leptin and Placental-Insufficiency

Intra-uterine growth retardation (IUGR), caused by maternal undernutrition or placental insufficiency, is usually associated with disproportionately large reductions in the growth of some fetal organs and tissues (thymus, liver, spleen, thyroid) and impaired cellular development of other tissues (small intestine, secondary wool follicles, skeletal muscle). Growth of other tissues, most notably brain, is relatively unimpaired. In our restudy of postnatal consequences of IUGR in the offspring of prolific ewes, growth-retarded newborn lambs tended to be hypoglycaemic and showed sluggish postnatal engagement of the growth hormone (GH)-insulin-like growth factor (IGF) system. When artificially reared in an optimum environment, low birth weight lambs grew at rates similar to those of normal lambs. However, low birth weight lambs were fatter at any given weight, apparently related to their high energy intakes, especially soon after birth, had low maintenance energy requirements, and limited capacity for bone and muscle growth. These growth characteristics were accompanied by higher plasma concentrations of GH and leptin, and lower concentrations of insulin-like growth factor I (IGF-I) during the first 2 weeks of postnatal life, and higher concentrations of insulin during subsequent growth up to 20 kg body weight. Emerging evidence indicates that in sheep, as in rodents, fetal programming of postnatal cardiovascular and metabolic dysfunctions is associated with IUGR and may be mediated partly by overexposure of the fetus to cortisol. Similar postnatal responses can be elicited by maternal undernutrition or cortisol treatment in early to mid-pregnancy without changing the growth of the fetus or placenta.

Topics: Animals; Animals, Newborn; Female; Fetal Growth Retardation; Growth Disorders; Growth Hormone; Hydrocortisone; Insulin; Insulin-Like Growth Factor I; Leptin; Malnutrition; Maternal Nutritional Physiological Phenomena; Placental Insufficiency; Pregnancy; Sheep; Sheep Diseases

Leptin is an adipocyte-derived hormone that decreases food intake and body weight via its receptor in the hypothalamus. In rodents, it also modulates glucose metabolism by increasing insulin sensitivity. We previously reported that leptin is produced by human placental trophoblasts. We also revealed that leptin gene expression in the placenta was augmented in severe pre-eclampsia, and suggested that placental hypoxia may play a role in this augmentation. Maternal plasma leptin levels correlated well with mean blood pressure, but not with body mass index. Plasma leptin levels in pre-eclamptic women with IUGR were higher than those without IUGR (P< 0.05). We further examined the effects of hyperleptinemia on the course of pregnancy by using transgenic mice (Tg) overexpressing leptin. In pregnant Tg mice, food intake was significantly less than non-Tg, and the fetal body weights were reduced to approximately 70 per cent of those of non-Tg. Resistin is a novel adipocyte-derived hormone that decreases insulin sensitivity and increases plasma glucose concentration, thus contributing the development of obesity-related type II diabetes mellitus. We recently found that resistin gene is expressed in the human placenta as well as adipose tissue. In this review, possible roles of placental leptin and resistin are discussed.

Topics: Adult; Animals; Eating; Female; Fetal Weight; Hormones, Ectopic; Humans; Intercellular Signaling Peptides and Proteins; Leptin; Maternal-Fetal Exchange; Mice; Mice, Transgenic; Nerve Growth Factor; Placenta; Placental Insufficiency; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Proteins; Resistin

We have previously reported a reduced incidence of preeclampsia in women who were at risk and were taking vitamin C (1000 mg/d) and vitamin E (400 IU/d) supplements. In this study, we determined whether supplementation in the same cohort was associated with an improvement in indices of placental dysfunction and oxidative stress toward values determined in women who were at low risk of preeclampsia.. Seventy-nine women who were at high risk and who were taking vitamin supplements and 81 who were taking placebos were compared with 32 women who were at low risk and who were not taking supplements who were studied simultaneously.. Indices of oxidative stress and placental function were abnormal in the placebo group. When the placebo group was compared with the women who were at low risk, ascorbic acid, plasminogen activator inhibitor-2, and placenta growth factor concentrations were decreased; and 8-epi-prostaglandin F(2alpha),leptin, and the plasminogen activator inhibitor-1/-2 ratio were increased. In the group that received vitamin supplements, ascorbic acid, 8-epi-prostaglandin F(2alpha), leptin, and plasminogen activator inhibitor-1/-2 values were similar to women who were at low risk.. Antioxidant supplementation in women who were at risk of preeclampsia was associated with improvement in biochemical indices of the disease.

Topics: Adult; Ascorbic Acid; Dietary Supplements; Endometrium; Female; Humans; Leptin; Oxidative Stress; Placenta; Placenta Growth Factor; Placental Insufficiency; Plasminogen Activator Inhibitor 1; Plasminogen Activator Inhibitor 2; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Risk; Vitamin E

Intrauterine growth restriction (IUGR) is defined as a fetus that fails to achieve its genetically determined growth potential. The exact molecular mechanisms of placental insufficiency IUGR pathogenesis are a little known. Our goal was to identify key genes and gene co-expression modules related to placental insufficiency IUGR.. We used weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis to examine the IUGR dataset GSE114691 from NCBI Gene Expression Omnibus. Core modules and hub nodes of the protein-protein interaction network were identified. A gene network was constructed and genes were classified by WGCNA into different modules. The validation of potential key genes was carried out using additional datasets (GSE12216 and GSE24129).. We identified in GSE114691 539 down regulated genes and 751 up regulated genes in placental tissues characteristic of placental insufficiency IUGR compared with non-IUGR, and defined 76 genes as hub nodes in the protein-protein interaction network. Genes in the key modules of the WGCNA network were most closely associated with placental insufficiency IUGR and significantly enriched in biological process such as cellular metabolic process and macromolecule metabolic process. We identified as key genes TGFB1, LEP, ENG, ITGA5, STAT5A, LYN, GATA3, FPR1, TGFB2, CEBPB, KLF4, FLT1, and PNPLA2. The RNA expression levels of ENG and LEP, as biomarkers, were validated.. A holistic gene expression profile of placental insufficiency IUGR has been generated and the key genes ENG and LEP has potential to serve as circulating diagnosis biomarkers and therapeutic targets for placental insufficiency IUGR.

Topics: Biomarkers; Databases, Genetic; Down-Regulation; Endoglin; Female; Fetal Growth Retardation; Gene Expression Profiling; Gene Regulatory Networks; Humans; Leptin; Placental Insufficiency; Pregnancy; Protein Interaction Maps; Reproducibility of Results; Up-Regulation; Vascular Endothelial Growth Factor Receptor-1

Uteroplacental insufficiency compromises maternal mammary development, milk production and pup organ development; this is ameliorated by cross-fostering, which improves pup growth and organ development and prevents adult diseases in growth-restricted (Restricted) offspring by enhancing postnatal nutrition. Leptin is transported to the fetus from the mother by the placenta; we report reduced plasma leptin concentrations in Restricted fetuses associated with sex-specific alterations in placental leptin transporter expression. Pup plasma leptin concentrations were also reduced during suckling, which may suggest reduced milk leptin transport or leptin reabsorption. Mothers suckled by Restricted pups had impaired mammary development and changes in milk fatty acid composition with no alterations in milk leptin; cross-fostering restored pup plasma leptin concentrations, which may be correlated to improved milk composition and intake. Increased plasma leptin and altered milk fatty acid composition in Restricted pups suckling mothers with normal lactation may improve postnatal growth and prevent adult diseases.. Uteroplacental insufficiency reduces birth weight and adversely affects fetal organ development, increasing adult disease risk. Cross-fostering improves postnatal nutrition and restores these deficits. Mothers with growth-restricted pups have compromised milk production and composition; however, the impact cross-fostering has on milk production and composition is unknown. Plasma leptin concentrations peak during the completion of organogenesis, which occurs postnatally in rats. Leptin is transferred to the fetus via the placenta and to the pup via the lactating mammary gland. This study investigated the effect of uteroplacental insufficiency on pup plasma leptin concentrations and placental leptin transporters. We additionally examined whether cross-fostering improves mammary development, milk composition and pup plasma leptin concentrations. Fetal growth restriction was induced by bilateral uterine vessel ligation surgery on gestation day 18 in Wistar Kyoto rats (termed uteroplacental insufficiency surgery mothers). Growth-restricted (Restricted) fetuses had reduced plasma leptin concentrations, persisting throughout lactation, and sex-specific alterations in placental leptin transporters. Mothers suckled by Restricted pups had impaired mammary development, altered milk fatty acid composition and increased plasma leptin concentrations, despite no changes in milk leptin. Milk intake was reduced in Restricted pups suckling uteroplacental insufficiency surgery mothers compared to Restricted pups suckling sham-operated mothers. Cross-fostering Restricted pups onto a sham-operated mother improved postnatal growth and restored plasma leptin concentrations compared to Restricted pups suckling uteroplacental insufficiency surgery mothers. Uteroplacental insufficiency alters leptin homeostasis. This is ameliorated with cross-fostering and enhanced milk fatty acid composition and consumption, which may protect the pups from developing adverse health conditions in adulthood.

Topics: Animals; Female; Fetal Growth Retardation; Leptin; Mammary Glands, Animal; Milk; Nutritional Support; Placental Insufficiency; Pregnancy; Rats; Rats, Wistar

Being born small programs adult diseases later in life, with the early postnatal growth rate in growth-restricted offspring playing a role in the reduction of the risk of disease in adulthood. In addition, early postnatal growth is critical for puberty onset (PO). Using cross-fostering, we determined the effects of growth restriction and prenatal and postnatal environments on PO and sex steroids. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control), performed on Gestational Day 18 in Wistar-Kyoto rats induced fetal growth restriction. Control, Reduced (Control litter size reduced to five pups) and Restricted pups were cross-fostered onto different Control (normal lactation) or Restricted (impaired lactation) mothers on Day 1. The day of vaginal opening (females) and balanopreputial separation (males) characterised PO. Blood was sampled for sex steroid and leptin analysis. Restricted pups were born lighter than Controls (P<0.05). PO was delayed by 3.4-4 days in Restricted-on-Restricted males and females (P<0.05). Plasma leptin concentrations at PO were lower in both sexes in all groups compared with Restricted-on-Control and Control-on-Control (P<0.05). PO occurred earlier in Restricted-on-Control (~2 days) with normal leptin concentrations and accelerated growth compared with Restricted-on-Restricted (P<0.05). Testosterone concentrations were lower in male Restricted-on-Restricted than Control-on-Control at 6 months (P<0.05). Restricted-on-Restricted females had lower progesterone at PO compared with Control-on-Control (P<0.05). Female Restricted-on-Restricted had lower oestradiol, with Restricted-on-Control having higher testosterone concentrations at 6 months than Control-on-Control (P<0.05). Growth restriction reduced postnatal growth and leptin concentrations, delaying PO in both sexes and programming altered sex steroids. This highlights the importance of the interaction between prenatal and postnatal growth in the programming of adult reproductive status.

Topics: Age Factors; Animals; Estradiol; Female; Lactation; Leptin; Male; Parturition; Placental Insufficiency; Pregnancy; Rats; Rats, Inbred WKY; Sexual Maturation; Testosterone

Leptin availability in perinatal life critically affects metabolic programming. We tested the hypothesis that uteroplacental insufficiency and intrauterine stress affect perinatal leptin availability in rat offspring. Pregnant rats underwent bilateral uterine vessel ligation (LIG; n = 14), sham operation (SOP; n = 12), or no operation (controls, n = 14). Fetal livers (n = 180), placentas (n = 180), and maternal blood were obtained 4 hours (gestational day [E] 19), 24 hours (E20), and 72 hours (E22) after surgery. In the offspring, we took blood samples on E22 (n = 44), postnatal day (P) 1 (n = 29), P2 (n = 16), P7 (n = 30), and P12 (n = 30). Circulating leptin (ELISA) was significantly reduced in LIG (E22, P1, P2) and SOP offspring (E22). Postnatal leptin surge was delayed in LIG but was accelerated in SOP offspring. Placental leptin gene expression (quantitative RT-PCR) was reduced in LIG (E19, E20, E22) and SOP (E20, E22). Hepatic leptin receptor (Lepr-a, mediating leptin degradation) gene expression was increased in LIG fetuses (E20, E22) only. Surprisingly, hypoxia-inducible factors (Hif; Western blot) were unaltered in placentas and were reduced in the livers of LIG (Hif1a, E20; Hif2a, E19, E22) and SOP (Hif2a, E19) fetuses. Gene expression of prolyl hydroxylase 3, a factor expressed under hypoxic conditions contributing to Hif degradation, was increased in livers of LIG (E19, E20, E22) and SOP (E19) fetuses and in placentas of LIG and SOP (E19). In summary, reduced placental leptin production, increased fetal leptin degradation, and persistent perinatal hypoleptinemia are present in intrauterine growth restriction offspring, especially after uteroplacental insufficiency, and may contribute to perinatal programming of leptin resistance and adiposity in later life.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Female; Hypoxia-Inducible Factor 1, alpha Subunit; Leptin; Liver; Placenta; Placental Insufficiency; Pregnancy; Rats; Rats, Wistar; Receptors, Leptin; RNA, Messenger

To measure amniotic fluid leptin levels in fetuses with twin-twin transfusion syndrome (TTTS) with and without placental insufficiency (PI) and determine its usefulness as a biomarker of PI.. A retrospective case control study of TTTS stage III patients from 2009 to 2011 was conducted. Cases were pregnancies with PI (TTTS-PI, n = 18) matched by stage, gestational age, and degree of cardiomyopathy to controls without PI (TTTS, n = 26). PI was strictly defined using biometric parameters. Amniotic fluid from recipient twins (RT) was taken during second trimester fetoscopic laser therapy. Leptin concentrations were determined and compared to growth parameters and birth weight.. RT-adjusted leptin was 66% higher in TTTS-PI (p = 0.016) compared to TTTS controls. Cases had significantly higher growth discordance (p = 0.004) and lower RT birth weight (p = 0.041) compared to controls. Significantly higher adjusted leptin levels were observed at birth in the TTTS-PI group when comparing those with SGA donor twins to those of normal weight (p = 0.016).. These data suggest a role for leptin in pregnancies complicated by TTTS with placental insufficiency. However, further studies are needed to define its mechanism and potential role as a biomarker in amniotic fluid for placental pathophysiology.

Topics: Adult; Amniotic Fluid; Biomarkers; Case-Control Studies; Female; Fetofetal Transfusion; Humans; Leptin; Placental Insufficiency; Pregnancy; Pregnancy Trimester, Second; Retrospective Studies

Low birth weight and catch-up growth predict increased adiposity in children and adults. This may be due in part to leptin resistance, as adults who were born small exhibit increased plasma leptin concentration relative to adiposity. Placental restriction (PR), a major cause of intrauterine growth restriction, reduces size at birth and increases feeding activity and adiposity by 6 wk in sheep. We hypothesized that PR would increase plasma leptin concentration and alter its relationship with feeding activity and adiposity in young lambs. Body size, plasma leptin, feeding activity, adiposity, leptin, and leptin receptor gene expression in adipose tissue were measured (12 control, 12 PR). PR reduced size at birth and increased adiposity. Plasma leptin concentration decreased with age, but to a lesser extent after PR and correlated positively with adiposity similarly in control and PR. PR increased plasma leptin concentration and perirenal adipose tissue leptin expression. Feeding activity correlated negatively with plasma leptin concentration in controls, but positively after PR. PR increases adipose tissue leptin expression and plasma leptin concentration, however, this increased abundance of peripheral leptin does not inhibit feeding activity (suckling event frequency), suggesting PR programs resistance to appetite and energy balance regulation by leptin, leading to early onset obesity.

Topics: Adipose Tissue; Adiposity; Age Factors; Animals; Animals, Newborn; Animals, Suckling; Birth Weight; Blood Glucose; Disease Models, Animal; Fatty Acids, Nonesterified; Feeding Behavior; Female; Fetal Growth Retardation; Hyperphagia; Insulin; Lactation; Leptin; Male; Placental Insufficiency; Pregnancy; Receptors, Leptin; Sheep; Up-Regulation

Although small size at birth is associated with hypertension and associated co-morbidities such as insulin resistance and type II diabetes mellitus, many of the animal models employed to simulate this phenomenon do not closely mimic the ontogeny of growth restriction observed clinically. While intrauterine growth restriction (IUGR) is often detected near mid-pregnancy in women and persists until term, most rodent models of IUGR employ ligation of uterine arteries for a brief period during late gestation (days 19-21 of pregnancy). We hypothesized that IUGR associated with chronic reduction in uteroplacental perfusion (RUPP) and placental ischemia during the third trimester of pregnancy in the rat alters the amniotic fluid (AF) environment and results in hypertensive offspring presenting with metabolic abnormalities such as glucose intolerance and insulin resistance. Insulin-like growth factor-1 (IGF-1), IGF-2, Na(+) concentration and oxidative stress in the AF were increased, while K(+) concentration was decreased in the RUPP compared with normal pregnant (NP) fetuses. RUPP-offspring (RUPP-O) were smaller (6.1 +/- 0.2 versus 6.7 +/- 0.2 g; P < 0.05) at birth compared with NP-offspring (NP-O) groups. At nine weeks of age, mean arterial pressure (121 +/- 3 versus 107 +/- 5 mmHg; P < 0.05), fasting insulin (0.71 +/- 0.014 versus 0.30 +/- 0.08 ng/mL; P < 0.05), glucose (4.4 +/- 0.2 versus 3.1 +/- 0.3 mmol/L; P < 0.05), leptin (3.8 +/- 0.5 versus 2.3 +/- 0.3 ng/mL; P < 0.05) and the homeostasis model assessment of insulin resistance index was greater (2.9 +/- 0.6 versus 1.0 +/- 0.3; P < 0.05) in the RUPP-O compared with the NP-O rats. These data indicate that chronic placental ischemia results in numerous alterations to the fetal environment that contributes to the development of impaired glucose metabolism, insulin resistance and hyperleptinemia in young offspring.

Topics: Amniotic Fluid; Animals; Animals, Newborn; Birth Weight; Blood Glucose; Cholesterol; Female; Glucose Tolerance Test; Insulin Resistance; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Ischemia; Leptin; Oxidative Stress; Placenta; Placental Insufficiency; Pregnancy; Rats; Rats, Sprague-Dawley; Sodium; Triglycerides

Regulatory process may be altered in response to the intrauterine environment, leading to the development of altered growth trajectory and disease later in life. Previously, our lab reported reduced leptin levels in pregnant hypertensive Sprague-Dawley rat dams with placental insufficiency. The purposes of this study were to investigate the relationship between leptin levels, growth and hypertension in two generations of offspring exposed to placental insufficiency. Leptin levels were significantly different only at 12 weeks in female first generation offspring (p < 0.05). Variations in postnatal body and organ weights were evident in first generation females at 3 and 12 weeks of age. There were no significant correlations with plasma leptin levels and systolic blood pressure in offspring groups at any age point. Our findings indicate that fetal exposure to maternal hypertension and hypoleptinemia is associated with altered leptin and growth patterns in mature female offspring and not perpetuated to a second generation.

Topics: Animals; Blood Pressure; Body Weight; Female; Growth; Leptin; Placental Insufficiency; Pregnancy; Rats; Rats, Sprague-Dawley

Placental restriction (PR) of fetal growth results in a low birth weight and an increased visceral fat mass in postnatal life. We investigated whether PR alters expression of genes that regulate adipogenesis [IGF1, IGF1 receptor (IGF1R), IGF2, IGF2R, proliferator-activated receptor-gamma, retinoid-X-receptor-alpha], adipocyte metabolism (lipoprotein lipase, G3PDH, GAPDH) and adipokine signaling (leptin, adiponectin) in visceral adipose tissue before birth. PR was induced by removal of the majority of endometrial caruncles in nonpregnant ewes before mating. Fetal blood samples were collected from 116 days gestation, and perirenal visceral adipose tissue (PAT) was collected from PR and control fetuses at 145 days. PAT gene expression was measured by quantitative RT-PCR. PR fetuses had a lower weight (PR 2.90 +/- 0.32 kg; control, 5.12 +/- 0.24 kg; P < 0.0001), mean gestational arterial Po(2) (P < 0.0001), plasma glucose (P < 0.01), and insulin concentrations (P < 0.02), than controls. The expression of IGF1 mRNA in PAT was lower in the PR fetuses (PR, 0.332 +/- 0.063; control, 0.741 +/- 0.083; P < 0.01). Leptin mRNA expression in PAT was also lower in PR fetuses (PR, 0.077 +/- 0.009; control, 0.115 +/- 0.013; P < 0.05), although there was no difference in the expression of other adipokine or adipogenic genes in PAT between PR and control fetuses. Thus, restriction of placental and hence, fetal substrate supply results in decreased IGF1 and leptin expression in fetal visceral adipose tissue, which may alter the functional development of the perirenal fat depot and contribute to altered leptin signaling in the growth-restricted newborn and the subsequent emergence of an increased visceral adiposity.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; DNA, Complementary; Fatty Acids, Nonesterified; Female; Fetal Development; Fetus; Glyceraldehyde-3-Phosphate Dehydrogenases; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Kidney; Leptin; Lipoprotein Lipase; Oxygen; Placental Insufficiency; PPAR gamma; Pregnancy; Receptor, IGF Type 1; Receptor, IGF Type 2; Retinoid X Receptor alpha; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sheep

An adequate supply of taurine during fetal life is important for normal beta-cell development and insulin action. An altered availability of taurine may programme glucose metabolism in utero and result in type 2 diabetes in adult age. We examined whether maternal taurine supplementation in late pregnant rats affects postnatal growth, adult body composition, insulin sensitivity and endogenous insulin secretion in intrauterine growth restricted (IUGR) and normal offspring. Uterine artery ligation or sham operations were performed on gestational day (GD) 19. Taurine supplementation was given to half of the dams from GD 18 until term, resulting in four groups of offspring: sham (n = 22), sham/taurine (n = 22), IUGR (n = 22) and IUGR/taurine (n = 24). The offspring were studied at 12 weeks of age. In offspring with normal birth weight, fetal taurine supplementation markedly stimulated postnatal growth. In sham/taurine females, fat depots, plasma free fatty acid and leptin concentrations were increased, and insulin sensitivity was reduced. Insulin sensitivity was unaltered in IUGR and IUGR/taurine offspring. However, whereas IUGR offspring showed little catch-up growth, 50% of IUGR/taurine animals displayed complete catch-up at 12 weeks of age, and these animals had increased fat depots and reduced insulin sensitivity. In conclusion, taurine supplementation in late gestation resulted in accelerated postnatal growth, which was associated with adult obesity and insulin resistance in both IUGR and normal offspring. This effect was particularly evident in females. These data suggest that fetal taurine availability is an important determinant for postnatal growth, insulin sensitivity and fat accumulation.

Topics: Adipose Tissue; Animals; Animals, Newborn; Body Composition; Body Weight; Female; Gestational Age; Glucose Clamp Technique; Hyperglycemia; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Lipid Metabolism; Maternal Nutritional Physiological Phenomena; Obesity; Placental Insufficiency; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Taurine

The prenatal nutritional environment influences the subsequent risk of hypertension in adulthood. Animal studies have used, generally, the rat as a model species to illustrate the association between maternal nutrient intake and blood pressure in the resulting adult offspring. No study to date has shown programming of adult cardiovascular function in the sheep through maternal dietary intervention. We therefore fed pregnant sheep to either 100% recommended intake from day 0 of gestation to term [ approximately 147 days gestational age (dGA); controls n = 8] or to 50% recommended intake from day 0 to 95 dGA and thereafter to 100% intake (NR; n = 9). Sheep lambed naturally, offspring were weaned at 16 wk, and the male offspring were reared on pasture until 3 yr of age. At this time, cardiovascular catheters were inserted under halothane anesthesia and sheep were allowed 2-4 days recovery. Basal cardiovascular status and pressor responses to infusion of norepinephrine, angiotensin II, and captopril were then assessed alongside basal plasma concentrations of glucose, cortisol, and leptin. NR sheep were of similar birth weight to controls but at 3 yr of age had higher blood pressure before, but not after, feeding. Peripheral sensitivity to vasoconstrictor infusion was similar between dietary groups, although a reflex bradycardia was not apparent in NR sheep during norepinephrine infusion. Circulating leptin correlated well with fat mass and increased more after vasoconstrictor infusion in NR sheep. In conclusion, early NR has been shown to program aspects of cardiovascular control and adipocyte function in adult sheep.

Topics: Algorithms; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Baroreflex; Birth Weight; Blood Glucose; Blood Pressure; Body Composition; Captopril; Female; Heart Rate; Hemodynamics; Hormones; Hydrocortisone; Leptin; Male; Norepinephrine; Placental Insufficiency; Pregnancy; Prenatal Exposure Delayed Effects; Sheep; Stress, Physiological; Vasoconstrictor Agents

To investigate placental leptin production in placental insufficiency, placental leptin production was measured in women with severe preeclampsia (group 1) and in normotensive pregnancies associated with intrauterine growth restriction (group 2), compared to controls (group 3). Placental leptin content was increased 3-fold in group 1 compared to group 2 (192.5.1 +/- 39.5 vs. 67.8 +/- 10.6 ng/g) and 8-fold in group 1 compared to group 3 (192.5.1 +/- 39.5 vs. 25.4 +/- 6.9 ng/g). Placental leptin content was positively correlated with maternal leptin/BMI ratio (r = 0.62) and the resistance index of the umbilical artery (r = 0.60). These data demonstrate that placental insufficiency is associated with a dramatic increase in placental leptin production. This results in a rise in maternal leptinemia that may be taken as an early index of placental dysfunction.

Topics: Adult; Birth Weight; Body Mass Index; Cross-Sectional Studies; Female; Fetal Blood; Fetal Growth Retardation; Humans; Leptin; Organ Size; Placenta; Placental Insufficiency; Pre-Eclampsia; Pregnancy; RNA, Messenger; Umbilical Arteries; Vascular Resistance

Various hypothalamic functions such as feeding behavior, energy expenditure, body weight gain, level of anxiety, and sexual maturation are mediated by a balance between the concentrations of neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). To test the hypothesis that maternal uteroplacental insufficiency alters the offspring's brain NPY and/or CRF levels, we examined the effect of maternal uterine artery ligation with intrauterine growth restriction (IUGR) (p < 0.05) upon fetal (20 d) and postnatal (4, 14, and 21 d) brain NPY and CRF synthesis, concentrations, and regional distribution. An age-related increase in NPY (0.8 kb) and CRF (1.4 kb) mRNA levels with peak amounts at the 14-d postnatal age (p < 0.05) was observed. IUGR was associated with a 75% increase in fetal brain NPY mRNA levels (p < 0.05) with no change in NPY peptide, CRF mRNA and peptide amounts. Although the increase in NPY mRNA levels persisted postnatally (p < 0.05) at d 4 and 21, CRF mRNA amounts were 2.5-fold higher only in the 4-d IUGR (p < 0.05). Paralleling the mRNA changes, an age-related increase in RIA of NPY and CRF peptide concentrations was noted (p < 0.05). IUGR caused postnatal brain NPY and CRF peptide changes similar to corresponding mRNA levels (p < 0.05), despite normal postnatal circulating glucose, insulin, corticosterone, and leptin concentrations. The age-specific intergroup differences in the NPY and CRF peptide immunoreactivity appeared predominantly in the hypothalamic region. We conclude that maternal uteroplacental insufficiency causing IUGR leads to a pretranslational imbalance in the immediate (4 d) postnatal brain NPY and CRF peptide concentrations, thereby altering the developmental pattern. This alteration in NPY and CRF peptide concentrations, despite normalization of the metabolic milieu was associated with a persistent diminution in body weight. The IUGR-associated pretranslational increase in NPY and not CRF peptide levels at d 21, may herald changes in feeding behavior during the postsuckling phase.

Topics: Animals; Animals, Suckling; Blood Glucose; Brain; Corticosterone; Corticotropin-Releasing Hormone; Female; Gene Expression; Insulin; Leptin; Neuropeptide Y; Placental Circulation; Placental Insufficiency; Pregnancy; Proteins; Rats; Rats, Sprague-Dawley