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Department of Animal Science, Cornell University, Ithaca, New York 14853
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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To better understand the biology of leptin during prenatal life, the developmental and spatial regulation of leptin was studied in ovine fetuses. Fetal plasma leptin increased steadily between days 40 and 143 postcoitus (PC), but it was unrelated to fetal weight or placental weight at day 135 PC. Leptin gene expression was detected in fetal brain and liver during most of gestation and in fetal adipose tissue after day 100 PC. At day 130 PC, expression in fetal perirenal adipose tissue was ~10% of maternal expression. In contrast, leptin gene expression was never detected in the placenta and other uteroplacental tissues. When ewes were fed 55% of requirements between days 122 and 135 PC, fetal plasma leptin remained constant despite acute reduction in maternal concentration. We conclude that fetal plasma leptin originates mostly from nonadipose tissue in early pregnancy and, in addition, from fetal adipose tissue near term. The role of fetal plasma leptin remains uncertain given the lack of nutritional regulation and association with fetal growth.
pregnancy; placenta; nutrition
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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DURING FETAL LIFE, EXTRACELLULAR signals are required for complete growth and normal development. For example, mice lacking insulin-like growth factor-I or -II, insulin, or their receptors are growth retarded at birth (15, 36, 51). This growth deficit reflects the essential roles played by these signals in promoting cell proliferation (15, 36) and anabolic disposal of nutrients (9, 59). Additional signals are likely to be involved in coordinating the anabolic drive with availability of nutrients.
After birth, an important signal involved in coordinating the use of available energy is leptin. Leptin is synthesized almost exclusively by adipocytes in proportion to their degree of hypertrophy and supply of energy (2, 56, 60). The role of leptin in coordinating energy metabolism is most obvious during periods of nutritional insufficiency when reduced plasma leptin concentration promotes neuroendocrine and metabolic adaptations necessary for survival (3). Recent observations suggest that leptin may play a similar role during fetal life, particularly near term when nutrient supply is increasingly limited by placental function (5). Leptin is expressed in a variety of mouse embryonic tissues (29, 30) and stimulates energetically expensive processes that occur prominently in the fetal-placental unit, such as hematopoiesis and angiogenesis (6, 44, 55). Moreover, leptin is present in plasma of human and rodent neonates (23, 27, 54), and its concentration is positively correlated with birth weight in humans (12, 34, 54).
Our understanding of the roles played by leptin during fetal life is limited and based almost exclusively on studies of gene expression in rodents (29, 30) and plasma concentration in humans (21, 22, 34, 54). For example, it is not known whether leptin gene expression in nonadipose tissues is limited to the rodent embryo (29, 30) or represents a universal feature of prenatal life. As part of our efforts to understand the role of leptin during fetal life, we performed studies in the sheep, an important and widely used model of fetal biology (5). Our studies show that leptin is present in plasma during most of fetal life and probably originates from tissues such as liver in early life and from adipose tissue near birth. We also show that in near-term fetuses, plasma leptin is not influenced by moderate maternal undernutrition.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals and design. Experimental procedures were conducted with the approval of the Cornell University Animal Care and Use Committee. Animals consisted of Finn × Dorset cross ewes (age: 3-6 yr) mated to Finn × Dorset rams. The number of fetuses carried by each ewe was determined at 38-60 days postcoitus (PC) by ultrasound examination (16).
Spatial and developmental regulation.
Twenty-four pregnant ewes bearing one to three fetuses were studied
between days 40 and 143 PC. They were fed a
single total mixed ration (TMR) at or above predicted nutrient
requirements (43). At the time of study, ewes had an
average body condition score of 3.6 ± 0.2 [1 = thin, 5 = fat (Ref. 52)]. Blood samples were obtained from the
ewes by jugular venipuncture and processed to plasma. Immediately
afterward, they were then killed by captive bolt stunning and
exsanguination. Venous blood was obtained from fetuses within 5 min of
maternal exsanguination, immediately before administration of a lethal
intravascular injection of pentobarbital sodium (Buthanasia,
Schering-Plough, Kenilworth, NJ). Uterine tissues (endometrium,
myometrium, fused chorioallantoic membranes, and umbilicus) were
dissected as described previously (16). Fetal and maternal
tissues (brain, skeletal muscle, kidney, liver, and perirenal and
subcutaneous adipose) were excised within 10 min of death, snap-frozen
in liquid N2, and stored at 
80°C. Eight placentomes
were collected from each placenta, snap-frozen in liquid
N2, and pulverized in liquid N2 using a Waring
blendor (New Hartford, CN).
Nutritional regulation. From days 85 to 90 PC, 10 twin-pregnant, multiparous ewes were housed in a controlled environment (16:8-h light-dark cycle; 18°C). The TMR consisted of coarsely chopped alfalfa/grass hay, cracked corn, and soybean meal and contained 120 g crude protein and 2.4 Mcal metabolizable energy/kg dry matter. Ewes were fed the TMR between days 85 and 90 and day 117 at a level designed to meet nutrient requirements of the conceptus and to maintain energy equilibrium in nongravid maternal tissues (43, 49).
Indwelling vascular catheters were inserted surgically in each fetus at days 112-114 PC by a hysterotomy approach (53). Briefly, ewes were anesthetized by a continuous intravenous infusion of ketamine (Ketaset, Fort Dodge Animal Health, Fort Dodge, IA). Polyvinyl catheters (1.27-mm outside diameter, 0.86-mm inside diameter; Dural Plastics c/o Critchley Electric, Silverwater, New South Wales) were placed in the fetal abdominal aorta and amniotic cavity of both fetuses. Ampicillin (Polycillin, Apothecon, Princeton, NJ) was administered daily for 6 days to the ewe (10 mg/kg body wt im) and to each fetus (250 mg via the amniotic catheter). Catheters were flushed daily with sterile saline containing heparin (100 U/ml). Fetal health was monitored daily for the first 4 days postsurgery and every 3 days thereafter by measurement of blood hemoglobin content, oxyhemoglobin saturation, and glucose concentration. Starting on day 117, the daily feed allowance was distributed into 12 equal portions offered at 2-h intervals. On day 122, ewes were randomly allocated either to remain on the previous plane of nutrition (Fed) or to receive 55% of that level (Underfed). Each nutritional treatment lasted 14 days (days 122-135 PC). Heparinized fetal (3 ml) and maternal (12 ml) blood was obtained on days 119, 121, 123, 126, 129, 132, and 135 PC. Plasma was prepared and stored at20°C. On
day 135 PC, the gravid uterus was dissected after lethal
intravascular administration of pentobarbital sodium to ewes and fetuses.
Analytic methods. Hemoglobin content and oxyhemoglobin saturation were analyzed with an OSM2 hemoximeter (Radiometer, Copenhagen, Denmark). Plasma glucose concentration was measured by the glucose oxidase method (17). Plasma insulin was assayed with a commercial RIA (Linco Research, St. Louis, MO) as previously described (17). The concentration of leptin in plasma and amniotic fluid was measured by a bovine leptin RIA previously validated in ovine plasma (18). Sensitivity of the assay, defined as the lowest standard mass distinguishable from the zero standard, was 0.25 ng/ml. Displacement of 125I-labeled bovine leptin by serial dilution of fetal ovine plasma or amniotic fluid was parallel to that obtained with bovine leptin standard. For all assays, intra- and intercoefficients of variation were <5 and 8%, respectively.
Total RNA was isolated from tissues by the acid guanidinium thiocyanate-phenol-chloroform method and quantified by absorbance at 260 nm (17). Ovine leptin and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA were quantified simultaneously in a ribonuclease protection assay as described previously (17). The leptin probe corresponded to nt +64 to nt +316 (relative to A+1TG) of the ovine leptin cDNA (14) and contains sequence from the last two coding exons of the gene. Signals were quantified by phosphorimaging (Fujix-Bio-Imaging Analyzer BAS 1000, Fuji Medical Systems, Stanford, CT). The GAPDH signal varied significantly across tissues and age. Therefore, leptin signals were normalized to the mass of input RNA. Mass and quality of RNA were assessed by absorbance at A260 (A260/A280 ratios ranged between 1.9 and 2.0) and by denaturing agarose gels stained with Sybrgreen II dye (Molecular probes, Eugene, OR).Statistical methods. Linear regression was used to assess the relation between plasma leptin concentration and time PC and the relation between plasma leptin concentration and fetal or placental weight. One-way analysis of variance was used to assess effects of development on leptin gene expression. A repeated-measure model accounting for time as the fixed effect and animal as the random effect was used to evaluate the effects of nutrition on maternal and fetal variables during late pregnancy. All statistical analyses were performed using the Statistical Analysis System (Cary, NC).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Leptin is present in fetal circulation at day 40 PC.
Blood samples were obtained from well-fed pregnant ewes and their
fetuses at regular intervals from days 40 to 143 PC. Plasma leptin concentration declined in the dams from early to late
pregnancy (P < 0.001; Fig.
1), whereas it increased slightly over
the same time period in fetuses (P < 0.001; Fig. 1).
Neither the number of fetuses borne by the ewe (n = 1 to 3) nor their sex affected leptin concentration in fetal or maternal
plasma. Within a ewe, leptin concentration was always higher in
maternal than in fetal plasma, with overall means of 8.7 ± 1.4 and 2.6 ± 0.2 ng/ml, respectively. At days
140-143 PC, leptin was lower in amniotic fluid than in fetal plasma (1.1 vs. 3.0 ng/ml, P < 0.01, n = 6). The relationship between plasma leptin
concentration and fetal weight was evaluated at day 135 PC
in a subset of ewes (n = 15). There were no significant relationships between fetal or maternal concentration of leptin in plasma and fetal weight (results not shown).
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Expression of leptin mRNA in uteroplacental tissues.
The presence of leptin in fetal plasma at day 40 PC was
unexpected given that white adipose tissue (WAT) is absent before day 70 PC in the sheep (4). Nonadipose
synthesis was first evaluated in uteroplacental tissues because the
placenta expresses leptin in some species (19, 25, 42).
Despite using conditions that are ~600-fold above those required to
detect leptin mRNA in maternal WAT, a signal was not seen in sheep
placenta at any time between days 40 and 140 PC
(Fig. 2). Similarly, gene expression was
never detected between days 40 and 135 PC in
endometrium, myometrium, fused chorioallantoic membrane, and umbilical
tissue (results not shown). Finally, neither fetal nor maternal plasma leptin concentrations were related to placental weight at day 135 PC in ewes fed predicted requirements (results not shown). We
conclude that uteroplacental tissues make negligible contributions to
either the fetal or maternal plasma leptin pool in sheep.
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Leptin is expressed in brain and liver during most of fetal life.
Next, leptin gene expression was surveyed in brain, liver, skeletal
muscle, and kidney obtained from sheep fetuses at days 40 to
130 PC (Fig. 3A).
Leptin mRNA was detected in fetal brain and liver at all stages of
pregnancy. In both tissues, expression peaked between days
40 and 80 PC. Relative to these peak levels, day
130 PC expression declined by 33% in brain (P < 0.01) and by 75% in liver (P < 0.01). In pregnant
ewes, leptin gene expression was absent in liver but remained visible
in the brain at 20% of the level detected at day 130 PC
(Fig. 3B). In contrast, leptin was never detected in kidney
or skeletal muscle during fetal and adult life (Fig. 3A and
results not shown). These data suggest that brain and liver are
significant sites of leptin synthesis during ovine fetal life,
especially before day 80 PC.
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Leptin production by fetal adipose tissue becomes significant in
late pregnancy.
In fetal sheep, the first visible accumulation of fat occurs after
day 70 in the perirenal adipose depot and has the
morphological appearance of brown adipose tissue (4).
Leptin gene expression was easily detected in that depot at day
100 PC and increased 40% by day 130 PC
(P < 0.01; Fig.
4A).
However, at day 130 PC, expression in fetal perirenal
adipose tissue was only 10% of that observed in adult perirenal WAT
(Fig. 4, A and C).
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Effects of moderate maternal undernutrition on fetal plasma leptin.
Next, we examined whether the concentration of leptin in fetal
plasma is regulated by maternal nutrition. Ewes bearing twin fetuses
surgically implanted with chronic catheters were fed either 100% (Fed)
or 55% of estimated nutrient requirements (Underfed) between
days 121 and 135 PC. Fetal lambs from both groups
were healthy as indicated by normal values for hemoglobin content and oxyhemoglobin saturation throughout the treatment period (Table 1).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies on the regulation of leptin synthesis during fetal life have been performed almost exclusively in humans and rodents (12, 22, 29, 30, 34, 54). Leptin is present in fetal plasma by week 17 of pregnancy in humans (21) and at term in rodents (27). In the present study, we show that in sheep, plasma leptin is already present in fetal plasma by day 40 PC. Leptin concentration is consistently lower in the fetal than in the maternal circulation, in agreement with data obtained in humans and rodents (27, 35, 54). Overall, these results suggest that leptin is present in plasma during most of mammalian fetal life.
In human fetuses, adiposity is an important factor influencing plasma leptin concentration. Plasma leptin remains static until week 33 of gestation, and then it increases rapidly parallel with the rate of fat deposition (21, 34). Consequently, plasma leptin in human neonates is correlated with fat mass or related anthropometric characteristics (i.e., fetal weight or ponderal index) (12, 22, 35, 54), and it is increased by conditions associated with greater fatness such as the female sex (34, 35) and gestational diabetes (40, 48). We now show that, in sheep, plasma leptin increases at a very slow rate during fetal life. In contrast to humans, plasma leptin does not increase near birth and is not different between the sexes. These differences may be attributed to the much lower body fat content of fetal sheep, particularly near term (percentage of body weight accounted for by fat tissue, 1.8 vs. 15, sheep vs. human) (4, 11). Nevertheless, our data indicate that at day 130 PC, leptin mRNA abundance in perirenal adipose tissue is many fold higher than that of brain (12-fold) and liver (24-fold). Thus adipose tissue is likely to contribute significantly to plasma leptin in the near-term sheep fetus. A similar conclusion has been reached for the human fetus (Fig. 4) (33).
Absence of adipose depots in fetal sheep before day 70 PC (4) implies that plasma leptin originates from other tissues during early-mid pregnancy. The placenta has been proposed as a possible source based on measurable levels of mRNA in humans, baboons, and rats (19, 25, 26, 42). In the mouse, placental expression is undetectable by Northern analysis (20) and is only seen by ultrasensitive methods (RT-PCR, in situ hybridization; Ref. 29). Even in species with high expression such as humans, this may not be as important as originally thought because <5% of placentally synthesized leptin enters the fetal circulation (38, 39). Here we show that the levels of leptin mRNA reported by others in the sheep placenta by nonquantitative RT-PCR are at best negligible (10, 58). Therefore, the sheep placenta cannot contribute meaningful amounts of leptin to either the fetal or maternal circulation. This includes the period of rapid growth and vascularization of the placenta occurring between days 40 and 80 PC in the sheep (16, 57), when the angiogenic properties of leptin might be anticipated to be the most beneficial (55). Finally, our results also confirm that adipose tissue is, in part, responsible for the rise of plasma leptin in early pregnant ewes (17). This is supported by positive correlation between adipose mRNA levels and plasma concentrations of leptin in pregnant ewes (17). Similar relationships are not observed in pregnant women, presumably because the human placenta contributes significantly to the elevation of maternal plasma leptin (38, 39, 42).
In contrast to the placenta, fetal brain and liver have significant
levels of leptin mRNA, particularly between days 40 and 80 PC, when they represent a disproportionately large
fraction of fetal weight. For example, the liver accounts for 
8% of
fetal body weight at day 40 PC (Ehrhardt, unpublished
observations) and, therefore, could secrete significant amounts of
leptin in the circulation. Our results raise a number of important
issues. First, the developmental profile of leptin gene expression in the fetal brain and liver needs to be characterized before day 40 PC. Detection of leptin in media of cultured fetal brain and liver cells would provide direct evidence of production by these tissues. Second, the hypothalamus and pituitary express the leptin gene
in adult rats (46), but whether these structures account for the presence of leptin mRNA in the fetal and adult sheep brain is
unknown. Finally, the spatial pattern of leptin gene expression in
fetal sheep is, so far, in complete agreement with that of the mouse
(i.e., expression in brain and liver but not in kidney or muscle)
(29, 30). Whether this agreement extends to other tissues
shown to express leptin in the mouse (i.e., heart, hair follicles,
bone, and cartilage) remains to be determined.
In this study, the plasma concentration of leptin in pregnant ewes decreased by 46% within 24 h of feed restriction. This was expected given the negative effects of nutritional insufficiency on the synthesis of leptin in postnatal animals, including ruminants (8, 41, 58). In contrast, the plasma concentration of leptin did not decrease in near-term fetuses, even after 14 days of maternal undernutrition. At least two factors could explain these contrasting maternal and fetal responses. First, the nutritional restriction we used may not have caused a significant reduction in the supply of energy to the fetus. Undernutrition promotes adaptations that maintain delivery of glucose to the fetus, such as decreased insulin responsiveness in maternal tissues (49) and increased placental glucose transport capacity (5). In support of this, maternal undernutrition did not affect fetal weight and only modestly reduced the concentration of fetal plasma glucose, the primary oxidative fuel of conceptus tissues. Second, the fetal production of leptin, particularly that by nonadipose tissues, may not be regulated by nutrient supply. In human fetuses, preeclampsia, hypoxia, and maternal diabetes increase plasma leptin concentration (31, 48) by stimulating placental production (37, 45). Because the ovine placenta does not produce leptin, these factors appear unlikely to have similar effects in sheep fetuses.
The functional significance of fetal leptin remains uncertain. Leptin signaling is apparently not essential for fetal life because ob/ob and db/db mouse embryos are able to complete embryonic life (47). Nevertheless, many have argued that leptin is a positive regulator of growth, based on positive correlations between fetal plasma leptin and various indexes of growth (24, 28). Our data in the sheep offer little support for this hypothesis as no relationships were identified between fetal or maternal plasma leptin and fetal or placental weight. Rather, as discussed above, positive association between fetal plasma leptin and growth is more likely to reflect adiposity and overall energy status of the fetus (12, 50). A recent study even suggested the opposite relationship, i.e., increased plasma leptin in growth-retarded sheep fetuses (10). This study, however, must be viewed cautiously because plasma concentrations were assayed with a commercial RIA and were 5- to 10-fold higher than those measured by others using extensively validated homologous RIA (7, 18, 41, 58). On the other hand, locally produced leptin may support specific processes during embryonic development. Leptin directly stimulates proliferation and differentiation of hematopoietic precursor cells (6, 44), an observation that could be significant given that these processes occur in liver when leptin gene expression is highest (13). Leptin also promotes the proliferation of fetal islet cells (32). Finally, ob/ob neonates have decreased brain weight and abnormal expression of neuronal and glial cell markers, defects that can be corrected by leptin therapy in early postnatal life (1).
Our studies show that plasma concentration and tissue expression of leptin are developmentally regulated in the ovine fetus. A functional role for either source has yet to be defined. Fetal sheep provide an ideal model to perform such studies given their use as a model of human fetal metabolism and the ease with which plasma hormones can be manipulated experimentally in vivo (9, 59).
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ACKNOWLEDGEMENTS |
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We thank R. Rhoads for assistance with tissue collection and R. Slepetis for helping perform surgeries and RIA.
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FOOTNOTES |
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This work was supported by the United States Department of Agriculture National Research Initiative Competitive Grant Program (Award 00-35206-9352 to Y. R. Boisclair) and by the Cornell University Agricultural Experiment Station.
Address for reprint requests and other correspondence: Y. Boisclair, 259 Morrison Hall, Dept. of Animal Science, Cornell Univ., Ithaca, NY 14853 (E-mail: yrb1{at}cornell.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 7, 2002;10.1152/ajpregu.00750.2001
Received 18 December 2001; accepted in final form 1 February 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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) and fetal (
)
plasma leptin concentration was measured by RIA. The relationship
between plasma leptin concentration and day of pregnancy was
significant for dams (y = 17.6 
,
fed; 
, underfed) and analyzed for concentrations of
insulin, glucose, and leptin.