Fetal growth factors and fetal nutrition

Hormones involved in fetal growth are nutritionally regulated in the fetus and also regulate substrate uptake and metabolism. The major fetal growth factors are the insulinlike growth factors (IGF)-I and II, with insulin having a passive role in fetal growth. The roles of other hormones such as growth hormone (GH), placental lactogen, leptin and ghrelin are as yet less clear.

Insulin levels in the fetus are clearly regulated by fetal nutrient supply. Fetal glucose infusion stimulates insulin secretion by the fetus,170,171 and insulin and glucose concentrations were closely correlated in studies of different nutritional regimens in the sheep.172 Amino acids appear to potentiate glucose-inducedinsulinrelease.173,174 In turn, insulin stimulates glucose and amino acid uptake into fetal tissues. Fetalpancreatectomy, to preventfetalinsulin secretion, results in impaired fetal growth.175 However, infusion of high doses of insulin restores growth only to the rate of that in controls, demonstrating that insulin itself cannot stimulate fetal growth in the absence of additional nutrient supply. In diabetic pregnancies the fetus is exposed to increased concentrations of maternal glucose. As pla-cental transfer of glucose occurs down the maternal -fetal concentration gradient, fetal glucose concentrations are also increased. Fetal insulin release and circulating insulin concentrations are increased in response to the elevated glucose concentrations, and the combination of increased insulin and substrate results in increased fetal growth.

In prenatal life the IGFs are critical in the regulation of fetal growth, acting in both paracrine and endocrine fashion. Direct evidence for the role of IGF-I in fetal growth comesfrom experiments in mice usinghomologous recombination of defective IGF-I or IGF type 1 receptor genes to produce animals homozygous for these defects.176 Less direct evidence is provided by the finding in all species studied that birth-weight correlates with cord blood IGF-I concentrations.177-179 In babies, levels of IGF-I in umbilical cord blood and blood obtained in utero by fetal blood sampling are reduced in IUGR.180-183 A case report of partial deletion of the IGF-I gene in a boy with severe IUGR is definitive evidence in the human for the role of IGF-I in fetal growth.184 Deletion of the IGF type 1 receptor gene has also been reported to result in IUGR, with a Silver-Russell phenotype.185

The IGFs are anabolic hormones, and in fetal life circulating levels of these important growth-regulating hormones are regulated by fetal nutrient supply. In fetal sheep IGF-I, IGF-II and IGFBP-3 levels fall with severe maternal undernutrition while IGFBP-1 and -2 levels rise.186,187 Replacement of glucose or insulin restores fetal IGF-I levels within 24 hours.188,189 Circulating maternal IGF-I levels in pregnancy are also partly regulated by nutritional status, and maternal IGF-I levels also influence birth weight.190 In pregnant rats IGF-I concentrations were correlated with changes in nitrogen balance.191

In turn, IGF-I regulates fetal nutrient uptake. In fetal sheep IGF-I infusion reduces fetal protein breakdown, increases fetal glucose uptake and appears to alter nutrient distribution between fetus and placenta to enhance fetal nutrient availability.192,193 IGF-I infusion is also anabolic, increasing the fractional protein synthetic rate,194 and increasing the conversion of serine to glycine, which would increase the availability of one-carbon groups for biosynthesis.195 Chronic IGF-I infusion alters placental glucose transfer and placental clearance of MeAIB.196 Recent evidence from sheep studies suggests that growth-restricted fetuses may be resistant to some of the anabolic effects ofIGF-I.159,193,197

IGF-II is thought to be most important in embryonic and early gestational growth,198 acting as an embryonic growth factor by activating cell cycle entry/progression.199 IGF-II is first expressed in the placenta by 18 days gestation in the human,200 and is highly expressed in pro-liferative cytotrophoblasts of the first trimester placenta, acting as a placental growth factor.201 Recently Constancia et al. have demonstrated in mice that deletion from the Igf2 gene of a transcript (P0) that is specifically expressed in the labyrinthine trophoblast of the placenta results in reduced growth of the placenta that occurs before fetal growth restriction.148 Interestingly, placental transport of methylaminoisobutyric acid (MeAIB, a non-metabolizable analog of amino acids utilizing the system A amino acid transporter) is initially up-regulated in these mice. When this up-regulation fails, fetal growth restriction ensues. Passive permeability of the mutant placenta is also decreased. The temporal separation of placental from fetal growth restriction in this P0 knockout is distinct from the contemporaneous growth restriction of both that occurs in the Igf-II(p-) knockout,198 leading the authors to propose that fetal IGF-II may signal to the placenta to up-regulate amino acid transport.202 There are many other imprinted genes, some of which are also expressed in the placenta. In general, paternally expressed imprinted genes, such as Igf2, Peg1, Peg3, and insulin enhance fetal growth, whereas maternally expressed genes, such as Igf2r and H19 suppress fetal growth.203-205 This has led Reik et al. to propose that imprinted genes may be involved in the regulation of the balance of fetal nutrient demand and maternal nutrient supply.202

Growth hormone levels are also nutritionally regulated, with maternal and fetal GH levels rising in response to undernutrition.206 It is increasingly becoming apparent that GH does have a role in fetal growth and anabolic metabolism, although the extent of this role is still not clear. GH receptors (GHR) are present in a large number of fetal tissues207 and GHR/BP mRNA has been shown to co-localize with IGF-I mRNA in the rat fetus.208 Congenital GH deficiency is associated with a reduction in length at birth,209 and hypophysectomized fetal lambs supplemented with thyroxine (to abolish the effects of hypothyroidism) have shorter limbs and long bones210 and reduced IGF-I levels.211 IGF-II levels were unaffected. Recent data from Bauer etal. provide the first evidence that GH supplementation in fetuses can influence IGF-I levels in utero. A 10-day pulsatile infusion of GH to growth-restricted ovine fetuses resulted in an increase in IGF-I levels and an increase in liver and thymus weight.212 Placental lactate production and fetal lactate uptake were also increased in this study.

Thyroid hormones are also involved in regulating fetal metabolism and thus growth. The metabolic action of thyroxine is mainly via stimulation of oxygen utilizationby fetal tissues.213 This appears to be a general increase in oxidative metabolism, rather than in glucose oxidation alone.76 Thyroid hormones are reduced, and thyroid stimulating hor mone increased (TSH), in fetuses with impaired substrate supply, suggesting that these hormones are also nutritionally regulated in utero. 214

The role of other hormones that are involved in postnatal nutrition and growth, such as leptin and ghrelin, are beginning to receive more attention in the fetus.215 Both leptin and ghrelin are expressed in the placenta216-218 and both can be nutritionally regulated.218-221 The precise role of these hormones, and other nutritionally regulated hormones such as placental lactogen, remains to be elucidated, but a recurring theme for hormones that are also expressed in the placenta is the possibility that they may play a role in nutrient partitioning between mother and fetus.

Thus there is a close and reciprocal relationship between many of the fetal hormones involved in fetal growth (and thus the utilization of fetal nutrients) and the fetal nutrient supply. Furthermore, there appears to be input from the maternal hormonal milieu on nutrient supply, and the placenta, which is exposed to both maternal and fetal hormonal and nutrient influences, itself produces many of the hormones involved in fetal growth.

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