. Attention is therefore focused on the potential

sig-*Corresponding author. Tel.: 133-2-2348-5046; fax: 1

33-2-nificance of milk-borne IGF-I in the growth and

2348-5080.

E-mail address: [email protected] (I. Louveau). functional development of the neonatal pig.

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2. Nutrition of the suckling piglet 3. Growth and development during suckling

Once suckling is established in the newborn, During the 2- to 4-week suckling period, piglets

nutrition and therefore growth are almost entirely from modern genotypes grow at the rate of about dependent on colostrum and milk availability. This is 250–270 g / day (King et al., 1999). The precise rate is

attested by the strong relationship (R 50.87–0.90) very variable and is dependent mainly on the availa-between preweaning growth of piglets and sow’s bility of milk, with growth rate increasing by 0.33 g milk output (Noblet and Etienne, 1987). A complete for each additional gram increase in milk intake description of sow’s colostrum and milk is provided (Marion and Le Dividich, 1999, unpublished data).

in a recent review by Darragh and Moughan (1998). The rapid increase in body weight is associated

Briefly, compared with milk, colostrum has higher with marked changes in organ growth and body

crude protein and lower fat and lactose contents. The composition. Widdowson et al. (1976) first reported

level of protein is high (14–16%) in the first that colostrum elicits dramatic growth of the

gas-colostrum, decreases to 6–7% 24 h later and remains trointestinal tract, and especially of the small intes-constant (5–6%) thereafter. This decrease is related tine. Feeding the piglet ad libitum with colostrum to the fall in immunoglobulins (mainly IgG) which during the first 36 h postnatally induces an 80% account for 80% of total protein in the first colos- increase in small intestinal weight (Schober et al., trum, decreasing to 35 and 14% after 1 and 21 days 1990; Le Dividich et al., 1997b); this is caused by of lactation, respectively (Klobasa et al., 1987). Fat both a transient retention of colostral

macromole-accounts for 35–45% and 55–65% of the energy cules and an enhanced protein synthesis (Burrin et

provided by colostrum and mature milk, respectively, al., 1992). The specific effects of colostrum on depending on the fat composition of the sow’s diet. protein synthesis have been studied in gastrointesti-In contrast, milk protein and lactose are only marginal and peripheral tissues. Tissue protein synthesis is nally dependent on the composition of the sow’s higher in 7- than in 26-day-old piglets (Davis et al., diet, and the amino acid composition of colostrum 1996). Marion et al. (1999) reported that feeding and milk is remarkably constant. In addition, colos- stimulates whole-body protein synthesis: for exam-trum (and to a lesser extent milk) contains a variety ple, in 7-day-old piglets, whole body protein syn-of polypeptide growth factors including insulin, IGF thesis increased linearly with the level of metabolis-and epidermal growth factor (Grosvernor et al., able milk energy intake. The stimulatory effect of 1992). Concentrations of most of these factors are colostrum ingestion on protein synthesis is attributed

higher in colostrum than in milk (Table 1). Both largely to the supply of macronutrients and to

colostrum and milk are extremely well utilised by the colostral growth factors (Kelly, 1994). However, piglet, with the apparent digestibility of energy and whereas it is clear that colostrum has an immediate nitrogen both averaging 98.5% (Marion and Le effect on growth of the small intestine, its mid-term

Dividich, 1999). and long-term effects are unclear.

Table 1

Concentrations (mean6S.D.) of insulin and insulin-like growth factors (IGFs) in sow’s colostrum and milk Days following parturition

0 1 2 3 7–21

Insulin (mUI / ml) 4116214 2636190 1336113 28617 59650

IGF-I (ng / ml) 136623 72611 31617 2769.3 1162

IGF-II (ng / ml) 291665 165618 77650 50614 1763

a ¨

Westrom et al. (1987). b

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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 (N36.25), % 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

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 Mr|7500 single-chain

poly-2

(g / day)50.96Pi (g / day)20.48 (R 50.99); and aF peptides that retain 70% amino acid homology with 2

(g / day)50.58Fi (g / day)26.8 (R 50.93) (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 polypeptider under the influence of GH. Local production of both 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,

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ligand-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 ofr

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-3r (Kampman et al., 1993; Lee et al., 1993).

and an additional M 85 000 protein known as ther The postnatal rise in plasma IGF-I concentration is 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),r these two tissues (Duchamp et al., 1996;

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

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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 TRbisoforms. that body weight is 10% greater in pGH-treated than Distinct muscle-specific differential expression pat-in control pigs. The lack of response pat-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 early3 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 T3

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 ; 3,5,3₄ 9-triiodo-L-thyronine 1993,1996). The postnatal surge in TH may be

or triiodothyronine, T ) play central roles in the3 explained in part by depletion of preformed

hormon-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 T3 is also produced in The fall in ambient temperature at birth may also 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-4 either directly by stimulation of the thyroid gland or

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 (birth5114 / 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.

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5. Interactions between nutrition, hormones and Thus, plasma T concentrations, hepatic 53 9

-deiodin-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).r is profoundly affected by IUGR in all four striated Energy and fat intake also have a profound influence muscles investigated (White and Dauncey, unpub-on the tissue-specific mRNA expressiunpub-on 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-4 responses involved. For example, whereas moderate 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 status3 Severe food restriction from birth to 7 days of age

(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

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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 TRaisoforms 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 (3mg / 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)

formula1IGF-I (3.5 mg / kg / day)

Formula or Birth to 14 days ↔ Houle et al. (1997)

formula1IGF-I (200mg / kg / day)

Colostrum vs. formula Birth to 1 day ↑ Wester et al. (1998b)

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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

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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

1986. Effect of fasting neonatal piglets on blood hormone and metabolite profiles and on skeletal muscle metabolism. J.

The neonatal period is associated with marked Anim. Sci. 63, 1418–1427.

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to weaning and changes in post-weaning diet in the young pig.

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actions between nutrition, hormones, growth factors _{Cioffi, J.A., Wang, X., Kopchick, J.J., 1990. Porcine growth} and growth are extremely complex. Our recent _{hormone cDNA sequence. Nucleic Acids Res. 18, 6451.} observations, together with previous findings, sup- Coleman, M.E., Pan, Y.C., Etherton, T.D., 1991. Identification and

NH2-terminal amino acid sequence of three insulin-like growth

port the strong relationship between energy intake

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and circulating IGF-I in the neonatal pig. Changes in

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receptor (GHR, IGF-IR, TR) expression in response _{Darragh, A.J., Moughan, P.J., 1998. The composition of colostrum} to nutritional status need to be investigated further. _{and milk. In: Verstegen, M.W.A., Moughan, P.J., Schrama, J.W.} Taken together, a number of studies suggest a role (Eds.), The Lactating Sow. Wageningen Pers, Wageningen, pp.

3–21.

for milk-borne growth factors in the development of

Dauncey, M.J., 1990. Thyroid hormones and thermogenesis. Proc.

the neonatal gastrointestinal tract. However, very

Nutr. Soc. 49, 203–215.

little is known about the underlying mechanisms by _Dauncey, _M.J., _1997. _From _early _nutrition _and _later which the effects are mediated. The possible absorp- _{development . . . to underlying mechanisms and optimal health.} tion of IGF-I and of other growth factors, and the Br. J. Nutr. 78, S113–123.

Dauncey, M.J., Geers, R., 1990. Nuclear 3,5,39-triiodothyronine

contribution to circulating growth factors needs to be

receptors in skeletal muscle of normal- and

small-for-gestation-clarified. Further studies are needed to determine

al age newborn piglets. Biol. Neonate 58, 291–295.

whether other colostral components are involved. _{Dauncey, M.J., Rudd, B.T., White, D.A., Shakespear, R.A., 1993.} The impact of early nutrition on long-term develop- _{Regulation of insulin-like growth factor binding proteins in} ment also needs to be further evaluated. young growing animals by alteration of energy status. Growth

Regul. 3, 198–207.

Dauncey, M.J., Burton, K.A., Tivey, D.R., 1994a. Nutritional modulation of insulin-like growth factor-I expression in early

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5. Interactions between nutrition, hormones and

Thus, plasma T concentrations, hepatic 5

9 -deiodin-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

Energy and fat intake also have a profound influence

muscles investigated (White and Dauncey,

unpub-on the tissue-specific mRNA expressiunpub-on 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

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

(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

(2)

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

TR

a

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 (3mg / 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)

formula1IGF-I (3.5 mg / kg / day)

Formula or Birth to 14 days ↔ Houle et al. (1997)

formula1IGF-I (200mg / kg / day)

Colostrum vs. formula Birth to 1 day ↑ Wester et al. (1998b)

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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

m

g / 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

m

g / 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

m

g / 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

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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

1986. Effect of fasting neonatal piglets on blood hormone and metabolite profiles and on skeletal muscle metabolism. J.

The neonatal period is associated with marked

Anim. Sci. 63, 1418–1427.

Carrol, J.A., Veum, T.L., Matteri, R.L., 1998. Endocrine responses

changes in growth and development and also in the

to weaning and changes in post-weaning diet in the young pig.

endocrine system. This review shows that the

inter-Domest. Anim. Endocrinol. 15, 183–194.

actions between nutrition, hormones, growth factors

_{Cioffi, J.A., Wang, X., Kopchick, J.J., 1990. Porcine growth}

and growth are extremely complex. Our recent

_{hormone cDNA sequence. Nucleic Acids Res. 18, 6451.}

observations, together with previous findings, sup-

Coleman, M.E., Pan, Y.C., Etherton, T.D., 1991. Identification and

NH2-terminal amino acid sequence of three insulin-like growth

port the strong relationship between energy intake

factor-binding proteins in porcine serum. Biochem. Biophys.

and circulating IGF-I in the neonatal pig. Changes in

Res. Commun. 181, 1131–1136.

receptor (GHR, IGF-IR, TR) expression in response

_{Darragh, A.J., Moughan, P.J., 1998. The composition of colostrum}

to nutritional status need to be investigated further.

_{and milk. In: Verstegen, M.W.A., Moughan, P.J., Schrama, J.W.}

Taken together, a number of studies suggest a role

(Eds.), The Lactating Sow. Wageningen Pers, Wageningen, pp.

3–21.

for milk-borne growth factors in the development of

Dauncey, M.J., 1990. Thyroid hormones and thermogenesis. Proc.

the neonatal gastrointestinal tract. However, very

Nutr. Soc. 49, 203–215.

little is known about the underlying mechanisms by

_Dauncey, _M.J., _1997. _From _early _nutrition _and _later

which the effects are mediated. The possible absorp-

_{development . . . to underlying mechanisms and optimal health.}

tion of IGF-I and of other growth factors, and the

Br. J. Nutr. 78, S113–123.

Dauncey, M.J., Geers, R., 1990. Nuclear 3,5,39-triiodothyronine

contribution to circulating growth factors needs to be

receptors in skeletal muscle of normal- and

small-for-gestation-clarified. Further studies are needed to determine

al age newborn piglets. Biol. Neonate 58, 291–295.

whether other colostral components are involved.

_{Dauncey, M.J., Rudd, B.T., White, D.A., Shakespear, R.A., 1993.}

The impact of early nutrition on long-term develop-

_{Regulation of insulin-like growth factor binding proteins in}

ment also needs to be further evaluated.

young growing animals by alteration of energy status. Growth

Regul. 3, 198–207.

Dauncey, M.J., Burton, K.A., Tivey, D.R., 1994a. Nutritional modulation of insulin-like growth factor-I expression in early

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