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The Journal of Nutrition Vol. 128 No. 2 February 1998,
pp. 315S-320S
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* Department of Dairy and Poultry Sciences, Department of Animal Science, and the Interdisciplinary Concentration in Animal Molecular and Cell Biology, University of Florida, Gainesville, FL 32611-0920
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ABSTRACT |
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Abstract
References
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The IGF system is implicated in the regulation of cellular response to protein- and energy-restriction. Although it is clear that the IGF and their binding proteins are profoundly influenced by dietary factors, a number of important questions remain about this relationship. In particular, although studies to date have focused on nutritional modulation of hepatic IGF gene expression, the molecular mechanisms underlying metabolic regulation of liver IGF and IGF binding protein genes remain relatively unknown. Moreover, the potential effects of altered nutrition on the expression and/or actions of IGF system components in tissues other than the liver have been examined only in cursory fashion. Many of these studies have used rats, an admittedly important model, but one which differs from the human in a potentially significant way: rats lack circulating IGF-II and IGFBP-2 during post-weaning and adult life. Here, we summarize current research on the porcine IGF system and highlight the particular usefulness this system may offer for unraveling the complex relationships of nutrition and systemic/local IGF expression and actions that are relevant to human nutritional physiology.
KEY WORDS: insulin-like · IGF-binding protein · regulation · gene · porcine
The insulin-like growth factors (IGF-I and IGF-II) and their soluble, membrane- and extracellular matrix (ECM)-associated binding proteins (IGFBP-1 to -7) (Oh et al. 1996
Liver.
The overall abundance of IGF-I mRNAs in porcine liver is substantially lower than for a number of other tissues, including uterus, skeletal muscle and adipose. Normally, pig liver IGF-I mRNAs are characterized by the relative absence of exon 2 sequences, indicating minimal activity of this gene's promoter-2 and its encoded IGF-I prepeptide leader (Brameld et al. 1995 Skeletal muscle and adipose.
The abundance of IGF-I and IGF-II mRNAs in skeletal (hindlimb) muscle exhibits marked developmental regulation (Lee et al. 1993b Cardiac muscle.
In growing pigs, the heart muscle expresses IGF-I transcripts at levels that exceed those for liver. Porcine cardiac IGF-I transcript levels are negatively modulated by food deprivation and diabetes (Leaman et al. 1990 Mammary glands and secretions.
Mammary gland secretions of humans and pigs are rich sources of IGF and their BP (reviewed in Donovan and Odle 1994 Uterus.
The porcine uterus has been extensively used to examine the hormonal regulation and functional aspects of the IGF system during implantation and pregnancy (Green et al. 1995 Ovary.
Ovarian function requires the rapid and continuous growth of follicles. Prior to ovulation, the theca and granulosa cells of pre-antral and small antral follicles proliferate and undergo functional differentiation. Recent studies have identified granulosa cells as a major site of IGF-I synthesis, reception and action (reviewed in Giudice 1992 Testis.
Little information is available concerning a putative testicular IGF system in pigs or other vertebrates. A recent study however, demonstrated the presence of IGF-I and IGF-II mRNAs in boar testis (Clark et al. 1994 Nutritional restriction leads to adaptive cellular and somatic changes that include reduction in or cessation of cell proliferation in certain tissues and organ systems. The IGF system is implicated in this mediation of cellular response, although many questions remain unanswered. Although it is recognized that nutrition can markedly affect the relative amounts and ratio of circulating IGF-I and IGF-II, the association of IGF-I and IGF-II with specific IGFBP in blood has not been examined as a function of nutrient or energy intake. Such changes would be predicted to influence the serum half-lives of the IGF, the relative partitioning of IGF, IGFBP and IGF:IGFBP complexes between the bloodstream and extravascular and cellular compartments, and the bioavailability and bioactivity of circulating as well as locally synthesized IGF and IGFBP. These alterations may affect overall somatic growth as well as the mitotic activity and differentiation state of target cells in tissue-specific fashion.
The IGF system constitutes an important control point by which nutritional or hormonal interventions might be used to effect physiological benefits in humans and other mammals. However, the development of such strategies requires a more complete understanding of the basic functional characteristics and interrelationships of the IGF system components and nutritional status. Similarly, the metabolic regulators of IGF, IGFBP and IGF receptor biosynthesis, secretion and half-life and the molecular determinants that confer tissue specificity to metabolically responsive IGF/IGFBP genes remain unclear. The current state of knowledge concerning the regulation, by postnatal nutritional status, of 1) IGF-II synthesis and secretion; 2) formation and disassociation of IGF-II:IGFBP complexes; 3) partitioning of IGF-II:IGFBP-2 complexes and non-liganded IGFBP-2 among the circulation, extravascular space and cell surface; 4) circulating half-life and role of IGFBP-2; and 5) local expression and actions of the IGF system in mitotically repressed or otherwise compromised tissues is only rudimentary. Pigs may prove to be a particularly useful model organism for addressing such questions and for examining the possible applications of IGF and IGFBP to human nutrition.
We sincerely regret that many important contributions to this area of research could not be cited due to space limitations.
PORCINE ENDOCRINE INSULINE-LIKE
GROWTH FACTOR SYSTEM
) and receptors (types I and II IGF receptors) constitute an endocrine/autocrine/paracrine-acting system that mediates growth, differentiation and/or apoptosis of vertebrate cells. Previous studies have implicated this evolutionarily conserved system in the regulation of homeostatic and cellular growth responses to protein, nutrient and energy restriction (reviewed in Clemmons and Underwood 1991). The IGF are anabolic, mitogenic, differentiative and anti-apoptotic factors whose bioactivities, under appropriate conditions, are either stimulated or inhibited by IGFBP, which may also exert ligand-independent actions (Clemmons 1993). Anabolic and mitotic activities of certain cellular and tissue compartments are differentially responsive to nutrient and energy restriction; thus, a central role of the IGF system in linking nutritional intake with somatic and tissue growth cessation or stimulation in vivo seems likely.
, Lee et al. 1991, McCusker et al. 1991, Table 1). Pigs, like humans, manifest significant amounts of IGF-II and IGFBP-2 in blood, postweaning and throughout adulthood. During nutritional deficits, serum IGF-I and IGF-II concentrations are reduced in these species. Food deprivation of newborn pigs decreased the amounts of intact IGFBP-2 in serum; paradoxically, this was accompanied by a fourfold increase in serum immunoreactive IGFBP-2 content due to increased amounts of the 22- and 14-kDa IGFBP-2 subfragments that have minimal IGF-binding activity (McCusker et al. 1991). In both humans and pigs, GH is required for maintenance of normal circulating levels of IGF-I and IGF-II, although dependence on GH is more significant for IGF-I than IGF-II. Treatment of growing pigs with exogenous GH (porcine somatotropin, pST) leads to elevated serum IGF-I and depressed serum IGF-II and IGFBP-2, endocrine changes that may underlie in part the dramatic alterations in carcass composition (e.g., increased leanness) elicited by in vivo administration of pST (Etherton et al. 1986, Table 1). Serum IGF-I was reduced in pigs with Streptozotocin-induced diabetes, and this reduction was amplified when food deprivation was additionally imposed on this condition (Leaman et al. 1990). However, insulin therapy restored serum IGF-I to normal concentrations in diabetic animals.
View this table:
Table 1.
Metabolic and porcine somatotropin (pST) regulation of circulating and hepatic insulin-like growth factor (IGF) system components in pigs
PORCINE TISSUE INSULIN-LIKE GROWTH FACTOR SYSTEMS
and 1996). However, pigs that were previously energy-restricted, but which subsequently received supplemental energy, synthesized increased amounts of hepatic exon 2-containing IGF-I transcripts (Weller et al. 1994). Animals that received pST also manifest a greater proportion of exon 2-containing IGF-I mRNAs in liver RNA (Brameld et al. 1996). A single injection of pST induces a rapid increase in IGF-I mRNA content in liver, suggesting transcriptional effects (Ramsay et al. 1995). Collectively, these results suggest that the exon 2-encoded IGF-I prepeptide is preferentially utilized under conditions where circulating IGF-I is increased (endocrine response). Similarly, in vitro cultured porcine hepatocytes maintain their endogenous IGF-I gene transcription and exhibit GH-stimulated increases in IGF-I mRNA expression in which both exons 1- and 2-containing transcripts are induced (Brameld et al. 1995). The latter may therefore represent a useful in vitro model for delineating the molecular mechanisms underlying metabolic regulation of hepatic IGF genes in concert with GH and insulin. In this regard, diabetes caused a reduction in steady-state hepatic IGF-I mRNA abundance that was concordant with circulating IGF-I. In contrast, the expression levels of IGF-II mRNA were unaffected by diabetes or food deprivation (Leaman et al. 1990). Maternal diabetes increased IGF-I mRNA abundance in fetal liver and muscle and decreased the IGF-I mRNA content in fetal adipose tissue (Ramsay et al. 1994).
). Glucocorticoids, insulin, and amino acid availability may constitute nutritional factors that affect liver IGF and IGFBP gene expression. In this regard, food deprivation increases plasma concentrations of corticosterone, which in turn stimulates hepatic IGFBP-1 and -2 gene expression through glucocorticoid-responsive cis-elements in the promotor regions of these genes (Goswami et al. 1994, Mouhieddine et al. 1996). Food deprivation also decreases plasma insulin, which is a suppressor of hepatic IGFBP-1 and IGFBP-2 gene transcription (Goswami et al. 1994, Suwanickul et al. 1993).
), with both mRNAs maximally expressed in fetal muscle during the second half of gestation. Similarly, fetal skeletal muscle exhibits relatively higher levels of types I and II IGF receptors and their corresponding mRNAs than does postnatal muscle (Lee et al. 1993b). In young pigs, skeletal muscle IGF-I mRNA abundance is reduced during food deprivation and diabetes (Leaman et al. 1990). In the latter, insulin therapy restored these mRNA levels to normal.
). Insulin-like growth factor-I is a potent mitogen for S-V cells and also stimulates their functional differentiation (i.e., lipid deposition). Interestingly, these dual effects of IGF-I are more pronounced in fetal than postnatal cells, which may relate to differences in cellular IGF receptor levels. Moreover, cultured fetal-derived S-V cells secrete more IGF-I than do postnatal S-V cells. The above results identify skeletal muscle and adipose as two important fetal target tissues for local IGF-I. Insulin-like growth factor-II has been less studied in these tissues, although fetuses representative of a genetically lean line of pigs have more circulating IGF-II than do pre-obese fetuses of an obese genetic line (Hausman et al. 1991).
). In pigs in the diabetic condition, insulin therapy is able to partially restore IGF-I transcript levels to normal, a situation that differs from those for liver and skeletal muscle (above). Porcine aortic smooth muscle cells secrete IGFBP-2 and IGFBP-4 as well as proteases for both IGFBP in culture (Gockerman and Clemmons 1995). These results point to a functional cardiac IGF system that may be subject to nutritional and metabolic regulation.
). The significant amounts of these proteins in colostrum and early lactation milk are consistent with possible paracrine role(s) in the gastrointestinal tract of neonates, a tissue that exhibits functional IGF receptors. Moreover, porcine mammary tissues exhibit IGF, IGFBP and IGF receptor genes, suggestive of the presence of a functional mammary IGF system that may contribute to this tissue's significant growth (mammogenesis) and differentiation (lactogenesis) during pregnancy and lactation (Lee et al. 1993a).
, F. A. Simmen et al. 1992, R.C.M. Simmen et al. 1990, Song et al. 1996). Although IGF gene expression is known to be under diverse hormonal (steroidal and growth factor) control (Rotwein et al. 1993, Simmen 1991), the role of GH, whose serum concentrations fluctuate with nutritional status, in uterine IGF expression has not been clearly established. In rodent models, uterine IGF-I gene expression is concordant with circulating GH concentration (Rotwein et al. 1993). Moreover, an increase in serum IGF-I concentration has been shown to be significantly correlated with uterine weight in prepubertal pigs (Booth et al. 1996), suggestive of systemic IGF-I effects at the level of the uterus. Thyroxine, a metabolic hormone whose maternal serum concentrations fluctuate with diet, causes a significant increase in IGF-I, IGFBP-1, IGFBP-2 and IGFBP-4 in hypophysectomized fetal pigs (Latimer et al. 1993); this suggests GH-independent effects on the porcine IGF system as well. To date, studies demonstrating uterine-specific molecular and cellular responses that establish a link among nutrition, the IGF system and reproduction in pigs are lacking.
). Insulin-like growth factor-I promotes both the replication and differentiation of granulosa cells and affects virtually all aspects of granulosa cell function, including enhancement of gonadotropin-stimulated production of progesterone, estrogen and proteoglycans, as well as LH receptor induction (references in Tonetta and diZerega 1990). In pig theca cell monolayers, IGF-I increased basal and gonadotropin-induced secretion of progesterone and enhanced hCG-induced synthesis of androstenedione and testosterone (Giudice 1992); IGF-I also enhanced low and high density lipoprotein metabolism and stimulated high density lipoprotein-supported progesterone biosynthesis (Giudice 1992). Cultured porcine granulosa cells exhibit robust expression of IGF-I mRNAs, which are inducible by GH and FSH at the level of gene transcription (Samaras et al. 1996). The paradigm of an intraovarian IGF system in which IGF-I constitutes the central modulatory signal is well-accepted.
). Cultured porcine granulosa cells secrete IGFBP-3, IGFBP-2 and IGFBP with Mrs of 22,000 and 29,000, under the influence of peptide and steroid hormones. Although the functions of intraovarian IGFBP are not fully understood, it is conceivable that these proteins antagonize the IGF enhancement of gonadotropin action on granulosa cells by sequestering granulosa-derived IGF peptides. In support of this, IGFBP-2 and -3 were found to inhibit both DNA synthesis and FSH-stimulated steroid production by preovulatory granulosa cells (Giudice 1992). Moreover, IGF-I and IGFBP-2 mRNAs increased and decreased, respectively, with porcine follicle development (Guthrie et al. 1995). Increased IGFBP-4 mRNA abundance was associated with granulosa cell luteinization, whereas concentration of IGFBP-2 in porcine follicular fluid was positively correlated with the percentage of apoptotic cells per follicle (Guthrie et al. 1995).
). Available evidence suggests that both Leydig and Sertoli cells possess IGF-I receptors and that the Leydig cell receptors are up-regulated by hCG (references in Clark et al. 1994). Addition of IGF-I to the culture medium was shown to increase both basal and LH-stimulated testosterone secretion by porcine Leydig cells. Although the specific role of IGF-I in testicular function is yet to be elucidated, one might hypothesize that IGF regulates Leydig cell function through its influence on LH responsiveness.
NUTRITIONAL EFFECTS ON GROWTH, REPRODUCTION AND THE PORCINE INSULIN-LIKE GROWTH FACTOR SYSTEM
). Pulsatile LH secretion in prepubertal pigs was suppressed by short-term, severe feed restriction but was rapidly restored by refeeding (Cosgrove et al. 1991). Severe hypoglycemia was associated with depressed LH pulse amplitude and low circulating IGF-I concentration (references in Cosgrove et al. 1992). Effects of refeeding at the ovarian level, with increased follicle size and uterine weight after 7 d of re-alimentation compared with littermates on continued feed restriction, have been demonstrated (Cosgrove et al. 1992). Although the mechanism or mechanisms whereby nutrition alters ovarian and uterine function are unclear, evidence suggests that changes in IGF-I and its binding proteins, at the systemic or tissue level or both, may constitute one link between metabolic regulation and reproduction.
, Thatcher et al. 1996). Similarly, the uterine IGF system may be a potential target tissue for nutritional and/or hormonal (pST/IGF) intervention for increasing reproductive efficiency via augmented embryo survival and feto-placental and uterine tissue growth (Kelley et al. 1995, Kirby et al. 1996). In limited studies, exogenous pST elicited positive effects on embryonic survival, embryo crown-to-rump lengths and feto-placental weights (Kelley et al. 1995, Sterle et al. 1995). Additionally, serum IGF-I concentrations in fetal pigs whose dams were administered pST are increased, suggesting that this treatment increases fetal nutrient uptake. Thus, although the molecular mechanism by which pST alters various reproductive events is presently unknown, it is tempting to speculate that these are modulated in part by components of the IGF system. Altering GH and/or IGF-I in the maternal circulation (and presumably in reproductive tissues such as the uterus) through nutritional manipulation or exogenous hormonal therapy may serve as a possible management strategy for enhancing reproductive efficiency in pigs.
). Moreover, there is a scattering of reports in the literature that seem to indicate that, under certain conditions, IGF-II elicits markedly distinct downstream events from IGF-I (Kanai-Azuma et al. 1993). Efforts to generate transgenic mice that manifest IGF-II in their blood postnatally have led to several different pathological or otherwise abnormal phenotypes (Rogler et al. 1994) that have complicated the interpretation of this protein's normal postnatal role. Pigs may constitute a particularly useful model for elucidating the postnatal and adult roles of IGF-II and IGFBP-2. In this regard, comparative analysis of IGFBP-2 protein sequences from a number of vertebrate organisms has highlighted the marked similarities of the human and porcine homologs (Fig. 1).
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Fig 1.
Vertebrate insulin-like growth factor binding protein (IGFBP)-2 proteins. Sequence similarities for mature IGFBP-2 proteins encoded by porcine (p), human (h), bovine (b), ovine (o), rat (r), mouse (m) and chicken (c) IGFBP-2 genes. Also indicated are conserved motifs for heparin-binding (HBM), integrin-binding (RGD), exon boundaries (E1-E4) of the porcine gene (Song et al. 1996 ), N-terminus of a three amino acid-truncated variant of porcine IGFBP-2 isolated from serum, and two tyrosine residues (*) identified as contributing to the IGF-I binding site (Hobba et al. 1996). Porcine IGFBP-2 is most similar in primary amino acid sequence to human IGFBP-2. Note the marked conservation of vertebrate IGFBP-2 peptides encoded by exon 2, a region that is not conserved between IGFBP-1-6 of humans. This may indicate a unique ligand-independent function(s) for this domain. A search for porcine IGFBP-2 homologs in current protein and DNA databases did not identify any novel vertebrate IGFBP nor any IGFBP-2-like proteins in invertebrate organisms.
, Xu et al. 1996). Intestinal tissues in porcine neonates apparently do not have the capacity to absorb significant amounts of ingested IGF-I and transport this peptide intact to the circulation (Donovan et al. 1997, Xu and Wang 1996). Insulin-like growth factors are anabolic and possible differentiation-inducing factors for intestinal epithelium of newborns. These recent observations have opened up the possible applications of recombinant IGF and IGF analogs for repair of damaged gastrointestinal tissues of humans (and pigs) and as intestinal growth-promoting factors for newborn pigs and other animals (Bryant et al. 1996, Fholenhag et al. 1996). The presence of relatively large amounts of IGF in porcine colostrum and early milk may therefore be physiologically relevant to the development of the gut in neonates, and, by inference, a similar scenario may apply to women and newborns. Growth hormone and IGF-I may have unique as well as interrelated or overlapping contributions to gastrointestinal growth; thus, the concerted actions of both molecules may be advantageous in this tissue.
, Lamberson et al. 1996). Serum IGF concentrations may therefore constitute useful indices for selection experiments to obtain genetic lines with increased feed efficiency, altered reproductive traits and/or leaner carcass composition. Moreover, pigs may help provide important information concerning the relative contributions of nutrition and genetics to somatic and cellular growth as well as the downstream events elicited by IGF action and relevant to growth and reproduction.
SUMMARY
ACKNOWLEDGMENTS
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FOOTNOTES |
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LITERATURE CITED |
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Abstract
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