leptin and Fetal-Growth-Retardation

Leptin is secreted by the placenta and has a multi-facetted role in the regulation of functions related to pregnancy. Metabolic disorders and insufficient homeostatic compensatory mechanisms involving leptin during pregnancy play a decisive role in the development of pre-eclampsia (PE) and give rise to compromised intrauterine growth conditions and aberrant birth weight of offspring. This review was compiled to elucidate the metabolic background of PE and its relationship with adverse intrauterine growth conditions through the examination of leptin as well as to describe possible mechanisms linking leptin to fetal growth restriction. This review illustrates that leptin in PE is dysregulated in maternal, fetal, and placental compartments. There is no single set of unifying mechanisms within the spectrum of PE, and regulatory mechanisms involving leptin are specific to each situation. We conclude that dysregulated leptin is involved in fetal growth at many levels through complex interactions with parallel pregnancy systems and probably throughout the entirety of pregnancy.

Topics: Animals; Female; Fetal Growth Retardation; Humans; Leptin; Placenta; Pre-Eclampsia; Pregnancy; Receptors, Leptin

Maternal and perinatal undernutrition affects the lung development of litters and it may produce long-lasting alterations in respiratory health. This can be demonstrated using animal models and epidemiological studies. During pregnancy, maternal diet controls lung development by direct and indirect mechanisms. For sure, food intake and caloric restriction directly influence the whole body maturation and the lung. In addition, the maternal food intake during pregnancy controls mother, placenta, and fetal endocrine systems that regulate nutrient uptake and distribution to the fetus and pulmonary tissue development. There are several hormones involved in metabolic regulations, which may play an essential role in lung development during pregnancy. This review focuses on the effect of metabolic hormones in lung development and in how undernutrition alters the hormonal environment during pregnancy to disrupt normal lung maturation. We explore the role of GLP-1, ghrelin, and leptin, and also retinoids and cholecalciferol as hormones synthetized from diet precursors. Finally, we also address how metabolic hormones altered during pregnancy may affect lung pathophysiology in the adulthood.

Topics: Animals; Cholecalciferol; Female; Fetal Development; Fetal Growth Retardation; Ghrelin; Glucagon-Like Peptide 1; Hormones; Humans; Leptin; Lung; Malnutrition; Maternal Nutritional Physiological Phenomena; Pregnancy; Retinoids; Tretinoin

Monitoring leptin concentration in maternal blood would be useful for earlier identification of mothers at risk of delivering small for gestational age (SGA) neonates. This study was performed to examine whether maternal blood leptin concentrations are different between SGA neonates and healthy controls. Meta-analysis was performed to summarize the data of all English-language studies providing the numbers of SGA neonates, the numbers of healthy controls, and the means and standard deviations of maternal blood leptin concentrations in these two groups. The studies were collected by searching ten databases including PubMed (MEDLINE) and investigating the PubMed Related Citations and bibliographic references. The Newcastle-Ottawa Scale was used to assess study quality. Publication bias was assessed using Egger's test. The primary outcome of this study was the standardized mean difference (SMD) in maternal blood leptin concentration between SGA neonates and healthy controls. Thirty-two overall good-quality studies involving 1734 women and their neonates were extracted from 17 articles. Synthetic evidence did not indicate statistically significant SMD in maternal blood leptin concentration between SGA neonates and healthy controls (P = 0.172). Egger's test showed no publication bias (P = 0.309).Conclusion: Maternal blood leptin concentration is not significantly different between SGA neonates and healthy controls. What is Known: • Monitoring leptin concentration in maternal blood would be useful for earlier identification of mothers at risk of delivering small for gestational age (SGA) neonates. What is New: • The results of this meta-analysis including 1734 women and their neonates in 32 overall good-quality studies showed that maternal blood leptin concentration is not significantly different between SGA neonates and healthy controls.

Topics: Biomarkers; Case-Control Studies; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Mothers; Pregnancy

Intrauterine growth restriction (IUGR) has been identified as a risk factor for adult chronic kidney disease (CKD), including hypertension (HTN). Accelerated postnatal catch-up growth superimposed to IUGR has been shown to further increase the risk of CKD and HTN. Although the impact of excessive postnatal growth without previous IUGR is less clear, excessive postnatal overfeeding in experimental animals shows a strong impact on the risk of CKD and HTN in adulthood. On the other hand, food restriction in the postnatal period seems to have a protective effect on CKD programming. All these effects are mediated at least partially by the activation of the renin-angiotensin system, leptin and neuropeptide Y (NPY) signaling and profibrotic pathways. Early nutrition, especially in the postnatal period has a significant impact on the risk of CKD and HTN at adulthood and should receive specific attention in the prevention of CKD and HTN.

Topics: Animals; Child Development; Disease Models, Animal; Fetal Growth Retardation; Humans; Hypertension; Infant Nutritional Physiological Phenomena; Infant, Low Birth Weight; Infant, Newborn; Leptin; Metabolic Networks and Pathways; Neuropeptide Y; Nutritional Status; Renal Insufficiency, Chronic; Renin-Angiotensin System

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency and aberration in sex hormone levels. As a neurotrophic hormone that is intimately involved in the cardiovascular regulation and whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus a therapeutic agent. As a product of maternal and late fetal adipocytes and the placenta, circulating leptin typically surges late in gestation and declines after delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish the circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction-adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates the leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation.

Topics: Adiposity; Adult; Animals; Animals, Newborn; Disease Models, Animal; Female; Fetal Growth Retardation; Hormone Replacement Therapy; Humans; Hypertension; Hypothalamus; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Leptin; Male; Mice; Nerve Tissue Proteins; Neurodevelopmental Disorders; Pregnancy; Receptors, Leptin; Recombinant Proteins; Signal Transduction

It is well known that adverse conditions during intrauterine life, such as intrauterine growth restriction (IUGR), can result in permanent changes in the physiology and metabolism of the newborn, which in turn leads to an increased risk of disease in adulthood (fetal origin of adult disease hypothesis). In the first part of this review the epidemiological studies in which a correlation between low birth weight and chronic pathologies in adulthood was observed are reported. The second part of the review is focused on metabolomics studies that have revealed an altered metabolism in IUGR patients compared to controls. Together with more classic biomarkers of IUGR, such as endothelin-1, leptin, protein S100B and visfatin, the new holistic metabolomics approach has assumed a crescent role in the identification of disorders in the neonatal metabolic profile, determined by the interconnection of the different processes.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Endothelin-1; Epigenomics; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Genotype; Humans; Infant, Low Birth Weight; Infant, Newborn; Leptin; Metabolomics; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Risk Factors

The incidence of obesity is rapidly increasing all over the world in epidemic proportions.The epidemia now affects young children and accumulative evidences suggest that the origin of the disease may occur during foetal development and early life. This has introduced the concept of "developmental programming" supported by experimental studies in animal models and numerous epidemiological data. This concept supports the idea that nutritional and hormonal status during pregnancy and early life could interfere irreversibly on the development of the organs involved in the control of food intake and metabolism and particularly the hypothalamic structures responsible of the establishment of the ingestive behaviour and regulation of energy expenditure. The mechanisms responsible of this developmental programming remain poorly documented. However, recent research indicate that the adipokine leptin plays a critical role in this programming.

Topics: Animals; Eating; Female; Fetal Growth Retardation; Genomic Imprinting; Humans; Leptin; Obesity; Pregnancy; Risk Factors

Recent epidemiology demonstrates higher rate of obesity and metabolic syndrome in offspring with undernutrition in utero. IUGR babies with intrauterine undernutrition grow rapidly to catch up with normal growth course. Leptin is an adipocyte derived satiety factor that regulates food intake and energy expenditure. We demonstrated in mice model with maternal food restriction during pregnancy that premature leptin surge during neonatal catch up growth of the offspring lead them to impaired leptin sensitivity and obesity in adulthood.

Topics: Animals; Disease Models, Animal; Eating; Energy Intake; Female; Fetal Growth Retardation; Humans; Leptin; Malnutrition; Metabolic Syndrome; Obesity; Pregnancy; Pregnancy Complications

Topics: Animals; Animals, Newborn; Animals, Suckling; Disease Models, Animal; Fatty Acids, Unsaturated; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Humans; Infant, Newborn; Lactation; Leptin; Maternal Nutritional Physiological Phenomena; Pregnancy; Prenatal Nutritional Physiological Phenomena; Rats

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11beta-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.

Topics: Animals; Disease Models, Animal; Female; Fetal Growth Retardation; Glucose; Humans; Insulin Resistance; Leptin; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Protein Deficiency; Rats

Preeclampsia and intrauterine growth restriction are both characterized by placental malfunction. The pathological processes of abnormal trophoblast invasion, partial absence of maternal spiral artery modification, increased apoptosis of trophoblast cells, and placental ischemia are all associated with the release of specific molecules. These proteins, as well as cell-free fetal DNA and RNA might be detected in the maternal peripheral circulation, quantified, and used for early identification and prediction of preeclampsia and intrauterine growth restriction, prior to the appearance of the clinical symptoms. As preeclampsia and intrauterine growth restriction are associated with increased maternal, perinatal, and neonatal morbidity and mortality, early identification of these pregnancy associated complications will permit the design of appropriate preventive measures. In this review a variety of factors reported to be useful as potential markers for early detection of pregnancies at increased risk will be discussed. Molecules associated with the establishment of the placenta and essential in fetal-maternal interactions, like interleukin 2-receptor, insulinlike growth factor-1, and insulinlike growth factor binding protein-1, placenta growth factor, hepatocyte growth factor, inhibin A, activin A, and human chorionic gonadotrophin seem to be the most likely candidates for presymptomatic markers for preeclampsia and/or intrauterine growth restriction. Detection and discrimination of these molecules through the placental RNA in maternal plasma based strategy has become a realistic option.

Topics: ATPases Associated with Diverse Cellular Activities; Biomarkers; Cell Adhesion Molecules; Cytokines; Female; Fetal Growth Retardation; Fibronectins; Humans; Leptin; Metalloendopeptidases; Placenta Growth Factor; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Complications; Pregnancy Proteins

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

There is clear evidence of placental leptin production, as shown recently in trophoblast cultures and by dual in vitro placenta perfusion (median production of 225 pg/min per g of tissue; 98.4% released into the maternal and 1.6% into the fetal circulation). However, the physiological impact for the mother and the fetus is unclear. The classical role of leptin is to provide information about energy stores to the central nervous system, and to reduce appetite if the energy stores are full. In pregnancy, maternal plasma leptin concentrations are elevated, and lack the well established correlation with body fat energy stores that is observed in non-pregnant women, indicating an alternative function for leptin during pregnancy and fetal development. Maternal and fetal plasma leptin levels are dysregulated in pathological conditions such as gestational diabetes, pre-eclampsia and intra-uterine growth retardation, representing an effect or a cause of disturbances in the feto/placento/maternal unit.

Topics: Female; Fetal Blood; Fetal Growth Retardation; Fetus; Humans; Hypoxia; Leptin; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications

Classical gene targeting has identified many genes important for fetal and placental development. Null mutation of these genes may lead to fetal growth restriction, malformation or embryonic death. Growth restriction of epigenetic basis can predispose to adult-onset diseases. The mechanisms underlying this process, termed 'fetal programming', are beginning to be understood.

Topics: Animals; Cardiovascular System; Embryonic and Fetal Development; Endocrine System; Female; Fetal Growth Retardation; Genetic Techniques; Glucocorticoids; Humans; Hypertension; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Leptin; Mice; Placenta; Pregnancy

Intrauterine growth retardation (IUGR) is characterized by the failure of the fetus to grow at a normal rate in utero and is associated with a number of endocrine and metabolic changes. Our knowledge of the placental nutrient supply and the endocrine status of the fetal-placental unit during pregnancies involving IUGR has greatly increased over the past decade as a result of the availability of fetal blood samples obtained under relatively steady state conditions. These studies have provided evidence that the supply of glucose is impaired only under severe conditions, whereas placental transfer of amino acids is reduced even in fetuses with normal oxygenation and feto-placental blood flow. Moreover, significant in utero relationships have been reported between fetal weight and circulating levels of growth factors such as insulin-like growth factor-I and leptin. When measured per kg fetal weight, however, levels of leptin are significantly higher in growth-retarded fetuses, with abnormal feto-placental blood flow and reduced oxygen content. The metabolic and endocrine changes observed should be interpreted in relation to the severity of the disease.

Topics: Adaptation, Physiological; Endocrine System; Female; Fetal Growth Retardation; Fetus; Humans; Leptin; Nutritional Physiological Phenomena; Pregnancy

Molecular genetics will continue to help us to make precise diagnoses. At present, the expertise to achieve this for a specific disease is often exclusive to one unit with a research interest. It will be important to establish a coordinated approach at a supraregional level to provide molecular diagnosis for rare disorders as a fast reliable clinical service. In addition understanding the molecular mechanisms of disease is likely to direct a search for new treatments. For instance, calcium channel blockers have been used in nesidoblastosis to reduce the hypersecretion of insulin, as a result of the recognition of the role that calcium has in the function of the beta-cell ATP sensitive K+ channel. Although the potential benefits of hGH are now being clearly defined in a range of growth disorders, the treatment is invasive and expensive. It is likely that future endocrine therapeutic developments could include slow release growth hormone preparations, orally active growth hormone mimetics, or even hormone production from an ectopic viral cDNA vector. The next "advances in endocrinology" will also reveal whether leptin will have a therapeutic role in appetite control or even the modulation of pubertal development.

Topics: Endocrine System Diseases; Female; Fetal Growth Retardation; Growth Hormone; GTP-Binding Proteins; Humans; Leptin; Pregnancy; Prenatal Exposure Delayed Effects; Proteins

The effects of undernutrition during pregnancy on prenatal and postnatal development of the offspring were evaluated in sows with obesity/leptin resistance. Females were fed, from day 35 of pregnancy onwards, a diet fulfilling either 100% (group control, n=10) or 50% of the nutritional requirements (group underfed, n=10). In the control group, maternal body weight increased during pregnancy (P<0.05) while it decreased or remained steady in the underfed group. At days 75 and 100 of gestation, plasma triglycerides were lower but urea levels were higher in restricted than in control sows (P<0.05 for both). Assessment of the offspring indicated that the trunk diameter was always smaller in the restricted group (P<0.01 at day 50, P<0.005 at days 75 and 100 and P<0.0001 at birth) while head measurements were similar through pregnancy, although smaller in the restricted than in the control group at birth (P<0.05). Newborns from restricted sows were also lighter than offspring from control females (P<0.01) and had higher incidence of growth retardation (P<0.01). Afterwards, during lactation, early postnatal growth in restricted piglets was modulated by gender. At weaning, males from restricted sows were still lighter than their control counterparts (P<0.05), while females from control and underfed sows were similar. Thus, the current study indicates a gender-related differential effect in the growth patterns of the piglets, with females from restricted sows evidencing catch-up growth to neutralise prenatal retardation and reaching similar development than control counterparts.

Topics: Animals; Animals, Newborn; Body Weight; Caloric Restriction; Drug Resistance; Female; Fetal Growth Retardation; Food; Leptin; Male; Obesity; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Sex Characteristics; Swine

Fetal growth improves in pregnant women who take daily maternal multiple micronutrients [United Nations International Multiple Micronutrient Preparation (UNIMMAP)] rather than iron and folic acid (IFA) alone.. Our objective was to test whether such an effect was mediated by changes in concentrations of cord hormones.. In a double-blind, controlled trial carried out in Burkina Faso, we randomly assigned 1426 pregnant women to receive UNIMMAP or IFA supplements. We measured concentrations of insulin-like growth factor I (IGF-I), leptin, insulin, free thyroxine, and cortisol in cord serum in a subsample of 294 live single newborns. We performed mediation analysis with an Aroian test.. UNIMMAP supplementation had no significant effect on cord hormone concentrations. However, UNIMMAP supplementation significantly affected concentrations of IGF-I (+30%; 95% CI: 8%, 52%; P = 0.009) and leptin in male newborns. In these infants, 51.1% (P = 0.08) of the effect of UNIMMAP supplementation on birth weight was mediated through IGF-I, whereas for female newborns, this proportion was negligible. UNIMMAP supplementation also increased cortisol concentrations by 36% (P = 0.009) in cord blood in primiparae (P for interaction = 0.02). Growth-retarded infants had 41.2% lower IGF-I (P < 0.0001) and 27.3% lower leptin (P = 0.04) than did infants with normal growth. Offspring of primiparae had reduced IGF-I and insulin concentrations, and their cortisol concentrations were 25% higher (P = 0.05). Male newborns had lower concentrations of IGF-I, leptin, and insulin than did female newborns.. UNIMMAP supplementation had sex-specific effects on cord IGF-I and leptin concentrations that were of unclear clinical significance. Other pathways may have been involved in the action of UNIMMAP on fetal growth. The specific hormonal pattern in primiparae could be related to constrained fetal growth. Confirmatory studies are warranted. This trial was registered at clinicaltrials.gov as NCT00642408.

Topics: Adult; Burkina Faso; Dietary Supplements; Female; Fetal Blood; Fetal Growth Retardation; Hormones; Humans; Hydrocortisone; Infant, Newborn; Insulin; Insulin-Like Growth Factor I; Leptin; Male; Malnutrition; Micronutrients; Multivariate Analysis; Pregnancy; Sex Factors; Thyroxine; Young Adult

To investigate a potential role of leptin and insulin-like growth factor (IGF)-I on fetal growth and metabolic function we determined plasma leptin and IGF-I concentrations in twins in relation to discordant fetal growth.. In studying monochorionic twins with inter-twin birth weight difference, we investigated the relative contribution of genetic (fetus) versus environmental (maternal/placental) factors on growth. Thirty-six sets of twins (14 with discordant growth, birth weight difference >15%) who had been treated for severe twin-to-twin transfusion syndrome (TTTS) by laser coagulation were studied. Cord blood samples were collected at birth and analyzed for IGF-I and leptin. Inter-twin differences (delta) of birth weight and head circumference were correlated to delta hormone levels.. An inter-twin correlation for leptin (r = 0.69; p <0.0001) and delta IGF-I (r = 0.49; p <0.0001) was found. delta birth weight correlated significantly with delta IGF-I (r = 0.67; p <0.0001) but not with delta leptin (r = 0.23; p = 0.19). delta IGF-I concentrations did not correlate with delta leptin (r = 0.18). delta head circumference correlated significantly with delta leptin (r = 0.47; p <0.01) and with delta IGF-I (r = 0.46; p <0.01). Using a multiple regression model with head circumference as dependent variable, adjusted for gestational age, head circumference remained significantly associated with higher leptin concentrations in all patients (p = 0.03).. IGF-I is a good indicator for fetal growth and brain development. Leptin seems to be mainly genetically determined but may play a role in fetal brain development and is not only an index for fetal fat mass.

Topics: Anthropometry; Birth Weight; Cephalometry; Female; Fetal Blood; Fetal Development; Fetal Growth Retardation; Fetofetal Transfusion; Gestational Age; Head; Humans; Insulin-Like Growth Factor I; Laser Coagulation; Leptin; Organ Size; Pregnancy; Reference Values; Statistics, Nonparametric; Twins, Monozygotic

Adipose tissue is not only a storage place for fat, but also an endocrine organ, secreting bioactive molecules which influence body metabolism. Such molecules are known as adipocytokines. In the past years the coincidence between adipocytokines and fetal growth restriction disorders was found. The aim of the study was to estimate serum levels of adiponectin, leptin and resistin in children born small for gestational age, compared to children born at an appropriate size for gestational age.. The study consisted of 35 children aged seven to nine years, born SGA (small for gestational age) on term and 25 healthy children (14 girls, 11 boys), born with proper birthweight (AGA-appropriate for gestational age)-control group.. Adiponectin and leptin levels were significantly higher in the SGA group compared to the AGA group (. Children born SGA have abnormal adipose tissue biomarkers profiles.

Topics: Adipokines; Adiponectin; Body Weight; Child; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin Resistance; Leptin; Male; Resistin

Being born with intrauterine growth restriction (IUGR) was associated with subsequent health issues later in life. However, the underlying role of adipokines in IUGR is unknown.. To measure the adiponectin and leptin concentrations in the cord blood of monochorionic (MC) twins with selective IUGR (sIUGR) and evaluate their associations with childhood growth trajectories.. Cord blood samples were collected from 22 pairs of MC twins with sIUGR and 20 pairs of normal MC twins. Adiponectin and leptin concentrations in cord blood were determined by ELISA. Data regarding perinatal outcomes and infantile growth trajectories from birth to 24 months were obtained.. Only cord blood adiponectin concentrations were associated with IUGR (β -1.51, 95% CI -2.45, -0.57, p = 0.002), and cord blood leptin concentrations were significantly lower in sIUGR twins compared to normal twins (2.8 ± 1.6 vs. 6.4 ± 3.0, p < 0.001). Adiponectin concentrations were negatively associated with height increments from birth to 6 months (β -0.28, 95% CI -0.51, -0.06, p = 0.015). Leptin concentrations were negatively associated with weight at 6 and 24 months (β -0.12 95% CI -0.22, -0.02, p = 0.002; β -0.18 95% CI -0.33, -0.03, p = 0.019) and weight and height increments from birth to 6 months (β -0.17 95% CI -0.29, -0.06, p = 0.020; β -0.40 95% CI -0.81, -0.01, p = 0.037).. Cord blood adiponectin concentrations were negatively associated with IUGR but did not predict childhood growth. Cord blood leptin concentrations were inversely associated with weight and height increments in the first 6 months.

Topics: Adiponectin; Birth Weight; Child; Female; Fetal Blood; Fetal Growth Retardation; Humans; Leptin; Pregnancy; Twins

To assess whether small-for-gestational-age (SGA) - an indicator of poor fetal growth, may affect metabolic health biomarkers in infancy and explore the predictors.. This was a nested matched (1:2) prospective observational study of 65 SGA (birth weight < 10th percentile) and 130 optimal-for-gestational-age (OGA, birth weight 25th-75th percentiles, control) infants in the 3D birth cohort with subjects recruited in Canada from 1 May 2010 to 31 August 2012. The outcomes included homeostasis model assessment of insulin resistance (HOMA-IR) and beta-cell function (HOMA-β), circulating leptin and adiponectin concentrations at age 2 years.. HOMA-IR, HOMA-β, leptin and adiponectin concentrations were similar in SGA versus OGA infants. Female sex and accelerated growth in length during mid-infancy (3-12 months) were associated with higher HOMA-IR. Caucasian ethnicity and decelerated growth in weight during late infancy (12-24 months) were associated with lower HOMA-IR. Current BMI was positively associated with circulating adiponectin in SGA infants only (+13.4% [4.0%-23.7%] per BMI z score increment).. Insulin resistance and secretion, circulating leptin and adiponectin levels were normal in SGA subjects in infancy at age 2 years. The novel observation in SGA-specific positive association between current BMI and circulating adiponectin suggests dysfunctional adiposity-adiponectin negative feedback loop development during infancy in SGA subjects.

Topics: Adiponectin; Birth Weight; Child, Preschool; Female; Fetal Growth Retardation; Humans; Infant; Insulin; Insulin Resistance; Leptin

Children born small for gestational age (SGA) are predisposed to obesity, insulin resistance (IR), and lipid disorders. The HOMA-IR index is commonly used to assess IR (IRIHOMA), calculated from fasting glucose and insulin. However, sometimes, during the oral glucose tolerance test (OGTT), elevated and prolonged postprandial insulin secretion is observed despite normal fasting insulin levels. IRIBelfiore is an IR index that analyses glucose and insulin levels during OGTT according to the method proposed by Belfiore.. was to assess the frequency of IR based on IRIHOMA and IRIBelfiore results in SGA children aged 6-8 years, after catch-up phenomenon, to determine the usefulness of IRIBelfiore in diagnosis of IR and in predicting future metabolic complications.. In 129 SGA normal-height children, aged 6-8 years, height, weight, waist circumference, blood pressure, as well as lipids, IGF-1, cortisol, C-peptide, leptin, adiponectin, and resistin concentrations were measured. The glucose and insulin concentrations were evaluated at 0, 60, and 120 minutes of OGTT.. IRIHOMA was normal in all children, while elevated IRIBelfiore was found in 22.5% of them. Children with IR diagnosed by IRIBelfiore were taller, had higher blood pressure, higher leptin, and lower HDL-cholesterol concentrations.. It seems worth recommending IRIBelfiore derived from OGTT as a valuable diagnostic tool for identifying IR in SGA prepubertal children. Abnormal IRIBelfiore is related to higher blood pressure and lower HDL-cholesterol concentration in this group.. Dzieci urodzone jako za małe w stosunku do wieku ciążowego (SGA) mają predyspozycje do występowania otyłości, insulinooporności (IR) oraz zaburzeń lipidowych. Do oceny IR powszechnie używany jest wskaźnik HOMA (IRIHOMA), wyliczany ze stężenia glukozy i insuliny na czczo. Jednak podczas doustnego testu obciążenia glukozą (OGTT) obserwuje się podwyższone poposiłkowe wydzielanie insuliny, pomimo prawidłowego stężenia insuliny na czczo. IRIBelfiore to indeks analizujący poziom glukozy i insuliny podczas OGTT wg metody zaproponowanej przez Belfiore.. była ocena częstości występowania IR na podstawie wyników IRIHOMA i IRIBelfiore u 6–8-letnich dzieci z SGA, które wykazały zjawisko „doganiania wzrostu”, w celu określenia przydatności wykorzystania IRIBelfiore w rozpoznawania IR i przewidywaniu przyszłych powikłań metabolicznych.. U 129 dzieci z SGA, z prawidłowym wzrostem, będących w wieku 6–8 lat zmierzono wzrost, masę ciała, obwód talii, ciśnienie krwi oraz stężenie lipidów, IGF-1, kortyzolu, peptydu C, leptyny, adiponektyny i rezystyny. Stężenia glukozy i insuliny oceniano w 0, 60. i 120. minucie OGTT.. IRIHOMA był prawidłowy u wszystkich dzieci, natomiast IRIBelfiore był podwyższony u 22,5% z nich. Dzieci z IR rozpoznaną dzięki IRIBelfiore były wyższe, miały wyższe ciśnienie krwi, większe stężenie leptyny i niższe HDL-cholesterolu.. Wydaje się, że warto zarekomendować ocenę IRIBelfiore obliczoną na podstawie OGTT jako użyteczne narzędzie diagnostyczne do rozpoznawania IR u dzieci z SGA będących w okresie przedpokwitaniowym. Nieprawidłowa wartość IRIBelfiore jest związana z wyższym ciśnieniem tętniczym krwi i gorszymi poziomami HDL-cholesterolu w tej grupie.

Topics: Blood Glucose; Child; Cholesterol; Fetal Growth Retardation; Gestational Age; Humans; Incidence; Insulin; Insulin Resistance; Leptin

Leptin is a polypeptide hormone, and in pregnancy, it is secreted by the placenta and maternal and fetal adipose tissues. Normal leptin production is a factor responsible for uncomplicated gestation, embryo development, and fetal growth. The study compared maternal serum and cord blood leptin concentrations at delivery in normal pregnancies and in pregnancies complicated by intrauterine growth restriction (IUGR).. The study was performed in 25 pregnant women with isolated IUGR and in 194 pregnant women without any complications. Leptin concentrations in maternal serum and in cord blood samples collected at delivery were measured by ELISA and subsequently analyzed by maternal body mass index (BMI), mode of delivery, and infant gender and birth weight. For comparative analyses of normally distributed variables, parametric tests were used, that is, the Student t test and a one-way ANOVA. The nonparametric Mann-Whitney test was used when the distribution was not normal. The Pearson correlation coefficient was calculated to assess the correlation between normally distributed variables (p < 0.05).. In pregnancies complicated by IUGR, the mean maternal serum leptin concentration at delivery was significantly higher (52.73 ± 30.49 ng/mL) than in normal pregnancies (37.17 ± 28.07 ng/mL) (p = 0.01). The mean cord blood leptin concentration in pregnancies complicated by IUGR was 7.97 ± 4.46 ng/mL and significantly lower than in normal pregnancies (14.78 ± 15.97 ng/mL) (p = 0.04). In normal pregnancies, but not in pregnancies complicated by IUGR, a statistically significant correlation was established between maternal serum leptin concentrations and maternal BMI at delivery (r = 0.22; p = 0.00). No statistically significant correlation was found between cord blood leptin concentrations and maternal BMI in either study subjects or controls. In normal pregnancies, but not in pregnancies complicated by IUGR, a strong correlation was observed between cord blood leptin concentrations and birth weight (r = 0.23; p = 0.00).. Elevated maternal blood leptin concentrations in pregnancies complicated by IUGR may indicate a significant adverse effect of elevated leptin on fetal growth. The differences in leptin concentrations, measured in maternal serum and in cord blood, between the study subjects and controls suggest that deregulated leptin levels may increase the risk of obstetric complications associated with placental insufficiency.

Topics: Birth Weight; Female; Fetal Blood; Fetal Growth Retardation; Humans; Leptin; Placenta; Pregnancy

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

Background: Leptin is a hormone regulating lifetime energy homeostasis and metabolism and its concentration is important starting from prenatal life. We aimed to investigate the association of perinatal leptin concentrations with growth trajectories during the first year of life. Methods: Prospective, longitudinal study, measuring leptin concentration in maternal plasma before delivery, cord blood (CB), and mature breast milk and correlating their impact on neonate’s bodyweight from birth to 1 year of age, in 16 full-term (FT), 16 preterm (PT), and 13 intrauterine growth-restricted (IUGR) neonates. Results: Maternal leptin concentrations were highest in the PT group, followed by IUGR and FT, with no statistical differences among groups (p = 0.213). CB leptin concentrations were significantly higher in FT compared with PT and IUGR neonates (PT vs. FT; IUGR vs. FT: p < 0.001). Maternal milk leptin concentrations were low, with no difference among groups. Maternal leptin and milk concentrations were negatively associated with all the neonates’ weight changes (p = 0.017 and p = 0.006), while the association with CB leptin was not significant (p = 0.051). Considering each subgroup individually, statistical analysis confirmed the previous results in PT and IUGR infants, with the highest value in the PT subgroup. In addition, this group’s results negatively correlated with CB leptin (p = 0.026) and showed the largest % weight increase. Conclusions: Leptin might play a role in neonatal growth trajectories, characterized by an inverse correlation with maternal plasma and milk. PT infants showed the highest correlation with hormone levels, regardless of source, seeming the most affected group by leptin guidance. Low leptin levels appeared to contribute to critical neonates’ ability to recover a correct body weight at 1 year. An eventual non-physiological “catch-up growth” should be monitored, and leptin perinatal levels may be an indicative tool. Further investigations are needed to strengthen the results.

Topics: Birth Weight; Body-Weight Trajectory; Female; Fetal Growth Retardation; Humans; Infant; Infant, Newborn; Leptin; Longitudinal Studies; Pregnancy; Prospective Studies

Children born small for gestational age (SGA) are at risk of future obesity and associated comorbidities. Therefore the identification of risk factors and novel biomarkers which are associated with this risk are needed for early detection and to improve preventive strategies. Spexin (SPX), a novel neuropeptide that is involved in the regulation of obesity and fat metabolism, is a candidate biomarker for predicting obesity and related comorbidities at an early age. The aim of this study was to investigate serum levels of SPX in term infants born small, appropriate, and large for gestational age (LGA) and its association with newborn anthropometric measurements.. One hundred and twenty term newborn babies classified as SGA, appropriate for gestational age (AGA), or LGA and their mothers were included. SPX, leptin and visfatin were measured in cord blood and maternal serum by enzyme-linked immunosorbent assay.. Fifty-six (46.7%) neonates were girls and 64 (53.3%) were boys. The mean birth weight was 3170.70±663 g, birth length was 48.9±2.79 cm, and head circumference was 34.5±1.67 cm. Birth weights, lengths, and head circumferences of the neonates in the SGA, AGA, and LGA groups were significantly different. Cord blood SPX and leptin levels in the SGA groups were significantly lower than those of both the LGA and AGA groups. Cord blood visfatin levels were significantly lower in the AGA group than the LGA and SGA groups. Maternal SPX levels of SGA babies were significantly lower than those of the mothers in both the LGA and AGA groups, but no significant difference was observed between the SGA and LGA groups. Maternal visfatin levels of the AGA babies were significantly higher than the maternal levels of SGA and LGA groups. There was no difference in terms of maternal leptin levels. Cord blood SPX and leptin levels were positively correlated with birth weight, length and head circumference. Birth weight increased significantly in line with maternal pregestational body mass index.. The lowest SPX levels were found in the SGA babies and cord SPX level was significantly correlated with newborn length, weight, and head circumference.

Topics: Birth Weight; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Male; Nicotinamide Phosphoribosyltransferase; Obesity; Peptide Hormones; Weight Gain

To evaluate the dynamical interplay between perinatal leptin concentrations and neonatal weight evolution until 3 months of age.. In a prospective observational study, maternal, cord blood and neonatal plasma leptin concentrations were correlated to birthweight and 3-month weight in 26 full-term, 20 preterm, and 17 intrauterine growth restriction (IUGR) mother-neonate couples.. The median of maternal, cord blood, neonatal leptin concentrations were significantly different among the three groups (. Our results showed that maternal leptin levels lost their influence on neonatal weight when considering confounders. At 3-month, once birthweight adjusted, the percent increasing of weight was statistically larger in preterm and IUGR than the full-term group and the correlation between cord blood leptin and weight turned negative, from positive at birth. These data may be a clue for further investigation on the relationship between perinatal leptin concentrations and catch-up growth.

Topics: Birth Weight; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant; Infant, Newborn; Leptin; Mothers; Pregnancy

Health in pregnancy and infancy can affect the risk of chronic non-communicable diseases. We aimed to describe leptin and adiponectin concentrations in low birth weight (LBW) infants and identify possible associations with maternal nutritional status, adequacy for gestational age, nutritional recovery, and current dietary intake. A cross-sectional study with LBW infants (9-12 months) including maternal background and pre-pregnancy nutritional condition was performed. From the Infants: anthropometry at birth and current was expressed as z-score (weight: WAZ, length, head circumference), nutritional recovery, dietary intake, leptin, and adiponectin blood concentrations. The mean age of the 54 infants was 10.0 ± 1.5 months, 32 (59.3%) were female, 36 (66.7%) preterm, 23 (42.6%) small for gestational age (SGA), and 25 pregnancies (46.3%) were twin. Almost all (98%) of the infants intake energy and protein above the recommendation, and 47 (87.6%) consumed ultra-processed foods. At the time of the assessment, 8 (14.8%) were overweight and 4 (7.4%) had short stature. SGA infants showed faster weight recovery (WAZ 1.54; 95% CI 1.17, 1.91; p = 0.001), higher leptin's concentration (3.0 ng/ml (1.7, 3.0) versus 1.6 ng/ml (0.9, 2.6); p = 0.032)), and leptin/adiponectin ratio (0.13 ± 0.08 versus 0.07 ± 0.07; p = 0.018). The pre-gestational BMI was a modifier of the effect of WAZ on leptin levels (p = 0.027) in LBW infants. Higher pre-gestational BMI increased the effect of WAZ variation (birth and current) on leptin levels. Concluding, LBW infants showed early changes in leptin and adiponectin concentrations, influenced by maternal (pre-gestational BMI), intrauterine (gestational age adequacy - SGA), and postnatal weight gain. This combination of factors may increase the risk of NCD for this group of children.

Topics: Adiponectin; Birth Weight; Cross-Sectional Studies; Female; Fetal Growth Retardation; Humans; Infant; Infant, Low Birth Weight; Leptin; Male; Maternal Health; Pregnancy

Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics.. A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed.. Mothers with both severe FGR and PE had significantly reduced FT levels (p < 0.001) and PlGF levels (p < 0.001), and increased levels of plasma IMA (p < 0.05), sFlt (p < 0.001), leptin (p < 0.05) and sRAGE (p < 0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p < 0.01) and plasma IMA (p < 0.001), leptin (p = 0.01) and sRAGE (p < 0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only.. There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.

Topics: Adult; Biomarkers; Female; Fetal Growth Retardation; Humans; Inflammation; Leptin; Oxidative Stress; Pilot Projects; Placenta; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Prospective Studies; Receptor for Advanced Glycation End Products; Serum Albumin, Human; Sulfhydryl Compounds; Vascular Endothelial Growth Factor Receptor-1

We examined whether maternal serum cytokine profiles of mothers with early-onset fetal growth restriction (FGR) were associated with delivery within 2 weeks after sampling during the third trimester.. This exploratory prospective cross-sectional study included a total of 20 singleton fetuses with early-onset FGR and 31 healthy controls. Maternal serum samples during the early third trimester were analyzed for 23 cytokines.. Of 20 fetuses with early-onset FGR, 14 had delivery within 2 weeks after sampling. Multivariate analysis revealed that maternal serum concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble CD40 ligand (sCD40L) were independently associated with delivery within 2 weeks in early-onset FGR. Among cases of early-onset FGR, concentrations of almost all maternal serum cytokines were similar. Maternal serum sVEGFR-1 concentrations were high when delivery occurred within 2 weeks. Maternal serum sCD40L concentrations were elicited only in cases in which delivery within 2 weeks occurred due to fetal deterioration.. We identified two biomarkers, one specific for FGR and the other dependent on severity, that were significant components of angiogenic activities and inflammation factors. Imbalances in serum protein expression may have a substantial effect on the pathogenesis of FGR.

Topics: Adult; Biomarkers; Birth Weight; Case-Control Studies; CD40 Ligand; Cesarean Section; Cross-Sectional Studies; Cytokines; Elective Surgical Procedures; Endoglin; Female; Fetal Growth Retardation; Heparin-binding EGF-like Growth Factor; Humans; Infant, Newborn; Infant, Small for Gestational Age; Labor, Induced; Leptin; Male; Multivariate Analysis; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Premature Birth; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

The impact of early life protein source (whey vs. casein) on short- and long-term glucose homeostasis and adiposity is unknown and was investigated in this study. At the end of the suckling period, non-IUGR (intrauterine growth restriction) and IUGR pups were separated from dams and were randomized into four groups. From age 21-49 days, non-IUGR and IUGR pups were fed ad-libitum chow or a semi-synthetic diet (20% from protein; casein or whey) and from age 50-199 days, all groups were fed ad-libitum chow. Food intake, body composition, glucose, and insulin homeostasis were assessed. Among the chow groups, IUGR had slower growth and higher fasting glucose at age 42 days, as well as higher fasting and AUC glucose at age 192 days relative to non-IUGR. The whey IUGR group had a slower growth rate and higher fasting glycemia in early life (age 21-49 days) and higher HOMA-IR later in life (age 120-122 and 190-192 days) relative to casein IUGR. This study shows the potential advantage of casein relative to whey during weaning on short term energy intake, growth, and glucose homeostasis in an IUGR model and reveals, for the first time, its long term impact on insulin sensitivity, which may have implications for later metabolic health, particularly in small-for-gestational-age populations at risk of type 2 diabetes.

Topics: Adiposity; Animals; Area Under Curve; Birth Weight; Blood Glucose; Body Composition; Caseins; Disease Models, Animal; Energy Intake; Fasting; Female; Fetal Development; Fetal Growth Retardation; Glucose; Homeostasis; Insulin; Insulin Resistance; Leptin; Lipids; Organ Size; Rats, Sprague-Dawley; Time Factors; Weaning; Whey

The present study aimed to determine the effect of perceived stress during pregnancy on neonatal outcomes and cortisol and leptin levels in mothers and their newborns.. This longitudinal study was carried out on 110 pregnant women in Miandoab city, Iran. Mothers, who had singleton pregnancies and gestational age of 24 to 28 weeks, were included in the study. The participants were asked to fill out Cohen's Perceived Stress Scale (PSS). The mothers were then tracked in gestational ages of 28-32 weeks, 32-36 weeks, and the time of delivery. The maternal and umbilical cord blood samples were obtained during labor in order to measure leptin and cortisol levels.. Umbilical cortisol level was significantly higher in newborns who had meconium stained amniotic fluid than those who did not. Maternal blood leptin levels at delivery were significantly higher in the mothers whose neonates had respiratory distress, low birth weight, low head circumference, low Apgar score, and were premature than those whose neonates did not have such problems. The level of leptin in umbilical cord blood was significantly higher in neonates who had respiratory distress than those who did not. The results also showed a significant correlation between maternal cortisol levels and PSS during weeks 24-28 and the entire pregnancy. A significant relationship was observed between umbilical leptin and maternal leptin levels.. It can be concluded that stress during pregnancy is accompanied by fetal distress. The probable reason for newborns distress may be related to increased maternal leptin levels.

Topics: Adolescent; Adult; Amniotic Fluid; Apgar Score; Body Height; Female; Fetal Blood; Fetal Growth Retardation; Head; Humans; Hydrocortisone; Infant, Low Birth Weight; Infant, Newborn; Leptin; Male; Meconium; Pregnancy; Pregnancy Complications; Premature Birth; Respiratory Distress Syndrome, Newborn; Stress, Psychological; Young Adult

Uteroplacental insufficiency in rats reduces nephron endowment, leptin concentrations and programmes cardiorenal disease in offspring. Cross-fostering growth-restricted (Restricted) offspring onto a mother with normal lactation restores leptin concentrations and nephron endowment. This study aimed to determine whether the reduced nephron endowment in Restricted offspring is due to delayed glomerular formation and dysregulation of renal genes regulating branching morphogenesis, apoptosis or leptin signalling. Furthermore, we aimed to investigate whether cross-fostering Restricted offspring onto Control mothers could improve glomerular maturation and restore renal gene abundance.. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on gestation day 18 (E18). Kidneys were collected at E20, postnatal day 1 (PN1) and PN7. An additional cohort was cross-fostered onto separate mothers at birth and kidneys collected at PN7.. Kidneys were lighter in the Restricted group, but weight was restored with cross-fostering. At E20, abundance of Bax, Flt1 and Vegfa was increased in Restricted offspring, while Ret and Bcl2 transcripts were increased only in Restricted females. At PN7, abundance of Gdnf and Ret was higher in Restricted offspring, as was Casp3. Restricted offspring had a wider nephrogenic zone with more immature glomeruli suggesting a delayed or extended nephrogenic period. Cross-fostering had subtle effects on gene abundance and glomerular maturity.. Uteroplacental insufficiency induced apoptosis in the developing kidney and delayed and extended nephrogenesis. Cross-fostering Restricted offspring onto Control mothers had beneficial effects on kidney growth and renal maturity, which may contribute to the restoration of nephron endowment.

Topics: Animals; Apoptosis; Female; Fetal Growth Retardation; Kidney; Leptin; Male; Organogenesis; Placental Circulation; Pregnancy; Pregnancy Complications; Rats; Rats, Inbred WKY

Early life events are associated with the susceptibility to chronic diseases in adult life. Perturbations of endoplasmic reticulum (ER) homeostasis activate the unfolded protein response (UPR), which contributes to the development of metabolic alterations. Our aim was to evaluate liver UPR in an animal model of intrauterine growth restriction (IUGR). A significantly increased expression of X-box binding protein-1 spliced (XBP1s) mRNA (p<0.01), Endoplasmic Reticulum-localized DnaJ homologue (Erdj4) mRNA (p<0.05) and Bip/GRP78-glucose-regulated protein 78 (Bip) mRNA (p<0.05) was observed in the liver of IUGR rats at birth. Furthermore, the expression of gluconeogenesis genes and lipogenesis genes were significantly upregulated (p<0.05) in IUGR pups. At 105 d, IUGR male rats showed significantly reduced glucose tolerance (p<0.01). A significant decreased expression of XBP1s mRNA (p<0.01) and increased expression of double-stranded RNA-dependent protein kinase-like ER kinase (PERK) and Asparagine synthetase (ASNS) (p<0.05) was observed in the liver of IUGR male adult rats. Liver focal steatosis and periportal fibrosis were observed in IUGR rats. These findings show for the first time that fetal exposure to uteroplacental insufficiency is associated with the activation of hepatic UPR and suggest that UPR signaling may play a role in the metabolic risk.

Topics: Animals; Aspartate-Ammonia Ligase; Disease Models, Animal; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Fatty Acids, Nonesterified; Female; Fetal Growth Retardation; Gene Expression Regulation; Glucose Tolerance Test; Heat-Shock Proteins; Leptin; Liver; Male; Metabolome; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Unfolded Protein Response; X-Box Binding Protein 1

Intra-uterine growth restriction (IUGR) is associated with adverse metabolic outcome later in life. Healthy mice challenged with a Western-style diet (WSD) accumulated less body fat when previously fed a diet containing large lipid globules (complex lipid matrix (CLM)). This study was designed to clarify whether an early-life CLM diet mitigates 'programmed' visceral adiposity and associated metabolic sequelae after IUGR. In rats, IUGR was induced either by bilateral uterine vessel ligation (LIG) or sham operation (i.e. intra-uterine stress) of the dam on gestational day 19. Offspring from non-operated (NOP) dams served as controls. Male offspring of all groups were either fed CLM or 'normal matrix' control diet (CTRL) from postnatal days (PND) 15 to 42. Thereafter, animals were challenged with a mild WSD until dissection (PND 98). Fat mass (micro computer-tomograph scan; weight of fat compartments), circulating metabolic markers and expression of 'metabolic' genes (quantitative real-time PCR) were assessed. CLM diet significantly reduced visceral fat mass in LIG at PND 40. At dissection, visceral fat mass, fasted blood glucose, TAG and leptin concentrations were significantly increased in LIG-CTRL v. NOP-CTRL, and significantly decreased in LIG-CLM v. LIG-CTRL. Gene expression levels of leptin (mesenteric fat) and insulin-like growth factor 1 (liver) were significantly reduced in LIG-CLM v. LIG-CTRL. In conclusion, early-life CLM diet mitigated the adverse metabolic phenotype after utero-placental insufficiency. The supramolecular structure of dietary lipids may be a novel aspect of nutrient quality that has to be considered in the context of primary prevention of obesity and metabolic disease in at-risk populations.

Topics: Animals; Biomarkers; Blood Glucose; Diet; Diet, Western; Dietary Fats; Female; Fetal Growth Retardation; Humans; Infant; Infant Nutritional Physiological Phenomena; Insulin-Like Growth Factor Binding Protein 1; Intra-Abdominal Fat; Leptin; Ligation; Lipid Metabolism; Lipids; Liver; Male; Mesentery; Pregnancy; Rats, Wistar; Triglycerides; Uterus

Children born with IUGR develop features of the metabolic syndrome and exhibit deranged markers of hepatorenal physiology. Metabolic and hepatorenal biochemistry and the rs9939609 FTO polymorphism were investigated in prepubertal children born with IUGR. Ninety-eight prepubertal children (46 IUGR and 52 AGA), subdivided in <5 years and >5 years old groups were included. Anthropometry; creatinine, eGFR, urea, AST, ALT, triglycerides, uric acid, total cholesterol, HDL-c, LDL-c, glucose, C-peptide, insulin and glucagon z-scores; HOMA-IR; leptin and adiponectin concentrations; rs9939609 FTO polymorphism frequency were measured. In males, weight and ALT were higher and adiponectin was lower, in IUGR < 5 years; C-peptide, insulin and leptin were higher in IUGR > 5 years; C-peptide was higher in all IUGR, than the respective AGA. In females, creatinine and triglycerides were higher in IUGR < 5 years old; creatinine was higher and eGFR was lower in all IUGR, than the respective AGA. In males and females, creatinine was higher in all IUGR, than the respective AGA; C-peptide, insulin and HOMA-IR were lower, and AST was higher in IUGR < 5 than in IUGR > 5 years old. FTO rs9939609 frequency did not differ between IUGR and AGA. In conclusion prepubertal males born with IUGR increased weight, insulin and leptin and decreased adiponectin, as compared to males born AGA, emerge as early metabolic syndrome characteristics. The concentrations of these hormones do not differ between prepubertal males and females born with IUGR. Weight control, healthy nutrition and physical exercise should be recommended to these children. The deranged renal (particularly evident in females below the age of 5) and liver biochemistry in prepubertal children born with IUGR suggests that hepatorenal derangements might commence in utero. Regular checkup of biochemical and lipid profile is recommended for all children born with IUGR.

Topics: Adiponectin; Alanine Transaminase; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Analysis of Variance; Aspartate Aminotransferases; Birth Weight; Blood Glucose; Carbohydrate Metabolism; Chi-Square Distribution; Child; Child, Preschool; Cohort Studies; Creatinine; Cross-Sectional Studies; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant; Insulin; Insulin Resistance; Leptin; Male; Polymorphism, Genetic; Pregnancy; Triglycerides; Uric Acid

Prenatal undernutrition and postnatal overnutrition increase the risk of some peripheral and central metabolic disorders in adulthood. We speculated that disturbances of appetite/metabolic regulatory factors might already have been established in the early stages of life and contribute to obesity later in life. The effects of a high-fat diet on the levels of peripheral and central appetite/metabolic regulatory factors were compared between the offspring of normally nourished dams and those of undernourished dams in the peri-pubertal period. In the offspring of the normally nourished dams (control), the consumption of the high-fat diet resulted in lower hypothalamic mRNA levels of orexigenic factors (neuropeptide Y (NPY) and prepro-orexin (pporexin)), whereas no such changes were seen in the offspring of the undernourished dams (subjected to intrauterine growth restriction). These results indicate that in high-energy conditions either the adaptive response does not function properly or has not been established in the offspring of undernourished dams. Because NPY and pporexin are negatively regulated by leptin, these findings suggest that in the intrauterine growth restriction group, the leptin resistance of hypothalamic functions, which is usually caused by diet-induced obesity in adulthood, had already been established in the peri-pubertal period.

Topics: Animals; Appetite Regulation; Diet, High-Fat; Female; Fetal Development; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Hypothalamus; Intra-Abdominal Fat; Lactation; Leptin; Malnutrition; Maternal Nutritional Physiological Phenomena; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Obesity; Orexins; Protein Precursors; Rats, Sprague-Dawley; Weaning

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

Intrauterine growth retardation (IUGR) and postnatal nutrition are risk factors for adult metabolic syndrome. However, the influences of long-term high-fat diet (HFD) intake on ectopic fat deposition in non-adipose tissues in IUGR pigs remain unclear. The present study was to determine whether HFD consumption would enhance ectopic fat deposition in IUGR pigs.. At day 28, IUGR and control pigs were fed ad libitum to either a regular diet or a HFD. Lipid store, enzymatic activities and mRNA expression of lipid metabolism-related factors in liver and semitendinosus muscle (SM) were quantified at postnatal day 178.. Feeding a HFD to IUGR pigs but not to control pigs significantly increased daily weight gain, carcass fat mass, plasma leptin level and lipid content and lipoprotein lipase (LPL) activity and mRNA abundances of LPL and peroxisome proliferator-activated receptor gamma (PPARγ) in liver and SM, but decreased daily feed intake and mRNA expression of hormone-sensitive lipase (LIPE) and carnitine palmitoyl transferase-1 (CPT-1) in liver and SM (P < 0.05). Compared with control pigs, IUGR pigs had a lower body weight but higher plasma levels of total cholesterol (TC) and insulin (P < 0.05). HFD-fed pigs exhibited greater body weight, plasma concentrations of triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), regardless of birth weight (P < 0.05).. Our results suggested that IUGR increased the vulnerability of HFD-fed pigs to ectopic fat deposition via enhanced fatty acid flux toward ectopic sites and reduced lipolysis and fatty acid oxidation.

Topics: Adipose Tissue; Animals; Body Composition; Diet, High-Fat; Fatty Acids; Fatty Liver; Fetal Growth Retardation; Gene Expression; Insulin; Leptin; Lipid Metabolism; Lipids; Lipolysis; Liver; Male; Muscle, Skeletal; Oxidation-Reduction; Sus scrofa; Swine

Intrauterine growth restriction (IUGR) is a risk factor for developing metabolic syndrome later in life. We explored whether adipokine concentrations in cord blood (CB) and on day 3 (D3) were related to impaired fetal growth and lipids in IUGR twins.. Thirty-six discordant (birth weight [BW] discordance ≥20% calculated in relation to the heavier co-twins) and 42 concordant (BW discordance ≤ 10%) twin pairs were included.. In IUGR twins, both adiponectin/BW and triglyceride (TG) levels were significantly higher, while total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol were lower in CB. On D3, both leptin and HDL-C levels were significantly lower and TG levels were significantly higher in IUGR twins. In the discordant group, the alterations in lipids were not related to any adipokine.. IUGR is related to lower leptin level and proatherogenic lipid profile (higher TG and lower HDL-C), which are not influenced by adipokine at birth.

Topics: Adipokines; Adult; Birth Weight; Diseases in Twins; Female; Fetal Blood; Fetal Development; Fetal Growth Retardation; Humans; Leptin; Lipids; Male; Middle Aged; Pregnancy; Pregnancy, Twin

The major goal of animal production is to obtain abundant and healthy meat for consumers. Maternal food restriction (MFR) is often applied in farms to reduce production costs. However, the suitability of MFR in livestock animals is questionable, as this management may compromise maternal fitness due to a severe negative energetic balance and can induce Intrauterine Growth Restriction (IUGR) and prenatal programming in the offspring. Here, we sought to determine, using pregnant rabbits, the consequences of MFR on maternal endocrine and metabolic status and conceptus development. Pregnant dams were distributed into three groups: CONTROL (ad libitum feeding throughout the entire pregnancy; mean pregnancy length being around 31 days), UNDERFED (50% MFR during the entire pregnancy) and EARLY-UNDERFED (50% MFR only during the preimplantation period, Days 0-7). Maternal leptin concentrations and glycemic and lipid profiles were determined throughout pregnancy, whilst conceptus development was assessed ex-vivo at Day 28. Placental parameters were determined by macroscopic and histological evaluations and apoptotic assessments (TUNEL and Caspase-3). The main results of the study showed that, despite MFR altered maternal plasma lipid concentration (P<0.05), there were no effects on maternal bodyweight, plasma leptin concentration or glycemic profile. Fetal crown-rump lengths were reduced in both undernourished groups (P<0.001), but a significant reduction in fetal weight was only observed in the UNDERFED group (P<0.001). Growth in both undernourished groups was asymmetrical, with reduced liver weight (P<0.001) and significantly increased brain: fetal weight-ratio (P<0.001) and brain: liver weight-ratio (P<0.001) when compared to the CONTROL group. A significant reduction in placental weight was only observed in the UNDERFED group (P<0.001), despite both undernourished groups showing higher apoptotic rates at decidua and labyrinth zone (P<0.05) than the CONTROL group. Thus, these groups evidenced signs of placental degeneration, necrosis and stromal collapse. In summary, MFR may encourage the mother to make strategic decisions to safeguard her metabolic status and fitness at the expense of growth reduction in the litter, resulting in enhanced apoptotic and pathological processes at placental level and IUGR.

Topics: Animals; Apoptosis; Blastocyst; Blood Glucose; Body Weight; Crown-Rump Length; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Weight; Fetus; Leptin; Lipid Metabolism; Malnutrition; Placenta; Pregnancy; Pregnancy Complications; Pregnancy, Animal; Rabbits

Insulin resistance (IR) in adults has been associated with intrauterine growth restriction (IUGR). Leptin and adiponectin correlations with anthropometric parameters and IR at 72 h in discordant twins were tested.. We included 24 discordant (birth weight discordance ≥20% in relation to the heavier cotwin) and 30 concordant (birth weight discordance ≤10%) twins.. A correlation between leptin (but not adiponectin) level and birth weight (BW), birth length and head circumference in IUGR twins was recorded (p<0.05). Insulin sensitivity (IS) and homeostatic model assessment (HOMA)-IR in IUGR twins were similar to appropriate-for-gestational-age cotwins and unrelated to adipokines. In IUGR twins, adiponectin and insulin associated positively. In larger concordant twins' leptin level correlated with HOMA-IR and insulin.. Leptin, but not adiponectin, levels correlate positively with anthropometric parameters in IUGR twins. IR in IUGR twins is unrelated to adipokines in the first few days of life.

Topics: Adiponectin; Adult; Age Factors; Anthropometry; Biomarkers; Cross-Sectional Studies; Female; Fetal Growth Retardation; Follow-Up Studies; Gestational Age; Humans; Insulin Resistance; Leptin; Male; Prospective Studies; Time Factors; Twins, Dizygotic

Intrauterine growth retardation/restriction (IUGR) is associated with fetal malnutrition. It has consequences for later life including increased incidence of obesity, diabetes mellitus, cardiovascular disease (CVD), and metabolic syndrome. Adipokines (adiponectin and leptin), adropin, and endothelin-1 are associated with obesity and metabolic syndrome regulation. Intrauterine changes in these mediators could affect programming of later adult obesity and metabolic syndrome. Our objectives were to compare the levels of these mediators in both cord and maternal blood between IUGR pregnancies and control, healthy pregnancies, and to study the correlation of adipokines with adropin and endothelin-1 in maternal and cord blood in IUGR pregnancies as well as in healthy control pregnancies. Maternal and cord blood samples were taken from 16 women with IUGR pregnancies and 16 women with healthy pregnancies. Serum levels of leptin, adiponectin, adropin, and endothelin-1 were measured by ELISA. Maternal blood adropin levels were significantly lower in the IUGR group than in the control group; the other mediators did not differ significantly. There was a positive correlation between maternal blood adropin and endothelin levels. (r=0.731, P=0.001) in the control but not the IUGR group. Cord blood adropin and adiponectin levels were significantly lower in the IUGR group compared with the control group, while leptin or endothelin-1 did not differ significantly. There was a negative correlation between adropin and leptin (r=-0.704, P=0.001) in the IUGR but not the control group cord blood. There were also positive correlations between endothelin and adropin for both groups (r=0.594, P=0.006; r=0.560, P=0.010, respectively); to the best of our knowledge, this is the first report of such a correlation. Differences in fetal expression of adropin and adiponectin in IUGR could influence programming of obesity, metabolic syndrome, diabetes, and CVD in later life.

Topics: Adiponectin; Adolescent; Adult; Biomarkers; Blood Proteins; Case-Control Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Growth Retardation; Humans; Infant, Newborn; Intercellular Signaling Peptides and Proteins; Leptin; Peptides; Pregnancy; Prospective Studies; Young Adult

This study tested whether the maternal transport of dexamethasone (DEXA) may affect the development of the neuroendocrine system. DEXA (0.2mg/kg b.w., subcutaneous injection) was administered to pregnant rats from gestation day (GD) 1-20. In the DEXA-treated group, a decrease in maternal serum thyroxine (T4), triiodothyronine (T3), and increase in thyrotropin (TSH) levels (hypothyroid status) were observed at GDs 15 & 20 with respect to control group. The reverse pattern (hyperthyroid status) was observed in their fetuses at embryonic days (EDs) 15 & 20. Although the maternal body weight was diminished, the weight of the thyroid gland was increased at studied GDs as compared to the control group. The fetal growth retardation, hyperleptinemia, hyperinsulinism, and cytokines distortions (transforming growth factor-beta; TGF-β, tumor necrosis factor-alpha; TNF-α, and interferon-γ; IFN-γ) were noticed at examined EDs if compared to the control group. Alternatively, the maternofetal thyroid dysfunctions due to the maternal DEXA administration attenuated the levels of fetal cerebral norepinephrine (NE) and epinephrine (E), and elevated the levels of dopamine (DA) and 5-hydroxytryptamine (5-HT) at considered days. These alterations were age-dependent and might damage the nerve transmission. Finally, maternal DEXA might act as neuroendocrine disruptor causing dyshormonogenesis and fetal cerebral dysfunction.

Topics: Animals; Anti-Inflammatory Agents; Cytokines; Dexamethasone; Endocrine Disruptors; Female; Fetal Development; Fetal Growth Retardation; Hyperinsulinism; Hypothyroidism; Injections, Subcutaneous; Leptin; Maternal-Fetal Exchange; Neurosecretory Systems; Organ Size; Pregnancy; Rats, Wistar; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine; Weight Gain

The aim of this study was to determine if maternal nutritional status, as defined by body composition, leptin, and insulin-like growth factor (IGF)-I levels, relates to foetal growth.. In this prospective study, mothers of foetuses with foetal growth restriction (FGR; cases; n = 46) and mothers of appropriate-for-gestational-age (AGA) foetuses (controls; n = 81) were consecutively recruited over a 14- month period. A maternal blood sample was obtained during the third trimester (between 32 and 34 weeks of gestation) for the assessment of IGF-I and leptin. Body composition was assessed by dual-energy X-ray absorptiometry within the first 15 days after delivery. The study used the SPSS-PC statistical package, version 19.0, and p < 0.05 was considered statistically significant.. Mean serum IGF-I levels were lower in the cases than in the controls (p < 0.05), whereas leptin concentrations were higher in the cases after adjusting for age, body mass index and cigarette consumption (p < 0.05). Cases had less lean and fat tissue than controls (p < 0.05) but a relatively higher fat percentage.. The mothers of foetuses with FGR have a body composition pattern characterized by a slightly increased fraction of fat mass, lower IGF-I concentrations, and increased serum leptin levels. Optimization of maternal nutritional status should be considered, as the nutritional status may be involved in the pathogenesis of FGR.

Topics: Absorptiometry, Photon; Adult; Body Composition; Female; Fetal Growth Retardation; Gestational Age; Humans; Insulin-Like Growth Factor I; Leptin; Maternal Nutritional Physiological Phenomena; Nutritional Status; Pregnancy; Prospective Studies; Smoking

Leptin is an adipokine that regulates energy homeostasis. The objective of this study was to establish a gestational age-specific standard for amniotic fluid leptin (AFL) levels and examine the relationship between AFL, maternal overweight and fetal growth restriction.. Amniotic fluid was obtained at mid-gestation from singleton gravidas, and leptin was quantified using enzyme-linked immunosorbent assay. Amniotic fluid samples from 321 term pregnancies were analyzed. Clinical data, including fetal ultrasound measurements and maternal and infant characteristics, were available for a subset of patients (n=45).. The median interquartile range AFL level was significantly higher at 14 weeks' gestation (2133 pg ml(-1) (1703 to 4347)) than after 33 weeks' gestation (519 pg ml(-1) (380 to 761), P trend<0.0001), an average difference of 102 pg ml(-1) per week. AFL levels were positively correlated with maternal pre-pregnancy body mass index (BMI) (r=0.36, P=0.03) adjusting for gestational age at measurement, but were not associated with fetal growth.. AFL levels are higher at mid-gestation than at late gestation, and are associated with maternal pre-pregnancy BMI.

Topics: Amniotic Fluid; Birth Weight; Body Mass Index; Enzyme-Linked Immunosorbent Assay; Female; Fetal Development; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Linear Models; Male; Overweight; Placenta; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third

It's known that blood leptin level is reduced in intrauterine growth retardation (IUGR) fetus, and placental leptin is the major source of fetal blood leptin. This study aimed to investigate the decreased fetal blood leptin level by prenatal caffeine exposure (PCE) and its underlying placental mechanisms. Pregnant Wistar rats were intragastrically administered caffeine (30-120 mg/kg day) from gestational day 9 to 20. The level of fetal serum leptin and the expression of placental leptin-related genes were analyzed. Furthermore, we investigated the molecular mechanism of the reduced placental leptin's expression by treatment with caffeine (0.8-20 μM) in the BeWo cells. In vivo, PCE significantly decreased fetal serum leptin level in caffeine dose-dependent manner. Meanwhile, placental mRNA expression of adenosine A2a receptor (Adora2a), cAMP-response element binding protein (CREB), a short-type leptin receptor (Ob-Ra) and leptin was reduced in the PCE groups. In vitro, caffeine significantly decreased the mRNA expression of leptin, CREB and ADORA2A in concentration and time-dependent manners. The addition of ADORA2A agonist or adenylyl cyclase (AC) agonist reversed the inhibition of leptin expression induced by caffeine. PCE induced a lower level of fetal blood leptin, which the primary mechanism is that caffeine inhibited antagonized Adora2a and AC activities to decreased cAMP synthesis, thus inhibited the expression of the transcription factor CREB and target gene leptin in the placenta. Meantime, the reduced transportation of maternal leptin by placental Ob-Ra also contributed to the reduced fetal blood leptin. Together, PCE decreased fetal blood leptin mainly via reducing the expression and transportation of leptin in the placenta.

Topics: Adenylyl Cyclases; Animals; Caffeine; Cells, Cultured; Colforsin; Cyclic AMP Response Element-Binding Protein; Down-Regulation; Female; Fetal Blood; Fetal Development; Fetal Growth Retardation; Fetus; Humans; Leptin; Male; Maternal Exposure; Placenta; Pregnancy; Rats; Rats, Wistar; Receptor, Adenosine A2A; Receptors, Leptin; RNA, Messenger

It has been reported that intrauterine undernutrition is closely associated with the pathogeneses of certain diseases in adulthood; i.e., insulin resistance and diabetes, and that leptin resistance plays a pivotal role in the pathology of such intrauterine growth restriction (IUGR)-related conditions. Therefore, examinations of IUGR-induced leptin resistance in early developmental period are important for protecting against future disease. In this study, the effects of prenatal undernutrition on the serum leptin levels and central leptin responses of rats during the neonatal and/or pre-pubertal period were examined. The 50% food-restricted undernourished dams' offspring (UNO) exhibited a significantly lower birth weight than the normal nutrition dams' offspring (NNO). However, the UNO grew rapidly, and their mean body weight had caught up with that of the NNO by postnatal day 8. Thus, there were no significant differences between the body weights of the two groups at postnatal day 12, 16, 20, or 28. The serum leptin levels of the UNO were significantly higher than those of the NNO at postnatal days 20 and 28. At postnatal day 28, no significant difference in the hypothalamic mRNA level of neuropeptide Y, which is the main target of leptin, or that of ObRb, which is the leptin receptor, was detected between the NNO and UNO. The chronic intracerebroventricular injection of leptin attenuated body weight gain in both the NNO and UNO; however, there were no significant differences between the body weights of the two groups at any of the examined postnatal time points, indicating that the UNO and NNO exhibited similar central sensitivity to leptin during the pre-pubertal period. These results suggest that prenatal undernutrition induces leptin resistance until the neonatal to pre-pubertal period and that these alterations might be caused by impaired transportation of leptin to central tissues.

Topics: Aging; Animals; Animals, Newborn; Birth Weight; Female; Fetal Growth Retardation; Humans; Infant Nutrition Disorders; Infant, Newborn; Injections, Intraventricular; Leptin; Male; Pregnancy; Pregnancy Complications; Puberty; Rats; Rats, Sprague-Dawley; Treatment Outcome; Weight Gain

We sought to investigate the relationship between a panel of angiogenic and inflammatory biomarkers measured in midpregnancy and small-for-gestational-age (SGA) outcomes in sub-Saharan Africa.. Concentrations of 18 angiogenic and inflammatory biomarkers were determined in 432 pregnant women in Dar es Salaam, Tanzania, who participated in a trial examining the effect of multivitamins on pregnancy outcomes. Infants falling below the 10th percentile of birthweight for gestational age relative to the applied growth standards were considered SGA. Multivariate binomial regression models with the log link function were used to determine the relative risk of SGA associated with increasing quartiles of each biomarker. Restricted cubic splines were used to test for nonlinearity of these associations.. A total of 60 participants (13.9%) gave birth to SGA infants. Compared to those in the first quartile, the risk of SGA was reduced among those in the fourth quartiles of vascular endothelial growth factor-A (adjusted risk ratio [RR], 0.38; 95% confidence interval [CI], 0.19-0.74), placental growth factor (adjusted RR, 0.28; 95% CI, 0.12-0.61), soluble fms-like tyrosine kinase-1 (adjusted RR, 0.48; 95% CI, 0.23-1.01), monocyte chemoattractant protein-1 (adjusted RR, 0.48; 95% CI, 0.25-0.92), and leptin (adjusted RR, 0.46; 95% CI, 0.22-0.96).. Our findings provide evidence of altered angiogenic and inflammatory mediators, at midpregnancy, in women who went on to deliver SGA infants.

Topics: Adolescent; Adult; Angiopoietins; Antigens, CD; Biomarkers; Birth Weight; C-Reactive Protein; Complement System Proteins; Cytokines; Endoglin; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Inflammation; Intercellular Adhesion Molecule-1; Leptin; Multivariate Analysis; Neovascularization, Physiologic; Placenta Growth Factor; Pregnancy; Pregnancy Proteins; Pregnancy Trimester, First; Pregnancy Trimester, Second; Receptors, Cell Surface; Receptors, Tumor Necrosis Factor, Type II; Regression Analysis; Tanzania; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Young Adult

Inadequate magnesium (Mg) intake is a widespread problem, with over 50% of women of reproductive age consuming less than the Recommended Dietary Allowance (RDA). Because pregnancy increases the requirement for Mg and the beneficial effects of magnesium sulfate for preeclampsia/eclampsia and fetal neuroprotection are well described, we examined the outcomes of Mg deficiency during pregnancy. Briefly, pregnant Swiss Webster mice were fed either control or Mg-deficient diets starting on gestational day (GD) 6 through euthanasia on GD17. Mg-deficient dams had significantly reduced weight gain and higher plasma adipokines, in the absence of inflammation. Livers of Mg-deficient dams had significantly higher saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) and lower polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) (P < 0.0001) and arachidonic acid (AA) (P < 0.0001). Mechanistically, Mg deficiency was accompanied by enhanced desaturase and elongase mRNA expression in maternal livers along with higher circulating insulin and glucose concentrations (P < 0.05) and increased mRNA expression of Srebf1 and Chrebp, regulators of fatty acid synthesis (P < 0.05). Fetal pups exposed to Mg deficiency were growth-restricted and exhibited reduced survival. Mg-deficient fetal livers showed lower MUFAs and higher PUFAs, with lower desaturase and elongase mRNA expression than controls. In addition, DHA concentrations were lower in Mg-deficient fetal brains (P < 0.05). These results indicate that Mg deficiency during pregnancy influences both maternal and fetal fatty acid metabolism, fetal growth and fetal survival, and support better understanding maternal Mg status before and during pregnancy.

Topics: Adiponectin; Amniotic Fluid; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Blood Glucose; Cytokines; Fatty Acids; Female; Fetal Development; Fetal Growth Retardation; Insulin; Leptin; Liver; Magnesium; Magnesium Deficiency; Metabolic Diseases; Mice; Nuclear Proteins; Pregnancy; RNA, Messenger; Sterol Regulatory Element Binding Protein 1; Transcription Factors

To investigate the relationships between the adipocytokine levels, markers of inflammation, and vascular remodelling in pregnancies complicated by intrauterine growth restriction (IUGR).. This was a retrospective study. One hundred and forty pregnant patients were enrolled. Adiponectin, leptin, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and C reactive protein (CRP) were assessed in IUGR, small for gestational age (SGA), and appropriate for gestational age (AGA) mother-child couples at delivery. IUGR and SGA fetuses were defined as fetuses whose estimated fetal weight (EFW) was below 10th percentile for gestational age with and without umbilical artery (UA) Doppler abnormalities, respectively. Fetal aorta intima media thickness (aIMT) was evaluated by ultrasound in the same fetal groups. Data were analyzed by R (version 2.15.2).. There were 37 IUGR mother-child couples, 33 SGA, and 70 AGA. Leptin, TNFα, IL-6, and CRP serum levels were higher in IUGR pregnant patients (P < 0.05). Adiponectin levels were significantly reduced in IUGR fetuses compared to SGA and AGA, while leptin, TNFα, and IL-6 levels were higher in IUGR group (P ≤ 0.05). Fetal aIMT was significantly higher in IUGR (P < 0.05) and in this group there was a negative correlation between aIMT and adiponectin/leptin ratio (A/L ratio) (P < 0.05) and between adiponectin and IL-6 levels (P < 0.05).. In conclusion, compared to SGA and AGA, IUGR fetuses had reduced circulating levels of adiponectin and elevated measures of aIMT and several inflammatory markers. Moreover, adiponectin levels were negatively correlated with aIMT in IUGR fetuses suggesting a possible causal link between reduced adiponectin and vessel remodelling.

Topics: Adiponectin; Adult; Aorta; Biomarkers; C-Reactive Protein; Female; Fetal Growth Retardation; Humans; Inflammation; Interleukin-6; Leptin; Mother-Child Relations; Pregnancy; Tumor Necrosis Factor-alpha; Tunica Media

Intrauterine growth restriction (IUGR) may be accompanied by inadequate thermoregulation, especially in piglets that are not considered to possess any brown adipose tissue (BAT) and are thus entirely dependent on shivering thermogenesis in order to maintain body temperature after birth. Leptin can stimulate heat production by promoting non-shivering thermogenesis in BAT, but whether this response occurs in piglets is unknown. Newborn female piglets that were characterised as showing IUGR (mean birth weight of approximately 0.98 kg) were therefore administered injections of either saline or leptin once a day for the first 5 days of neonatal life. The dose of leptin was 0.5 mg/kg, which is sufficient to increase plasma leptin by approximately tenfold and on the day of birth induced a rapid increase in body temperature to values similar to those of normal-sized 'control' piglets (mean birth weight of ∼1.47 kg). Perirenal adipose tissue was then sampled from all offspring at 21 days of age and the presence of the BAT-specific uncoupling protein 1 (UCP1) was determined by immunohistochemistry and immunoblotting. UCP1 was clearly detectable in all samples analysed and its abundance was significantly reduced in the IUGR piglets that had received saline compared with controls, but was raised to the same amount as in controls in those IUGR females given leptin. There were no differences in gene expression between primary markers of brown and white adipose tissues between groups. In conclusion, piglets possess BAT that when stimulated exogenously by leptin can promote increased body temperature.

Topics: Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Animals, Newborn; Body Temperature; Drug Administration Schedule; Female; Fetal Growth Retardation; Immunoblotting; Immunohistochemistry; Injections, Intramuscular; Ion Channels; Leptin; Mitochondrial Proteins; Swine; Thermogenesis; Uncoupling Protein 1

Intrauterine growth restriction (IUGR) is an important fetal developmental problem resulting from 2 broad causes: maternal undernutrition and/or decreased fetal nutrient delivery to the fetus via placental insufficiency. IUGR is often accompanied by up-regulation of the hypothalamo-pituitary-adrenal axis (HPAA). Sheep studies show fetal HPAA autonomy in late gestation. We hypothesized that IUGR, resulting from poor fetal nutrient delivery, up-regulates the fetal baboon HPAA in late gestation, driven by hypothalamo-pituitary glucocorticoid receptor (GR) insensitivity and decreased fetal leptin in peripheral plasma. Maternal baboons were fed as ad libitum controls or nutrient restricted to produce IUGR (fed 70% of the control diet) from 0.16 to 0.9 gestation. Peripheral ACTH, cortisol, and leptin were measured by immunoassays. CRH, arginine vasopressin (AVP), GR, leptin receptor (ObRb), and pro-opiomelanocortin peptide expression were determined immunohistochemically. IUGR fetal peripheral cortisol and ACTH, but not leptin, were increased (P < .05). IUGR increased CRH peptide expression, but not AVP, in the fetal hypothalamic paraventricular nucleus (PVN) and median eminence (P < .05). PVN ObRb peptide expression, but not GR, was decreased (P < .05) with IUGR. ObRb and pro-opiomelanocortin were robustly expressed in the anterior pituitary gland, but ∼1% of cells showed colocalization. We conclude that (1) CRH, not AVP, is the major releasing hormone driving ACTH and cortisol secretion during primate IUGR, (2) fetal HPAA activation was aided by GR insensitivity and decreased ObRb expression in the PVN, and (3) the anterior pituitary is not a site for ObRb effects on the HPAA.

Topics: Animals; Corticotropin-Releasing Hormone; Female; Fetal Growth Retardation; Hydrocortisone; Hypothalamus; Leptin; Papio; Pituitary-Adrenal System; Pregnancy; Pro-Opiomelanocortin; Receptors, Glucocorticoid; Receptors, Leptin

Babies with intra-uterine growth restriction (IUGR) are at increased risk for experiencing negative neonatal outcomes due to their general developmental delay. The present study aimed to investigate the effects of a short postnatal leptin supply on the growth, structure, and functionality of several organs at weaning. IUGR piglets were injected from day 0 to day 5 with either 0.5 mg/kg/d leptin (IUGRLep) or saline (IUGRSal) and euthanized at day 21. Their organs were collected, weighed, and sampled for histological, biochemical, and immunohistochemical analyses. Leptin induced an increase in body weight and the relative weights of the liver, spleen, pancreas, kidneys, and small intestine without any changes in triglycerides, glucose and cholesterol levels. Notable structural and functional changes occurred in the ovaries, pancreas, and secondary lymphoid organs. The ovaries of IUGRLep piglets contained less oogonia but more oocytes enclosed in primordial and growing follicles than the ovaries of IUGRSal piglets, and FOXO3A staining grade was higher in the germ cells of IUGRLep piglets. Within the exocrine parenchyma of the pancreas, IUGRLep piglets presented a high rate of apoptotic cells associated with a higher trypsin activity. In the spleen and the Peyer's patches, B lymphocyte follicles were much larger in IUGRLep piglets than in IUGRSal piglets. Moreover, IUGRLep piglets showed numerous CD79(+) cells in well-differentiated follicle structures, suggesting a more mature immune system. This study highlights a new role for leptin in general developmental processes and may provide new insight into IUGR pathology.

Topics: Animals; Animals, Newborn; CD79 Antigens; Female; Fetal Growth Retardation; Fetus; Forkhead Transcription Factors; Gene Expression Regulation, Developmental; Gonads; Humans; Immune System; Infant, Newborn; Injections, Intramuscular; Leptin; Liver; Male; Organ Size; Organogenesis; Pancreas; Swine

Severely growth-discordant monochorionic (MC) twins offer a unique opportunity to study fetal and placental growth based on a similar genetic background and maternal host environment where the healthy twin serves as an ideal control. Differences in development of MC twins may therefore be due to differential epigenetic regulation of genes involved in placental development and function. Growth-discordant twins are known for abnormal angio-architecture in the placenta of the smaller twin. Since the reasons for this phenotype are mostly unknown this study was aimed to investigate the expression and regulation of genes known to be involved in angiogenesis. We studied 10 severely growth-discordant MC twin placentas (birthweight difference ≥20%) without twin-twin-transfusion syndrome and 5 growth-concordant MC twin placentas. Growth-discordant twin placentas were phenotyped by histology. Placental mRNA expression of 88 angiogenesis-related genes was measured by PCR array. ELISA assay and immunohistochemistry were used to confirm PCR results. EpiTYPTER for DNA methylation was used to determine if methylation ratios were responsible for differential gene expression. The PCR array analysis showed significant mRNA up-regulation in the placental share of the smaller twin for several genes. These included leptin (24.6-fold, P = 0.017), fms-like tyrosine kinase 1 (Flt1, 2.4-fold, P = 0.016) and Endoglin (Eng, 1.86-fold, P = 0.078). None of the other 84 angiogenesis-related genes showed significant differences. ELISA confirmed significantly increased leptin protein expression (49.22 versus 11.03 pg/ml, P = 0.049) in the smaller twin of the discordant growth cohort. Leptin expression in smaller twins' placentas was associated with elevated DNA methylation of the leptin promotor region suggesting the inhibition of binding of a transcriptional activator/inhibitor in that region. We attempted to overcome the limitation of sample size by careful patient selection. We minimized any bias in placental sampling by random sampling from two different sites and by avoiding sampling from areas with grossly visible abnormalities using a standardized sampling protocol. In conclusion, the smaller twin's placenta is characterized by differentially increased gene expressions for Flt1 and Eng mRNA that may be causally associated with the villous pathology driven by abnormal feto-placental angiogenesis. The substantial up-regulation of leptin mRNA may be epigenetically conferred and relev

Topics: Diseases in Twins; Epigenesis, Genetic; Female; Fetal Development; Fetal Growth Retardation; Gene Expression Regulation; Humans; Infant, Newborn; Leptin; Male; Placenta; Pregnancy; Pregnancy, Twin; Twins, Monozygotic

The placental hormone leptin has important functions in fetal and neonatal growth, and prevents depressed respiration in leptin-deficient mice. The effect of leptin on respiratory distress suffered by low birth weight and premature infants has been studied. However, it is unclear how leptin enhances lung maturity in the fetus and ameliorates neonatal respiratory distress. In the present study, we found that antenatal treatment with leptin for 2 d significantly enhanced the relative alveolus area and improved the maturity of fetal lungs in a rat model of fetal growth restriction (FGR). Mean birth weight and lung wet weight were higher in the leptin-treated group than in the PBS-treated group, indicating promotion of fetal growth. Leptin upregulated the intracellular expression and extracellular secretion of surfactant protein (SP) A in type-II alveolar epithelial cells (AECs) in vivo and in vitro. Dual positive effects of leptin were found on protein expression and transcriptional activity of thyroid transcription factor-1 (TTF-1), a nuclear transcription essential for branching morphogenesis of the lung and expression of SP-A in type-II AECs. Knockdown of TTF-1 by RNA interference indicated that TTF-1 may play a vital role in leptin-induced SP-A expression. These results suggest that leptin may have great therapeutic potential for the treatment of FGR, and leptin-mediated SP-A induction and lung maturity of the fetus are TTF-1 dependent.

Topics: Animals; Epithelial Cells; Fetal Growth Retardation; Fetus; Leptin; Lung; Nuclear Proteins; Pulmonary Alveoli; Pulmonary Surfactant-Associated Protein A; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Thyroid Nuclear Factor 1; Transcription Factors; Transcription, Genetic; Up-Regulation

The present study aimed to determine the effects of breed and sex on growth patterns and metabolic features of advanced-pregnancy foetuses exposed to the same environmental conditions. Thus, at Day 62 of pregnancy, swine foetuses from an obese breed with leptin resistance (Iberian breed) were compared to lean crossbred foetuses (25% Large White ×25% Landrace ×50% Pietrain). There were differential developmental patterns in foetuses with leptin resistance, mainly a higher relative weight of the brain resembling "brain-sparing effect". Prioritization of brain growth may be protective for the adequate growth and postnatal survival of the Iberian individuals, an ancient breed reared in extensive semi-feral conditions for centuries. There were also clear sex-related differences in foetal development and metabolism in the Iberian breed. Female Iberian foetuses were similar in size and weight to male littermates but had a significantly higher relative liver to body weight ratio resembling "liver-sparing effect" and a trend for a higher relative intestine to body ratio. Moreover, the availability of triglycerides, cholesterol and IL-6 in female Iberian foetuses was similar to that of lean crossbred foetuses. Overall, these features may favour a better postnatal survival and development of females, the sex more critical for the species survival. These findings set the basis for future translational studies aimed at increasing the knowledge on the interaction between genetic and environmental factors in the early programming of the adult phenotype.

Topics: Animals; Breeding; Endocrine System; Female; Fetal Development; Fetal Growth Retardation; Fetus; Glucose; Inflammation; Leptin; Lipid Metabolism; Male; Obesity; Organogenesis; Placenta; Pregnancy; Reproduction; Sex Characteristics; Swine; Thinness

The effects of maternal moderate-low physical training on postnatal development, glucose homeostasis and leptin concentration in adult offspring subjected to a low-protein diet during the perinatal period were investigated. Male Wistar rats (aged 150 d old) were divided into four groups according to maternal group: untrained (NTp, n 8); trained (Tp, n 8); untrained with a low-protein diet (NT+LPp, n 8); trained with a low-protein diet (T+LPp, n 8). The trained mothers were subjected to a protocol of moderate physical training over a period of 4 weeks (treadmill, 5 d/week, 60 min/d, at 65 % VO(2max)) before mating. At pregnancy, the intensity and duration of exercise was progressively reduced (50-20 min/d, at 65-30 % VO(2max)). The low-protein diet groups received an 8 % casein diet, and their peers received a 17 % casein diet during gestation and lactation. The pups' birth weight and somatic growth were recorded weekly up to the 150th day. Fasting blood glucose, cholesterol, serum leptin concentration, glucose and insulin tolerance tests were evaluated. The Tp animals showed no changes in somatic and biochemical parameters, while the NT+LPp group showed a greater abdominal circumference, hyperglycaemia, hypercholesterolaemia, glucose intolerance and lower plasma leptin. In the T+LPp animals, all of those alterations were reversed except for plasma leptin concentration. In conclusion, the effects of a perinatal low-protein diet on growth and development, glucose homeostasis and serum leptin concentration in the offspring were attenuated in pups from trained mothers.

Topics: Animals; Behavior, Animal; Birth Weight; Diet, Protein-Restricted; Female; Fetal Development; Fetal Growth Retardation; Hypercholesterolemia; Hyperglycemia; Insulin Resistance; Lactation; Leptin; Male; Maternal Behavior; Maternal Nutritional Physiological Phenomena; Motor Activity; Muscle, Skeletal; Pregnancy; Random Allocation; Rats; Rats, Wistar; Weight Gain

Epidemiological data in humans and experiments in laboratory animals have demonstrated that the developmental programming of hypertension may occur as a consequence of dietary manipulations during pregnancy. Surprisingly, there is a scarcity of data regarding the development of hypertension as a consequence of a maternal low-protein diet (MLPD), particularly in the mouse. Furthermore, the role of sex in developmental programming is not well understood. We used FVB/NJ mice, because of their value in genetic/mechanistic analysis, to test the hypothesis that a MLPD during gestation leads to the sexually dimorphic developmental programming of hypertension and related disorders, such as intra-uterine growth restriction (IUGR), type 2 diabetes mellitus and obesity. We administered iso-caloric, normal (control), moderate protein (moderate MLPD) and severe protein (severe MLPD) diets to the mice, beginning 1 week before mating and continuing until the delivery of the pups. From 4 weeks onward, using a non-invasive tail-cuff method, we measured blood pressure and other parameters in the offspring. Our results demonstrate the following: (1) MLPD caused IUGR (low birthweight) in a dose-dependent manner; (2) Female offspring developed severe hypertension, whereas males were affected only moderately; (3) The blood glucose level was elevated only in females from the moderate MLPD group, although their insulin levels remained normal; (4) Rapid catch-up growth was observed in both sexes, with moderate MLPD females and severe MLPD males becoming overweight. Notably, blood leptin levels in the control group were significantly higher in females than in male offspring and were reduced in females from the severe MLPD group. We conclude that an antenatal MLPD during gestation leads to sexually dimorphic programming in mice.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diet, Protein-Restricted; Dietary Proteins; Female; Fetal Growth Retardation; Heart Rate; Hypertension; Insulin; Leptin; Male; Mice; Mice, Inbred Strains; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Sex Characteristics

It is well established that altered maternal nutrition may induce long-term metabolic consequences in offspring. However, the effects of maternal undernutrition during different developmental windows on sex-specific growth and metabolism in offspring are not well defined. We investigated the effect of moderate maternal undernutrition during pregnancy and/or lactation on postnatal growth and metabolic outcomes in offspring. Wistar rats were randomly assigned to one of four groups: (1) control (CONT) dams fed a standard diet throughout pregnancy and lactation; (2) dams undernourished to 50 % of CONT during pregnancy (UNP); (3) dams fed at 50 % of CONT throughout lactation (UNL); (4) dams fed at 50 % of CONT throughout pregnancy and lactation (UNPL). UNP and UNPL offspring were lighter at birth compared to CONT and UNL. UNL and UNPL offspring were growth restricted at weaning and remained smaller into adulthood. UNP males and females developed increased adiposity and hyperleptinaemia in adulthood compared to all other groups. Adiposity in UNL and UNPL males was similar to CONT offspring. In UNL and UNPL females, adiposity was lower than for CONT females. Markers of bone mass, lipid metabolism and hepatic function were altered in UNP offspring but were similar in UNL and UNPL offspring compared to CONT. Lack of catch-up growth during lactation in offspring of undernourished mothers prevented development of adiposity and related metabolic disorders in later life. These data highlight that the timing and duration of undernutrition during critical windows of development exert differential effects on postnatal outcomes in a sex-specific manner.

Topics: Adipogenesis; Adiposity; Animals; Body Weights and Measures; Bone Development; Female; Fetal Development; Fetal Growth Retardation; Lactation; Leptin; Lipids; Liver; Male; Malnutrition; Maternal Nutritional Physiological Phenomena; Pregnancy; Random Allocation; Rats; Rats, Wistar; Sex Characteristics

Intrauterine growth restriction (IUGR) is closely linked with metabolic diseases, appetite disorders and obesity at adulthood. Leptin, a major adipokine secreted by adipose tissue, circulates in direct proportion to body fat stores, enters the brain and regulates food intake and energy expenditure. Deficient leptin neuronal signalling favours weight gain by affecting central homeostatic circuitry. The aim of this study was to determine if leptin resistance was programmed by perinatal nutritional environment and to decipher potential cellular mechanisms underneath.We clearly demonstrated that 5 months old IUGR rats develop a decrease of leptin sentivity, characterized by no significant reduction of food intake following an intraperitoneal injection of leptin. Apart from the resistance to leptin injection, results obtained from IUGR rats submitted to rapid catch-up growth differed from those of IUGR rats with no catch-up since we observed, for the first group only, fat accumulation, increased appetite for food rich in fat and increased leptin synthesis. Centrally, the leptin resistant state of both groups was associated with a complex and not always similar changes in leptin receptor signalling steps. Leptin resistance in IUGR rats submitted to rapid catch-up was associated with alteration in AKT and mTOR pathways. Alternatively, in IUGR rats with no catch-up, leptin resistance was associated with low hypothalamic expression of LepRa and LepRb. This study reveals leptin resistance as an early marker of metabolic disorders that appears before any evidence of body weight increase in IUGR rats but whose mechanisms could depend of nutritional environment of the perinatal period.

Topics: Animals; Animals, Newborn; Central Nervous System; Drug Resistance; Energy Metabolism; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Growth and Development; Homeostasis; Leptin; Male; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Signal Transduction

It has been recognized that there is a relationship between prenatal growth restriction and the development of metabolic-related diseases in later life, a process involved in mitochondrial dysfunction. In addition, intrauterine growth retardation (IUGR) increases the susceptibility of offspring to high-fat (HF) diet-induced metabolic syndrome. Recent findings suggested that HF feeding decreased mitochondrial oxidative capacity and impaired mitochondrial function in skeletal muscle. Therefore, we hypothesized that the long-term consequences of IUGR on mitochondrial biogenesis and function make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. Normal birth weight (NBW), and IUGR pigs were allotted to control or HF diet in a completely randomized design, individually. After 4 weeks of feeding, growth performance and molecular pathways related to mitochondrial function were determined. The results showed that IUGR decreased growth performance and plasma insulin concentrations. In offspring fed a HF diet, IUGR was associated with enhanced plasma leptin levels, increased concentrations of triglyceride and malondialdehyde (MDA), and reduced glycogen and ATP contents in skeletal muscle. High fat diet-fed IUGR offspring exhibited decreased activities of lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD). These alterations in metabolic traits of IUGR pigs were accompanied by impaired mitochondrial respiration function, reduced mitochondrial DNA (mtDNA) contents, and down-regulated mRNA expression levels of genes responsible for mitochondrial biogenesis and function. In conclusion, our results suggest that IUGR make the offspring more susceptible to HF diet-induced mitochondrial dysfunction.

Topics: Animals; Blood Glucose; Diet, High-Fat; DNA, Mitochondrial; Eating; Female; Fetal Growth Retardation; Glucosephosphate Dehydrogenase; Glycogen; Insulin; Lactic Acid; Leptin; Male; Membrane Potentials; Metabolic Syndrome; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Pregnancy; Proton-Translocating ATPases; RNA, Messenger; Swine; Triglycerides

The placental syncytiotrophoblast is the major source of maternal plasma corticotropin-releasing hormone (CRH) in the second half of pregnancy. Placental CRH exerts multiple functions in the maternal organism: It induces the adrenal secretion of cortisol via the stimulation of adrenocorticotropic hormone, regulates the timing of birth via its actions in the myometrium and inhibits the invasion of extravillous trophoblast cells in vitro. However, the auto- and paracrine actions of CRH on the syncytiotrophoblast itself are unknown. Intrauterine growth restriction (IUGR) is accompanied by an increase in placental CRH, which could be of pathophysiological relevance for the dysregulation in syncytialisation seen in IUGR placentas.. We aimed to determine the effect of CRH on isolated primary trophoblastic cells in vitro. After CRH stimulation the trophoblast syncytialisation rate was monitored via syncytin-1 gene expression and beta-hCG (beta-human chorionic gonadotropine) ELISA in culture supernatant. The expression of the IUGR marker genes leptin and 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2) was measured continuously over a period of 72 h. We hypothesized that CRH might attenuate syncytialisation, induce leptin, and reduce 11beta-HSD2 expression in primary villous trophoblasts, which are known features of IUGR.. CRH did not influence the differentiation of isolated trophoblasts into functional syncytium as determined by beta-hCG secretion, albeit inducing syncytin-1 expression. Following syncytialisation, CRH treatment significantly increased leptin and 11beta-HSD2 expression, as well as leptin secretion into culture supernatant after 48 h.. The relevance of CRH for placental physiology is underlined by the present in vitro study. The induction of leptin and 11beta-HSD2 in the syncytiotrophoblast by CRH might promote fetal nutrient supply and placental corticosteroid metabolism in the phase before labour induction.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Corticotropin-Releasing Hormone; Female; Fetal Growth Retardation; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene Products, env; Humans; Leptin; Placenta; Pregnancy; Pregnancy Proteins; Receptors, Corticotropin-Releasing Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trophoblasts

Poor fetal growth, also known as intrauterine growth restriction (IUGR), is a worldwide health concern. IUGR is commonly associated with both an increased risk in perinatal mortality and a higher prevalence of developing chronic metabolic diseases later in life. Obesity, type 2 diabetes or metabolic syndrome could result from noxious "metabolic programming." In order to better understand early alterations involved in metabolic programming, we modeled IUGR rat pups through either prenatal exposure to synthetic glucocorticoid (dams infused with dexamethasone 100 µg/kg/day, DEX) or prenatal undernutrition (dams feeding restricted to 30% of ad libitum intake, UN). Physiological (glucose and insulin tolerance), morphometric (automated tissue image analysis) and transcriptomic (quantitative PCR) approaches were combined during early life of these IUGR pups with a special focus on their endocrine pancreas and adipose tissue development. In the absence of catch-up growth before weaning, DEX and UN IUGR pups both presented basal hyperglycaemia, decreased glucose tolerance, and pancreatic islet atrophy. Other early metabolic defects were model-specific: DEX pups presented decreased insulin sensitivity whereas UN pups exhibited lowered glucose-induced insulin secretion and more marked alterations in gene expression of pancreatic islet and adipose tissue development regulators. In conclusion, these results show that before any catch-up growth, IUGR rats present early physiologic, morphologic and transcriptomic defects, which can be considered as initial mechanistic basis of metabolic programming.

Topics: Adipose Tissue; Analysis of Variance; Animals; Blood Glucose; Blotting, Western; Body Weights and Measures; C-Peptide; Corticosterone; Dexamethasone; DNA Primers; Female; Fetal Growth Retardation; Gene Expression Profiling; Insulin; Insulin Resistance; Islets of Langerhans; Leptin; Malnutrition; Pregnancy; Prenatal Exposure Delayed Effects; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction

Being born small for gestational age (SGA), a proxy for intrauterine growth restriction (IUGR), and prenatal famine exposure are both associated with a greater risk of metabolic disease. Both associations have been hypothesized to involve epigenetic mechanisms. We investigated whether prenatal growth restriction early in pregnancy was associated with changes in DNA methylation at loci that were previously shown to be sensitive to early gestational famine exposure. We compared 38 individuals born preterm (< 32 weeks) and with a birth weight too low for their gestational age (-1SDS) and a normal postnatal growth (>-1SDS at 3 months post term; AGA). The SGA individuals were not only lighter at birth, but also had a smaller length (P=3.3x10 (-13) ) and head circumference at birth (P=4.1x10 (-13) ). The DNA methylation levels of IGF2, GNASAS, INSIGF and LEP were 48.5%, 47.5%, 79.4% and 25.7% respectively. This was not significantly different between SGA and AGA individuals. Risk factors for being born SGA, including preeclampsia and maternal smoking, were also not associated with DNA methylation at these loci. Growth restriction early in development is not associated with DNA methylation at loci shown to be affected by prenatal famine exposure. Our and previous results by others indicate that prenatal growth restriction and famine exposure may be associated with different epigenetic changes or non epigenetic mechanisms that may lead to similar later health outcomes.

Topics: DNA Methylation; Epigenesis, Genetic; Female; Fetal Growth Retardation; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Insulin-Like Growth Factor II; Leptin; Male; Pre-Eclampsia; Pregnancy; Smoking; Starvation

Animal studies suggest pathological foetal programming of hypothalamic circuits regulating food intake in the setting of leptin deficiency and intrauterine growth restriction (IUGR). We aimed to compare placental leptin synthesis and leptin-binding capability in venous cord blood between IUGR newborns and neonates born appropriate for gestational age (AGA).. Prospective controlled multicentre study.. Twenty-one ultrasound-proven IUGR and 33 AGA neonates.. The concentration of leptin and soluble leptin receptor (sOB-R) in venous cord blood at birth was determined. Moreover, placental gene and protein expression of leptin and placental mRNA expression of functional and total leptin receptor isoforms were measured.. Whereas log-leptin concentration in venous cord blood did not differ between IUGR and AGA newborns, the concentration of log-sOB-R was elevated in IUGR neonates (p(confounder adjusted)=0·009). Placental leptin protein synthesis as well as leptin mRNA was significantly higher in IUGR than in AGA infants (log-transformed, relative gene expression, p(confounder adjusted)=0·004). Analysis of gene expression of functional and total leptin receptor isoforms did not show any difference between both groups.. Leptin-binding capability in venous cord blood is increased in IUGR newborns. Thus, via foetal programming, reduced biologically active leptin levels might contribute to a perturbed regulation of appetite.

Topics: Adolescent; Adult; Blotting, Western; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Polymerase Chain Reaction; Pregnancy; Prospective Studies; Receptors, Leptin; Young Adult

Skeletal abnormalities are one of the hallmarks of growth delay during gestation. The aim of this study was to determine changes induced by leptin in skeletal growth and development in a rat model of intrauterine growth retardation (IUGR) and to elucidate the possible underlying mechanisms.. Intrauterine growth retardation was induced prepartum and the effects of leptin to mothers prenatally or to offspring postnatally were studied. Radii were harvested and tested mechanically and structurally. Tibias were evaluated for growth-plate morphometry.. On day 40 postpartum, total bone length and mineral density and tibial growth-plate width and numbers of cells within its zones of offspring treated with leptin were significantly greater than in the control group.. Postnatal leptin administration in an IUGR model improves the structural properties and elongation rate of bone. These findings could pave the way to preventing some phenotypic presentations of IUGR.

Topics: Animals; Bone and Bones; Bone Density; Disease Models, Animal; Female; Fetal Development; Fetal Growth Retardation; Growth Plate; Leptin; Pregnancy; Radius; Rats; Rats, Wistar; Skeleton; Tibia

Adult health is dependent, in part, on maternal nutrition and growth during early life, which may independently affect insulin sensitivity, body composition, and overall energy homeostasis. Since the publication of the "thrifty phenotype hypothesis" by Hales and Barker (Diabetologia 1992;35:595-601), animal experiments have focused on establishing the mechanisms involved, which include changes in fetal cortisol, insulin, and leptin secretion or sensitivity. Intrauterine growth retardation can be induced by either prolonged modest changes in maternal diet or by more severe changes in uterine blood supply near to term. These contrasting challenges result in different amounts of cellular stress in the offspring. In addition, shifts in the transcriptional activity of DNA may produce sustained metabolic adaptations. Within tissues and organs that control metabolic homeostasis (eg, hypothalamus, adipose tissue, stomach, skeletal muscle, and heart), a range of phenotypes can be induced by sustained changes in maternal diet via modulation of genes that control DNA methylation and by histone acetylation, which suggests epigenetic programming. We now need to understand how changes in maternal diet affect DNA and how they are conserved on exposure to oxidative stress. A main challenge will be to establish how the dietary environment interacts with the programmed phenotype to trigger the development of metabolic disease. This may aid in the establishment of nutrigenomic strategies to prevent the metabolic syndrome.

Topics: Adaptation, Physiological; Adult; Animals; Body Composition; Diet; DNA Methylation; Energy Metabolism; Epigenesis, Genetic; Female; Fetal Development; Fetal Growth Retardation; Genetic Predisposition to Disease; Homeostasis; Humans; Hydrocortisone; Insulin; Insulin Resistance; Insulin Secretion; Leptin; Male; Maternal Nutritional Physiological Phenomena; Metabolic Diseases; Models, Animal; Oxidative Stress; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats

Fetal growth restriction followed by accelerated postnatal growth contributes to impaired metabolic function in adulthood. The extent to which these outcomes may be mediated centrally within the hypothalamus, as opposed to in the periphery within the digestive tract, remains unknown. In a sheep model, we achieved intrauterine growth restriction experimentally by maternal nutrient restriction (R) that involved a 40% reduction in food intake through late gestation. R offspring were then either reared singly to accelerate postnatal growth (RA) or as twins and compared with controls also reared singly. From weaning, all offspring were maintained indoors until adulthood. A reduced litter size accelerated postnatal growth for only the first month of lactation. Independently from postnatal weight gain and later fat mass, R animals developed insulin resistance as adults. However, restricted accelerated offspring compared with both the control accelerated and restricted restricted offspring ate less and had higher fasting plasma leptin as adults, an adaptation which was accompanied by changes in energy sensing and cell proliferation within the abomasum. Additionally, although fetal restriction down-regulated gene expression of mammalian target of rapamycin and carnitine palmitoyltransferase 1-dependent pathways in the abomasum, RA offspring compensated for this by exhibiting greater activity of AMP-activated kinase-dependent pathways. This study demonstrates a role for perinatal nutrition in the peripheral control of food intake and in energy sensing in the gastric mucosal and emphasizes the importance of diet in early life in regulating energy metabolism during adulthood.

Topics: Abomasum; Adiposity; AMP-Activated Protein Kinases; Animals; Caloric Restriction; Carnitine O-Palmitoyltransferase; Cell Proliferation; Energy Metabolism; Female; Fetal Growth Retardation; Gastric Mucosa; Gene Expression Regulation; Insulin Resistance; Lactation; Leptin; Male; Maternal Nutritional Physiological Phenomena; Pregnancy; Random Allocation; RNA, Messenger; Sheep; TOR Serine-Threonine Kinases; Weight Gain

Intra-uterine growth restriction (IUGR) predisposes obesity in adulthood. This may be due to altered fetal nutrition causing sustained changes within the developing hypothalamic energy balance regulatory system. Using our established ovine model of IUGR, 130-day singleton fetuses (term=147 days) were obtained from growing adolescent mothers on control dietary intake (C), high intake (H) or H with growth hormone administration during either early (H+early GH) or late gestation (H+late GH) (n=6/group). GH increased maternal glycemia for the duration of treatment. H and H+early GH fetuses showed IUGR compared with C fetuses; body weight was partially restored in H+late GH fetuses, with 40% increased adiposity. In the fetal hypothalamic arcuate nucleus (ARC), cocaine- and amphetamine-regulated transcript mRNA (anorexigenic) was decreased in H fetuses and correlated across all groups with total fetal liver glycogen. Neuropeptide Y, agouti-related peptide (orexigenic) and proopiomelanocortin (anorexigenic) mRNAs were not different between groups. Insulin receptor mRNA in the ARC was increased in H, H+early GH and H+late GH fetuses and correlated negatively with fetal plasma insulin. Leptin receptor mRNA in the ARC correlated positively with fetal plasma leptin concentration and fetal fat content. Therefore, in IUGR fetuses, a key anorexigenic neuropeptide is sensitive to altered glucose supply and the hypothalamic leptin-signaling pathway is altered prenatally by increased adiposity and leptinemia. These changes could impact on postnatal energy balance regulation.

Topics: Adiposity; Agouti-Related Protein; Animals; Blood Glucose; Energy Metabolism; Female; Fetal Growth Retardation; Fetus; Gene Expression; Glycogen; Humans; Hypothalamus; Leptin; Nerve Tissue Proteins; Neuropeptide Y; Pregnancy; Pro-Opiomelanocortin; Receptor, Insulin; Sheep, Domestic

Besides foetal or maternal disorders, placental dysfunction is a major cause of intrauterine growth restriction (IUGR). Although numerous macro- and histopathological changes have been described, little is known about the precise aetiology and the contribution of foetal/placental genes in this disorder.. Placental tissues of 20 IUGR and control neonates were analysed by microarray technique. Four of the regulated genes with possible relevance in the pathogenesis of IUGR and its consequences were further studied in placentas of 27 IUGR and 35 control newborns.. Elevated gene expression of leptin, corticotrophin-releasing hormone (CRH), and IGF-binding protein-1 (IGFBP-1) in IUGR placentas could be confirmed in the larger group by real-time PCR, whereas prolactin showed no significant difference. Accordingly, protein expression of leptin and IGFBP-1 depicted by Western blot was elevated in IUGR, prolactin was not different. Birthweight standard deviation score (SDS) correlated negatively to leptin, IGFBP-1, and CRH, whereas placental weight correlated only to IGFBP-1. Leptin correlated negatively to gestational age of IUGR patients and positively to placental score, a marker of severity of impaired foeto-placental circulation.. As confirmed in a large group of IUGR and control samples, the up-regulated factors leptin, IGFBP-1, and CRH may serve as candidate genes for the prediction of subsequent metabolic consequences in IUGR newborns. These three factors may not only influence growth of the foetus, but might also interact with programming of its metabolic functions, which has to be determined in an ongoing study.

Topics: Adult; Blotting, Western; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Leptin; Male; Oligonucleotide Array Sequence Analysis; Placenta; Pregnancy; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; Young Adult

Being born small for gestational age (SGA) is a known risk factor for greater neonatal mortality and disease in later life. Some determinants of the incidence of SGA newborns have been studied but little is known about the role of leptin in the beginning of pregnancy.. To investigate the effect of serum leptin concentration in the 1st gestational trimester on the incidence of SGA newborns and to identify other determining factors in the occurrence of SGA.. Prospective study with 195 pairs of mothers and their children monitored in Rio de Janeiro, Brazil. The dependent variable was SGA newborns, while the independent variables were sociodemographic, reproductive, anthropometric and biochemical variables. Statistical analysis was performed by means of logistic regression.. The incidence of SGA was 11.3% (CI 95%: 7.31-16.46). The results showed that low concentrations (lowest tertile compared to 2nd and 3rd tertiles) of leptin (RR = 5.26; CI 95%: 1.91-9.56), insufficient gestational weight gain (RR = 3.16; CI 95%: 0.98-7.38), low stature (RR = 3.94; CI 95%: 1.22-8.57) and alcohol consumption during gestation (RR = 5.92; CI 95%: 1.44-12.92) were risk factors for SGA.. Lower leptin concentrations were associated with a significant risk for SGA after adjusting for confounding variables. Maternal serum leptin at the beginning of gestation can be used as a marker for the early detection of SGA.

Topics: Birth Weight; Brazil; Female; Fetal Growth Retardation; Follow-Up Studies; Humans; Incidence; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Pregnancy; Pregnancy Trimester, First; Prenatal Exposure Delayed Effects; Prospective Studies; Risk Factors

Nutritional programming, taking place in utero or early after birth, is closely linked with metabolic and appetite disorders in adulthood. Following the hypothesis that nutritional programming impacts hypothalamic neuronal organization, we report on discrepancies of multiple molecular and cellular early events that take place in the hypothalamus of rats submitted to intrauterine growth restriction (IUGR). Expression screening performed on hypothalami from IUGR rats at birth and at postnatal d 12 identified changes in gene expression of neurodevelopmental process (cell differentiation and cytoskeleton organization). Additionally, a slight reduction of agouti-related protein and a strong reduction of alpha-MSH-immunoreactive efferent fibers were demonstrated in the paraventricular nucleus of IUGR rats. Rapid catch-up growth of IUGR rats, 5 d after birth, had a positive effect on neurodevelopmental factors and on neuronal projections emanating from the arcuate nucleus. The molecular and cellular anomalies detected in IUGR rats can be related to the reduced and delayed plasma leptin surge from d 0-16 when compared with control and IUGR rats with catch-up growth. However, the ability of leptin to activate intracellular signaling in arcuate nucleus neurons was not reduced in IUGR rats. Other mechanism such as epigenetic regulation of the major appetite-regulating neuropeptides genes was analyzed in parallel with their mRNA expression during postnatal development. This study reveals the importance of an early catch-up growth that reduces abnormal organization of hypothalamic pathways involved in energy homeostasis, whereas protein restriction, maintained during postnatal development leads to an important immaturity of the hypothalamus.

Topics: Agouti-Related Protein; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Body Weight; DNA; DNA Methylation; Energy Intake; Female; Fetal Growth Retardation; Gene Expression Regulation; Hypothalamus; Leptin; Male; Nerve Fibers; Nerve Tissue Proteins; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin; Rats; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA; Signal Transduction

The human placenta as part of the feto-placental unit may influence fetal endocrine systems and may therefore represent a very important link between intrauterine growth restriction (IUGR) and metabolic disorders in later life. We aimed to analyze the effect of sample origin on gene expression of placental factors potentially involved in fetal programming in IUGR versus appropriate for gestational age growth (AGA) to standardize sample collection procedure for a multicenter approach.. Placental gene expression of insulin-like growth factor-binding protein (IGFBP)-1, prolactin, corticotropin releasing hormone (CRH) and leptin was measured and compared between proximal, intermediate and peripheral region of the placenta in 22 IUGR (proven by anomalous placental Doppler velocimetry) and 19 AGA neonates.. Whereas no difference in gene expression was seen in the proximal portion, in the intermediate placental region mRNA expression of IGFBP-1 (p = 0.01), prolactin (p = 0.04), CRH (p = 0.01) and leptin (p = 0.04) was increased in IUGR samples compared to controls. At the placental periphery, gene expression of these placental transcripts showed a higher expression level in IUGR placentas without statistical significance, except for leptin (p = 0.03).. Placental sampling site seems to be relevant for detecting differences in gene expression between IUGR and AGA neonates.

Topics: Adult; Corticotropin-Releasing Hormone; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Insulin-Like Growth Factor Binding Protein 1; Leptin; Male; Placenta; Pregnancy; Prolactin; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Statistics, Nonparametric

The cause of preeclampsia remains unknown. Excessive antiangiogenic proteins have been proposed to play a pathogenic role in preeclampsia.. Our objective was to determine the differences in soluble endoglin (sEndoglin), soluble fms-like tyrosine kinase receptor-1 (sFLT1), leptin, adiponectin, and endothelin 1 concentrations between normal and preeclampsia amniotic fluid (AF). Such results may help us understand the pathophysiology of preeclampsia.. We performed a nested case-control study. Seventy-one women with preeclampsia were matched to 71 normotensive controls. The preeclamptic women were broken into two subgroups according to the association with fetal intrauterine growth restriction (IUGR). AF concentrations of sEndoglin, sFLT1, leptin, adiponectin, and endothelin 1 were measured by ELISA. Receiver-operating characteristics curve analysis was used to compare the discriminative values of these potential biomarkers. Functional network analysis was performed using MetaCore to reveal the common functions of the interacting proteins.. Increased AF concentrations of sFLT1, sEndoglin, endothelin 1, and leptin were found in women who later developed preeclampsia. sFLT1, sEndoglin, leptin, and adiponectin were significantly higher in the preeclampsia with IUGR than those without IUGR. Leptin has the largest area under the curve (0.753). Network analysis revealed that elevated amniotic proteins are involved in the inflammatory process of the human placenta.. Significant elevation of leptin can be detected in AF 2 months earlier than the appearance of symptoms; thus, it may be used as a predictive marker for preeclampsia. The increase of these antiangiogenic proteins supports the roles of inflammation and oxidative stress in pathogenesis of preeclampsia.

Topics: Adiponectin; Adult; Amniotic Fluid; Analysis of Variance; Antigens, CD; Case-Control Studies; Chi-Square Distribution; Endoglin; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Humans; Leptin; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Prospective Studies; Receptors, Cell Surface; Regression Analysis; ROC Curve; Vascular Endothelial Growth Factor Receptor-1

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

Topics: Animals; Appetite Regulation; Disease Susceptibility; Fetal Development; Fetal Growth Retardation; Humans; Infant, Newborn; Insulin; Leptin; Obesity

Small birth weight and excess of early protein intake are suspected to enhance later adiposity. The present study was undertaken to determine the impact of diets differing in protein content on short-term growth, adipose tissue development, and the insulin-like growth factor (IGF) system in piglets. Normal (NW) and small (SW) birth weight piglets were fed milk-replacers formulated to provide an adequate (AP) or a high protein (HP) supply between 7 and 28 d of age. The fractional growth rate was higher (p < 0.01) in SW than in NW piglets. At 7 d of age, the lower (p < 0.05) weight of perirenal adipose tissue relative to body mass in SW than in NW piglets did not involve significant changes in plasma IGF-I, leptin, or insulin-like growth factor binding protein levels, but involved differences (p < 0.05) in the expression of IGF-I and leptin in adipose tissue. Growth rates did not differ between AP and HP piglets. At 28 d of age, HP piglets had lower (p < 0.001) relative perirenal adipose tissue weight but did not differ clearly from AP piglets with regard to the IGF system. It remains to be determined whether piglets fed such a high protein intake will stay subsequently with a low adiposity.

Topics: Adipose Tissue; Adiposity; Age Factors; Aging; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Birth Weight; Diet; Eating; Fetal Growth Retardation; Insulin-Like Growth Factor Binding Proteins; Leptin; Milk Proteins; Somatomedins; Swine; Weight Gain

Obesity and its associated comorbidities are of major worldwide concern. It is now recognized that there are a number of metabolically distinct pathways of obesity development. The present paper investigates the effect of moderate daily exercise on the underlying mechanisms of one such pathway to obesity, through interrogation of metabolic flexibility. Pregnant Wistar rats were either fed chow ad libitum or undernourished throughout pregnancy, generating control or intrauterine growth restricted (IUGR) offspring, respectively. At 250 d of age, dual-emission x-ray absorptiometry scans and plasma analyses showed that moderate daily exercise, in the form of a measured amount of wheel running (56 m/d), prevented the development of obesity consistently observed in nonexercised IUGR offspring. Increased plasma C-peptide and hepatic atypical protein kinase Czeta levels explained increased glucose uptake and increased hepatic glycogen storage in IUGR offspring. Importantly, whereas circulating levels of retinol binding protein 4 were elevated in obese, nonexercised IUGR offspring, indicative of glucose sparing without exercise, retinol binding protein 4 levels were normalized in the exercised IUGR group. These data suggest that IUGR offspring have increased flexibility of energy storage and use and that moderate daily exercise prevents obesity development through activation of distinct pathways of energy use. Thus, despite a predisposition to develop obesity under sedentary conditions, obesity development was prevented in IUGR offspring when exercise was available. These results emphasize the importance of tailored lifestyle changes that activate distinct pathways of metabolic flexibility for obesity prevention.

Topics: Animal Feed; Animals; Blood Glucose; Body Composition; C-Peptide; Diet, Reducing; Energy Intake; Female; Fetal Growth Retardation; Insulin; Leptin; Lipids; Obesity; Physical Conditioning, Animal; Pregnancy; Rats; Rats, Wistar; Retinol-Binding Proteins, Plasma

Adiponectin and leptin are members of the adipocytokine family. Adiponectin promotes and leptin inhibits apoptosis and both are regulators of angiogenesis. Adipocytokines and their receptors are expressed in the placenta, and in the pre-eclamptic (PE) mother the serum levels of both are higher than in healthy ones. Our aim was to study the expression of adiponectin, leptin, their receptor genes and apoptosis in severely PE and normal placentas.. The study group comprised 13 PE mothers and their 16 healthy controls. Placental biopsies were taken during cesarean section, the RNA was extracted and micro-array study was performed, followed by PCR and apoptosis studies.. The placental expression level of the leptin and adiponectin receptor 1 genes was significantly higher in PE mothers than in controls. No significant changes were observed in the levels of the adiponectin, adiponectin receptor 2 and Leptin receptor genes. The expression of the Adiponectin gene was low. The rate of apoptosis was higher in the PE placentas.. The activity of placental adipocytokines and their receptor genes in severe PE may suggest an important role in placental angiogenesis. Placental apoptosis induced by adiponectin could be mediated via the ADIPOR1-receptor.

Topics: Adiponectin; Adult; Apoptosis; Case-Control Studies; Female; Fetal Growth Retardation; Humans; Leptin; Oligonucleotide Array Sequence Analysis; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Receptors, Adiponectin; Receptors, Leptin

Intrauterine growth restriction (IUGR) is associated with an increased risk for short stature and diseases in adulthood thought to be inflicted by fetal programming. We hypothesized that placental endocrine systems involved in perinatal growth might also play a role in postnatal growth after IUGR. In a prospective controlled multicenter study, placental gene expression of IGF-binding protein-1 (IGFBP-1), leptin and 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) were measured in 14 IUGR infants and 15 children born appropriate for gestational age (AGA) proven by serial ultrasound examinations. Postnatally, IUGR infants experienced a significantly higher growth velocity than AGA neonates (at 1 y: p = 0.001). Gene expression of 11beta-HSD2 at birth correlated positively with birth length (r = 0.55, p = 0.04) and inversely with growth velocity in the first year of life (r = -0.69, p = 0.01) in the IUGR, but not in the AGA group. There was no correlation between gene expression of placental IGFBP-1, leptin and birth weight, length and growth velocity during the first year of life. AGA infants showed significantly higher concentrations of cortisone in venous cord blood after birth (p = 0.02) as a surrogate of a higher 11beta-HSD2 activity in the fetoplacental unit. In conclusion, placental 11beta-HSD2 gene expression might predict postnatal growth in IUGR.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; Anthropometry; Birth Weight; Female; Fetal Development; Fetal Growth Retardation; Gestational Age; Humans; Infant; Insulin-Like Growth Factor Binding Protein 1; Leptin; Male; Placenta; Pregnancy; Prospective Studies

Being born small is associated with an increased risk of visceral obesity and insulin resistance in adult life. We have investigated the effect of IUGR on adipogenic and lipogenic gene expression in visceral fat in the lamb at 3 wk of age. Perirenal fat mass, but not adipocyte size was greater in females than males, independent of birth weight. Plasma insulin concentrations during the first 24 h after birth predicted the size of the adipocytes and expression of adiponectin in visceral adipose tissue in both males and females. In females, plasma nonesterified fatty acids (NEFA) concentrations during the first 24 h after birth were directly related to peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA expression in the perirenal fat depot at 3 wk of age. In the males, in contrast to the females, PPARgamma and leptin expression in perirenal visceral fat were significantly lower in IUGR compared with control lambs. Thus, the early nutritional environment programs adipocyte growth and gene expression in visceral adipose tissue. The differential effect of sex and IUGR on PPARgamma and leptin expression in visceral fat may be important in the subsequent development of visceral obesity and the insulin resistant phenotype in later life.

Topics: Analysis of Variance; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Fatty Acids, Nonesterified; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Insulin; Intra-Abdominal Fat; Leptin; Male; PPAR gamma; Sex Factors; Sheep

Fetal growth restriction (FGR) followed by rapid weight gain during early life has been suggested to be the initial sequence promoting central adiposity and insulin resistance. However, the link between fetal and early postnatal growth and the associated anthropometric and metabolic changes have been poorly studied.. Over the first year of post-natal life, changes in body mass index, skinfold thickness and hormonal concentrations were prospectively monitored in 94 infants in whom the fetal growth velocity had previously been measured using a repeated standardized procedure of ultrasound fetal measurements. 45 infants, thinner at birth, had experienced previous FGR (FGR+) regardless of birth weight. Growth pattern in the first four months of life was characterized by greater change in BMI z-score in FGR+ (+1.26+/-1.2 vs +0.58 +/-1.17 SD in FGR-) resulting in the restoration of BMI and of fat mass to values similar to FGR-, independently of caloric intakes. Growth velocity after 4 months was similar and BMI z-score and fat mass remained similar at 12 months of age. At both time-points, fetal growth velocity was an independent predictor of fat mass in FGR+. At one year, fasting insulin levels were not different but leptin was significantly higher in the FGR+ (4.43+/-1.41 vs 2.63+/-1 ng/ml in FGR-).. Early catch-up growth is related to the fetal growth pattern itself, irrespective of birth weight, and is associated with higher insulin sensitivity and lower leptin levels after birth. Catch-up growth promotes the restoration of body size and fat stores without detrimental consequences at one year of age on body composition or metabolic profile. The higher leptin concentration at one year may reflect a positive energy balance in children who previously faced fetal growth restriction.

Topics: Adipose Tissue; Body Mass Index; Female; Fetal Growth Retardation; Growth; Humans; Infant; Infant, Newborn; Insulin; Leptin; Pregnancy; Prospective Studies

To explore the role of endothelin-1 (ET-1) and leptin in intrauterine growth restriction (IUGR) among preeclamptic and non-pre-eclamptic women.. Forty three patients with a pregnancy complicated by IUGR, 23 cases with severe pre-eclampsia and 20 cases of non-pre-eclamptic were enrolled. Control group comprised 15 cases with uncomplicated pregnancy. Blood samples from umbilical artery and maternal venous blood were collected at the time of delivery for analysis of ET-1 and leptin levels. Mode of delivery, birth weight and Apgar score were also recorded.. The mean maternal and fetal ET-1 level was significantly higher in pregnancies complicated by IUGR than in control group. The mean maternal leptin level was significantly higher in pre-eclamptic patients when compared to non-preeclamptic and control groups. Mean fetal leptin level was significantly lower in patients compared to control; however, when fetal leptin corrected to fetal weight, it was insignificantly different in the both groups. E-mail: m. alhaggar@yahoo.co.uk.. Maternal plasma ET-1 and leptin correlate with the degree of fetal growth restriction originating from deterioration of placental function. Maternal plasma leptin and ET-1 levels may reflect deterioration in fetal growth.

Topics: Adult; Analysis of Variance; Biomarkers; Birth Weight; Case-Control Studies; Chi-Square Distribution; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Linear Models; Maternal Age; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Outcome; Prenatal Care; Probability; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Ultrasonography, Prenatal; Young Adult

A mismatch between fetal and postnatal environment can permanently alter the body structure and physiology and therefore contribute later to obesity and related disorders, as revealed by epidemiological studies. Early programming of adipose tissue might be central in this observation. Moreover, adipose tissue secretes adipokines that provide a molecular link between obesity and its related disorders. Therefore, our aim was to investigate whether a protein restriction during fetal life, followed by catch-up growth could lead to obesity in 9-mo-old male mice and could alter the adipose tissue gene expression profile. Dams were fed a low-protein (LP) or an isocaloric control (C) diet during gestation. Postnatal catch-up growth was induced in LP offspring by feeding dams with control diet and by culling LP litters to four pups instead of eight in the C group. At weaning, male mice were fed by lab chow alone (C) or supplemented with a hypercaloric diet (HC), to induce obesity (C-C, C-HC, LP-C, and LP-HC groups). At 9 mo, LP offspring featured increased relative fat mass, hyperglycemia, hypercholesterolemia, and hyperleptinemia. Using a microarray designed to study the expression of 89 genes involved in adipose tissue differentiation/function, we demonstrated that the expression profile of several genes were dependent upon the maternal diet. Among the diverse genes showing altered expression, we could identify genes encoding several enzymes involved in lipid metabolism. These results indicated that offspring submitted to early mismatched nutrition exhibited alterations in adipose tissue gene expression that probably increases their susceptibility to overweight when challenged after weaning with a HC diet.

Topics: Adipocytes, White; Adipose Tissue, White; Animals; Blood Glucose; Body Composition; Body Weight; Carbohydrate Metabolism; Diet; Diet, Protein-Restricted; Down-Regulation; Eating; Female; Fetal Development; Fetal Growth Retardation; Gene Expression; Gene Expression Profiling; Leptin; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Up-Regulation

Increasing evidence suggests a role for prenatal environment in the onset of cardiovascular and metabolic disease in later life. In the rat, undernutrition in utero and a postnatal high-fat diet gives rise to a phenotype similar to the metabolic syndrome. As endothelial dysfunction is a feature of both CVD and the metabolic syndrome we investigated the impact of maternal undernutrition and/or postnatal high-fat on endothelial function. Virgin Wistar rats were mated and randomly assigned to groups to receive food either ad libitum (control) or at 30% of ad libitum intake throughout gestation. At postnatal day 250, a cohort from each group was challenged with a high-fat diet (D12451, 45% energy from fat; Research Diets, Inc., New Brunswick, NJ, USA) for the remainder of the study. At 1 year of age, small mesenteric arteries were dissected and mounted on a wire myograph and responses to phenylephrine, endothelin, acetylcholine, leptin and sodium nitroprusside assessed. Vasoconstriction to endothelin was significantly enhanced in all groups compared with controls (-log effective concentration equal to 50% of the maximal response (pEC50); P < 0.001). Endothelium-dependent vasodilatation to acetylcholine was significantly blunted in all groups compared with controls (% maximum response; P < 0.01), while dilatation to leptin and sodium nitroprusside was similar in all groups. These data demonstrate that both maternal undernutrition and postnatal high fat lead to vascular alterations and suggest that maternal undernutrition alone is at least as detrimental to offspring endothelial function as a long-term exposure to a high-fat diet in the offspring.

Topics: Animals; Dietary Fats; Endothelium, Vascular; Female; Fetal Growth Retardation; Leptin; Male; Malnutrition; Mesenteric Arteries; Pregnancy; Prenatal Nutritional Physiological Phenomena; Random Allocation; Rats; Rats, Wistar; Vasoconstriction; Vasodilation

Low birth weight (BW), small head circumference, reduced length, increased preterm births and neuro-endocrine dysfunctions are among known consequences of smoking during pregnancy. Few studies have linked leptin to clinical features of growth restriction associated with maternal smoking and explored interaction with other determinants of size at birth, such as gender.. Cord serum leptin concentrations were measured in 1215 term infants born to Caucasian mothers at completion of uneventful pregnancy. Serum concentrations were related to BW, gestational length, gender and maternal smoking and interaction with other determinants of size at birth evaluated.. Smoking was more frequent in younger (P<0.001) and shorter mothers (P=0.03) from lower socio-economic groups (SEGPs) (P<0.001). Infants born to smokers were lighter (190 g less), shorter and with smaller head circumference. Cord serum leptin concentrations were higher in girls (9.8 s.d. 7.6 ng/ml) than in boys (7.05 s.d. 5.8 ng/ml) (P<0.001). Boys were heavier (BW 3.52 s.d. 0.49 kg) than girls (3.39 s.d. 0.44 kg) (P<0.001), but girls had greater skinfold thickness measurements (sub-scapular and quadriceps skinfold thicknesses 5.5 s.d. 1.6 mm and 7.6 s.d. 1.9 mm respectively; boys 5.3 s.d. 1.6 vs 7.24+/-1.90 mm, P<0.001 respectively). Multivariate analyses showed gender (P<0.001), BW SDS (P<0.001), gestational length (P<0.001) and maternal smoking (P<0.042) as factors that influenced umbilical cord serum leptin concentrations in newborns.. Maternal smoking restrains foetal growth through placental vascular effects, and likely also via associated effects on leptin metabolism. More studies are needed to determine the influence that maternal smoking may have on placental syncytiotrophoblast and foetal adipose tissue.

Topics: Birth Weight; Body Height; Female; Fetal Blood; Fetal Growth Retardation; Follow-Up Studies; Gestational Age; Humans; Infant, Newborn; Leptin; Male; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Sex Characteristics; Smoking

Low birth weight resulting from intrauterine growth retardation (IUGR) is a risk factor for further development of metabolic diseases. The pig appears to reproduce nearly all of the phenotypic pathological consequences of human IUGR and is likely to be more relevant than rodents in studies of neonatal development. In the present work, we characterized the model of low-birth-weight piglets with particular attention to the hypothalamic leptin-sensitive system, and we tested whether postnatal leptin supplementation can reverse the precocious signs of adverse metabolic programming. Our results demonstrated that 1) IUGR piglets present altered postnatal growth and increased adiposity; 2) IUGR piglets exhibit abnormal hypothalamic distribution of leptin receptors that may be linked to further disturbance in food-intake behavior; and 3) postnatal leptin administration can partially reverse the IUGR phenotype by correcting growth rate, body composition, and development of several organs involved in metabolic regulation. We conclude that IUGR may be characterized by altered leptin receptor distribution within the hypothalamic structures involved in metabolic regulation and that leptin supplementation can partially reverse the IUGR phenotype. These results open interesting therapeutic perspectives in physiopathology for the correction of defects observed in IUGR.

Topics: Adipocytes, White; Adipose Tissue, White; Animals; Animals, Newborn; Birth Weight; Blood Glucose; Body Composition; Body Size; Body Weight; Female; Fetal Growth Retardation; Gene Expression; Hypothalamus; In Situ Hybridization; Leptin; Receptors, Leptin; Sus scrofa; Triglycerides; Weight Gain

Ligation of the uterine arteries (LIG) in rats serves as a model of intrauterine growth restriction and subsequent developmental programming of impaired glucose tolerance, hyperinsulinemia, and adiposity in the offspring. Its impact on lipid metabolism has been less well investigated. We compared parameters of glucose and lipid metabolism and glucocorticoid levels in the offspring of dams that underwent either LIG or sham operation (SOP) with those of untreated controls. Blood parameters including insulin, leptin, and visfatin as well as body weight, food intake, and creatinine clearance were recorded up to an age of 30 wk. Glucose tolerance tests were performed, and both leptin and visfatin expression in liver, muscle, and epididymal and mesenteric fat was quantified by RT-PCR. After catch-up growth, weight gain of all groups was similar, despite lower food intake of the LIG rats. LIG offspring showed impaired glucose tolerance from the age of 15 wk as well as elevated glycosylated hemoglobin and corticosterone levels. However, the body fat content of both LIG and SOP animals increased relative to controls, and both showed elevated triglyceride, total cholesterol, and leptin levels as well as a reduced proportion of high-density lipoprotein cholesterol. Thus, use of the LIG model requires both SOP and untreated controls. Although only LIG is associated with impaired glucose tolerance, pathogenic programming of the lipid metabolism can also be induced by SOP. Visfatin does not appear to be involved in the disturbed glucose metabolism after intrauterine growth restriction and may represent only a marker of fat accumulation.

Topics: Adipose Tissue; Animals; Animals, Newborn; Arteries; Creatinine; Disease Models, Animal; Eating; Female; Fetal Growth Retardation; Glucose; Leptin; Ligation; Lipid Metabolism; Lipids; Male; Nicotinamide Phosphoribosyltransferase; Placental Circulation; Pregnancy; Rats; Rats, Wistar; Uterus

Adiponectin and leptin, two adipose-tissue-derived proteins, have been reported to be elevated in women with established PE (pre-eclampsia). The aim of the present study was to investigate whether alterations in adiponectin and leptin levels predate the development of PE and FGR (fetal growth restriction) in women at increased risk of these complications, as assessed by Doppler examination of the uterine arteries during the second trimester of pregnancy. We also sought to investigate the circulating levels of adiponectin and leptin in women with established severe early-onset FGR. The study included three groups of pregnant women at 23-25 weeks: Group A (n=44) with normal uterine artery Doppler waveforms, Group B (n=49) with abnormal Doppler waveforms and normal fetal growth at the time of the examination, and Group C (n=15) with established severe FGR and abnormal Doppler waveforms. All women had plasma adiponectin and leptin measured by sensitive immunoassays. In Group B, 19 women had a normal outcome, 17 delivered infants with FGR and 13 developed PE. The women who developed PE delivered smaller babies earlier than women with a normal outcome (P<0.001). There were no significant differences in adiponectin levels between any of the groups (overall P=0.3). Leptin concentrations, expressed as MoM (multiples of the median) of Group A, were higher in women in Group C, i.e. established severe FGR at 2.5 (1.2-2.7) MoMs (overall P<0.001), compared with all of the other groups and subgroups. In conclusion, we found that, in pregnancies complicated by severe early-onset FGR, the maternal plasma concentration of leptin is twice as high as in normal pregnancies. However, the second trimester levels of maternal plasma adiponectin and leptin in pregnancies that subsequently develop PE and/or FGR are not significantly different from normal and, consequently, it is unlikely that these markers will be useful as predictors of these pregnancy complications.

Topics: Adiponectin; Adult; Biomarkers; Female; Fetal Growth Retardation; Humans; Leptin; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Retrospective Studies; Ultrasonography, Doppler, Color; Uterus

Leptin and adiponectin are two adipocytokines that play a critical role in the control of energy balance and metabolism as well as in conditions, such as insulin resistance, inflammation, and the development of the metabolic syndrome in adult life. Leptin has been associated with asymmetric intrauterine growth restriction (IUGR). The aim of this study was to investigate the perinatal implication of leptin and adiponectin in IUGR. Design Leptin and adiponectin were measured in the plasma of 40 mothers, in the umbilical cord (UC) blood of their 20 appropriate for gestational age (AGA) and 20 IUGR singleton, full-term fetuses, and neonates on day 1 (d1) and day 4 (d4) of life postnatally.. Serum leptin and adiponectin levels were measured by RIA. Serum cortisol levels were measured with an electrochemiluminescence immunoassay.. Leptin and adiponectin serum levels were higher and lower respectively in IUGR (mean+/-s.e.m., 32.5+/-3.8 and 5.4+/-0.9 mug/l respectively) compared with AGA (20.4+/-2.1 and 11.8+/-1.3 mug/l respectively) mothers (P<0.05), although body mass index did not differ between these two groups. Leptin levels positively correlated with adiponectin levels in the AGA (r=0.547, P<0.05) but not in the IUGR mothers. UC, d1, and d4 leptin and adiponectin levels did not differ between IUGR and AGA groups. UC were significantly higher than d1 leptin levels (P<0.05) in the IUGR group but not in the AGA group.. The increased UC leptin levels compared with d1 in IUGR fetuses might be directly and/or indirectly related to the subsequent development of insulin resistance in these neonates. This pathologic situation seems to be related to a specific profile of increased leptin and decreased adiponectin levels in IUGR mothers indicating a genetic predisposition for the development of insulin resistance.

Topics: Adiponectin; Adult; Anthropometry; Energy Metabolism; Female; Fetal Growth Retardation; Fetus; Gestational Age; Humans; Hydrocortisone; Infant, Newborn; Insulin Resistance; Leptin; Pregnancy; Prenatal Exposure Delayed Effects

To test the hypothesis that the bone metabolism of a growth-restricted foetus is regulated by genetic, placental and/or foetal factors through leptin, we investigated the foetal bone turnover in monochorionic pregnancies complicated with or without twin-twin transfusion syndrome (TTTS).. Maternal and cord bloods were collected from gestational-age-matched monochorionic twins with (n=15) and without (n=15) TTTS. The samples were assayed for leptin, cross-linked carboxyl terminal telo-peptide (ICTP, a marker of bone resorption) and pro-peptide (PICP, a marker of bone formation) of type I collagen by radioimmunoassay (RIA).. In the growth-restricted donor twin, the plasma concentration of leptin (P < 0.001), PICP (P < 0.001) was lower, while that of ICTP (P < 0.001) was higher than the recipient twin of the TTTS group. In contrast, leptin, PICP and ICTP were comparable in non-TTTS twins. In the recipient twin of TTTS and non-TTTS twins, leptin was positively associated with PICP (r=0.73; n=45, P < 0.001) and negatively with ICTP (r=-0.68; n=45; P < 0.001). No such association was found between leptin and bone marker in the growth-restricted donor twin of the TTTS group.. Our data suggest that, in AGA twins, leptin maintains bone metabolism by inhibiting resorption and enhancing bone formation. In contrast, growth-restricted donor twins have high bone turnover and this does not seem to be due to leptin deficiency.

Topics: Adolescent; Adult; Biomarkers; Birth Weight; Bone Resorption; Collagen Type I; Female; Fetal Blood; Fetal Growth Retardation; Fetofetal Transfusion; Gestational Age; Humans; Infant, Newborn; Leptin; Osteogenesis; Peptide Fragments; Peptides; Pregnancy; Procollagen; Twins, Monozygotic

Insulin resistance has been linked to intrauterine growth retardation (IUGR); adiponectin is a protein with insulin-sensitizing properties. This study was designed to test whether being born small for gestational age (SGA) has an effect on blood levels of adiponectin and leptin, insulin resistance parameters, and lipid profile in pre-puberty, taking into consideration the severity of IUGR.. Serum levels of adiponectin, leptin, total cholesterol (t-CHOL), high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, triglycerides, apolipoproteins A-1 (Apo A-1), Apo B and Apo E, lipoprotein(a) (Lp(a)), fasting glucose, and insulin (Ins), the homeostasis model assessment insulin resistance index (HOMA-IR) and anthropometric indices were evaluated in 70 children aged 6-8 years, born appropriate for gestational age (AGA; n = 35) and SGA (n = 35), matched for age, gender, height, and BMI. SGA children were divided into two subgroups according to the severity of IUGR: SGA<3rd percentile (n = 20), and SGA 3rd-10th percentile (n = 15). They were also subdivided in two subgroups, those with (n = 25) and those without (n = 10) catch-up growth, considering their actual height corrected for mid-parental height.. SGA children had higher Ins and HOMA-IR than AGA children (Ins, 42 +/- 23 vs 32 +/- 11 pmol/l; HOMA-IR, 1.30 +/- 0.8 vs 0.92 +/- 0.3; P<0.05). No significant difference in serum leptin was found between the SGA and the AGA groups but adiponectin showed a trend to be higher in SGA children (13.6 +/- 5.7 vs 10.8 +/- 5.9 microg/ml respectively). SGA children without catch-up growth had higher adiponectin (15.6 +/- 8.5 microg/ml, P<0.05) than AGA children. Among the SGA children, the subgroup <3rd percentile had higher Lp(a) than the subgroup 3rd-10th percentile (P<0.05). An independent positive correlation between adiponectin and Lp(a) was observed in SGA children (R = 0.59, P<0.01).. SGA children, although more insulin resistant, had similar or higher adiponectin levels than matched AGA children in pre-puberty. The severity of IUGR appears to affect their metabolic profile during childhood.

Topics: Adiponectin; Apolipoprotein A-I; Apolipoproteins B; Apolipoproteins E; Child; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Insulin Resistance; Leptin; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Male; Regression Analysis; Retrospective Studies; Severity of Illness Index; Triglycerides

Topics: Blood Vessels; Female; Fetal Growth Retardation; Fetus; Genes, Homeobox; Humans; Leptin; Neovascularization, Physiologic; Oxygen; Placenta; Pregnancy; Receptors, Cell Surface; Receptors, Leptin; Regional Blood Flow; Trophoblasts; Vascular Endothelial Growth Factor Receptor-1

Hypoglycaemia is common in preterm and intrauterine growth retarded (IUGR) newborns. Although preterm and IUGR infants have limited adipose tissue stores, the role of adipose tissue and the associated adipocytokines in glucose physiology is not known.. We report the case of a premature intrauterine growth retarded infant who had poor weight gain for the first 6 weeks of life and then developed severe hypoinsulinaemic hypoketotic hypoglycaemia.. There was markedly reduced adiposity with low serum leptin and adiponectin levels. Total energy expenditure and body composition measurements showed that body fat as a percentage of weight averaged 7% at 20 weeks and 28% at 28 weeks. At 20 weeks of age, the patient was equivalent to a deficit of >2 SD scores of body fat, but average fatness by 28 weeks. The hypoglycaemia completely resolved when the patient started gaining weight with an increase in fat mass and a concomitant increase in serum leptin and adiponectin level.. Although the precise mechanism of this patient's severe hypoglycaemia is unclear, further studies are required to understand the role of adipose tissue and adipocytokines in glucose homeostasis in preterm and IUGR infants.

Topics: Adiponectin; Adipose Tissue; Blood Glucose; Body Composition; Body Weight; Fetal Growth Retardation; Humans; Hypoglycemia; Infant, Newborn; Infant, Premature; Infant, Small for Gestational Age; Insulin; Leptin; Male; Weight Gain

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this 'programming' has generally been considered an irreversible change in developmental trajectory. Recent work has highlighted the importance of the hormone leptin during critical windows of development in the pathogenesis of programming related disorders.. Maintaining a critical leptin level during development may allow the normal maturation of tissues and pathways involved in metabolic homeostasis and a period of relative hypo or hyperleptinemia may induce some of the metabolic adaptations which underlie developmental programming. Furthermore, nutritional or therapeutic intervention in postnatal life can ameliorate the consequences of developmental malprogramming and, at least in the rodent, developmental programming is potentially reversible by intervention with leptin late in the phase of developmental plasticity.. Inappropriate growth during pregnancy or lactation can result in individuals with an increased risk of later obesity and related metabolic sequelae. Taken together, recent studies highlight the importance of leptin in disorders manifest as a consequence of developmental programming and offer exciting new strategies for therapeutic intervention, whether it be maternal or neonatal intervention or targeted nutritional manipulation in postnatal life.

Topics: Animals; Fetal Growth Retardation; Genomic Imprinting; Humans; Leptin; Obesity; Risk Factors

Neonates with intrauterine growth restriction (IUGR) are associated with reduced concentrations of IGF-I that might contribute to arterial wall thickening. Direct atherogenic effects of leptin have been described. We aimed to investigate the relationship among abdominal aortic intima-media thickness (aIMT), serum IGF-I, IGF binding protein-3, and leptin levels in neonates with IUGR. Abdominal aIMT was measured in 40 term neonates with IUGR and in 40 controls. Mean aIMT was significantly greater in neonates with IUGR (0.45 +/- 0.03 mm) than in controls (0.39 +/- 0.04 mm, p < 0.0001). Serum IGF-I and leptin levels were lower in neonates with IUGR than in controls. There was a significant positive correlation between aIMT and gestational age, whereas a significant negative correlation was determined between aIMT and IGF-I in the IUGR neonates. For aIMT, significant associations included serum IGF-I level (beta = -0.406, p = 0.006) and gestational age (beta = 0.331, p = 0.022) in a multiple stepwise linear regression analysis. In control neonates, serum IGF-I levels were negatively related to aIMT (beta = -0.750, p < 0.001). Neonates with IUGR have significant aIMT with decreased IGF-I. IGF-I levels determine aIMT not only in neonates with IUGR but also in healthy controls.

Topics: Aorta, Abdominal; Birth Weight; Body Height; Case-Control Studies; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Leptin; Linear Models; Male; Tunica Intima; Tunica Media; Ultrasonography, Doppler, Duplex

Leptin is a satiety hormone secreted from the adipose tissue and human placenta. We previously demonstrated that severe preeclampsia up-regulated leptin mRNA expression in the placenta and elevated maternal plasma leptin concentrations. Preeclampsia is frequently related to generation of small for gestational age (SGA) infant especially in cases with severe preeclampsia. However, it is still controversial whether the increase in maternal plasma leptin levels is associated with fetal growth restriction without complication of preeclampsia. Therefore, the aim of the present study was to explore the relationship between maternal plasma leptin levels and fetal growth in non-preeclamptic (n = 98) and preeclamptic (n = 40) women. In non-preeclamptic pregnant women, plasma leptin levels in SGA group (n = 11) were significantly higher than those in appropriate for gestational age (AGA) group (n = 87, P<0.05). In pregnant women with preeclampsia, likewise, plasma leptin levels in SGA group (n = 15) were significantly higher than those in AGA group (n = 25, P<0.05). In multiple linear regression analysis, maternal BMI, mean arterial blood pressure and Delta SD of neonatal body weight were significant factors for determining maternal plasma leptin levels in all population studied. Maternal BMI and Delta SD of neonatal body weight showed positive correlation with maternal plasma leptin levels when analysis was performed in non-preeclamptic subjects alone. In conclusion, maternal plasma leptin levels reflect, at least partly, deterioration in fetal growth.

Topics: Adult; Blood Pressure; Body Mass Index; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Leptin; Linear Models; Pre-Eclampsia; Pregnancy

This trial examined the effects of feeding six diets, which varied in either amount or composition, during the oestrous cycle prior to insemination on embryo survival and foetal development on day 27+/-2 of pregnancy in gilts. Ten or 11 gilts per group received either a maintenance (M) diet, 1.8 x M, 2.6 x M or nutritionally balanced diets in which the content of fibre, protein or starch was increased. Of the six diets tested, only the high fibre diet significantly increased embryo survival when compared to its 1.8 x M isoenergetic control (88.20+/-1.96% versus 81.25+/-2.67%; P<0.05). More litters from gilts fed the 1.8 x M and the starch diets had foetuses defined as intra-uterine growth retarded (IUGR; 50% and 62.5 of litters, respectively), compared to the other four groups in which 0-12.5% of litters contained IUGR foetuses (P<0.05). There was no effect of dietary treatment on foetal or placental size or on the within-litter variability in foetal and placental size. Plasma concentrations of oestradiol and progesterone on days 4-8 of the oestrous cycle and on day 27+/-2 of pregnancy were unaffected by treatment. Feed intake was positively related to mean plasma IGF-1 concentrations on days 4-8 of the cycle (P<0.01) and to mean leptin concentrations on days 4 and 5 (P<0.001). Leptin concentrations were unaffected by alterations in the composition of the diet, whereas IGF-1 concentrations were higher in gilts fed the starch diet compared to the M control (159+/-9.52 versus 127+/-7.65 ng/ml; P<0.05). These data demonstrate that alteration to the composition of the feed consumed during the cycle before insemination can affect both embryo survival and the distribution of foetal size within the litter. The underlying mechanism(s) remain to be determined, but probably involve dietary-induced changes in concentrations of reproductive hormones and/or intermediary metabolites that in turn affect ovarian follicular and oocyte development.

Topics: Adipose Tissue; Animal Nutritional Physiological Phenomena; Animals; Body Composition; Body Weight; Diet; Dietary Fiber; Dietary Proteins; Embryo, Mammalian; Estradiol; Female; Fetal Development; Fetal Growth Retardation; Fetal Weight; Insulin-Like Growth Factor I; Leptin; Organ Size; Placenta; Pregnancy; Progesterone; Starch; Swine; Swine Diseases

Overnourishing the adolescent sheep promotes rapid maternal growth at the expense of the gravid uterus. The growth of the placenta is impaired and results in the premature delivery of low-birthweight lambs. The present study details fetal adipose tissue development in these growth-restricted pregnancies. Singleton pregnancies were established by embryo transfer and, thereafter, adolescent ewes were offered a high (H; n = 12) or moderate (M; n = 14) level of a complete diet until necropsy on Day 131 of gestation. Fetal weight was lower (P < 0.001) in H compared with M groups. High maternal intake preserved brain and perirenal fat weight (P < 0.003), whereas relative weights of the heart, lungs, spleen and liver were unaltered. High nutrient intake resulted in significantly elevated maternal plasma concentrations of insulin, leptin, prolactin and glucose, no significant changes in fetal insulin, leptin or non-esterified fatty acids and attenuated fetal prolactin concentrations. Irrespective of nutritional intake, maternal plasma leptin, prolactin and glucose concentrations were negatively correlated with fetal weight and were positively correlated with fetal perirenal fat proportion (all P < 0.01). The mRNA expression for leptin, prolactin receptor and uncoupling protein (UCP) 1 in fetal perirenal fat was equivalent between groups, but, irrespective of maternal nutrition, UCP1 mRNA levels were negatively correlated with fetal weight (P < 0.01). Thus, overnourishing pregnant adolescent sheep preserves fat deposition in their growth-restricted fetuses, which may have implications for neonatal thermogenesis and for programming of postnatal adiposity.

Topics: Adipose Tissue; Animals; Base Sequence; Carrier Proteins; DNA, Complementary; Female; Fetal Development; Fetal Growth Retardation; Ion Channels; Kidney; Leptin; Membrane Proteins; Mitochondrial Proteins; Pregnancy; Prenatal Nutritional Physiological Phenomena; Receptors, Prolactin; RNA, Messenger; Sheep; Uncoupling Protein 1

Obesity and type 2 diabetes are world wide health issues and their incidence is rapidly increasing. Currently the biological factors responsible for the development of obesity are only partially understood. Recent research has shown that maternal nutrition during pregnancy may have long-term metabolic consequences in offspring. In the present study we investigated interactions between prenatal and postnatal nutrition on leptin sensitivity and obesity development. Wistar rats were time-mated and randomly assigned to either ad-libitum (AD) or to 30% of ad-libitum (UN) food intake throughout pregnancy. After weaning, female offspring were fed standard chow, a high-fat diet or a calorie restricted diet. Female offspring of UN dams were growth retarded at birth and showed increased susceptibility to diet-induced obesity on a high-fat diet. At 142 +/- 5 days of age, leptin sensitivity was measured as a response to 14 days of leptin treatment (2.5 microg/g/day, s.c.). In UN offspring fed chow, leptin treatment failed to reduce food intake and weight loss was diminished. This leptin resistance observed in UN offspring was independent of diet-induced obesity and was associated with fasting hyperinsulinemia and hypertriglyceridemia. Our study suggests that prenatal nutrition can shape future susceptibility to obesity through alterations in leptin sensitivity and changes in energy metabolism during adult life.

Topics: Animals; Animals, Newborn; Diet; Dietary Fats; Disease Susceptibility; Eating; Energy Intake; Female; Fetal Growth Retardation; Hyperinsulinism; Hypertriglyceridemia; Injections; Leptin; Nutrition Disorders; Obesity; Pregnancy; Prenatal Nutritional Physiological Phenomena; Rats; Rats, Wistar; Weight Loss

Leptin, an adipocyte hormone involved in energy homeostasis, is important in reproduction and pregnancy. Questions yet to be addressed include the source of higher leptin during pregnancy and its relationship to pregnancy outcome and fetal growth. The objective of this study was to investigate the relationship between placental leptin gene expression, placental leptin protein concentration and maternal plasma leptin concentration among control pregnant women, women with pre-eclampsia and women with growth-restricted infants. We also investigated the relationship between placental leptin expression and the placental expression of enzymes involved in cellular lipid balance: fatty acid translocase (CD36), carnitine palmitoyltransferase I (CPT-1B) and lipoprotein lipase (LPL). Placental leptin expression, placental protein and maternal plasma concentration were higher in pre-eclampsia than in controls but not in women with growth-restricted infants. Placental leptin expression and placental protein were higher in the preterm pre-eclamptic subjects, whereas maternal leptin was higher in the term pre-eclamptic subjects. The placental gene expression of CD36, CPT-1B and LPL were not different among the groups. This study suggests that despite similar failed placental bed vascular remodelling in pre-eclampsia and intrauterine growth restriction (IUGR), leptin gene expression is higher only in preterm pre-eclampsia.

Topics: Adult; Carnitine O-Palmitoyltransferase; CD36 Antigens; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Premature; Leptin; Lipoprotein Lipase; Maternal-Fetal Exchange; Placenta; Pre-Eclampsia; Pregnancy; Receptors, Leptin; Retrospective Studies; RNA, Messenger

Intrauterine growth restriction (IUGR) represents an important risk factor for perinatal complications and for adult disease. IUGR is associated with a down-regulation of placental amino acid transporters; however, whether these changes are primary events directly contributing to IUGR or a secondary consequence is unknown. We investigated the time course of changes in placental and fetal growth, placental nutrient transport in vivo and the expression of placental nutrient transporters in pregnant rats subjected to protein malnutrition, a model for IUGR. Pregnant rats were given either a low protein (LP) diet (n = 64) or an isocaloric control diet (n = 66) throughout pregnancy. Maternal insulin, leptin and IGF-I levels decreased, whereas maternal amino acid concentrations increased moderately in response to the LP diet. Fetal and placental weights in the LP group were unaltered compared to control diet at gestational day (GD) 15, 18 and 19 but significantly reduced at GD 21. Placental system A transport activity was reduced at GD 19 and 21 in response to a low protein diet. Placental protein expression of SNAT2 was decreased at GD 21. In conclusion, placental amino acid transport is down-regulated prior to the development of IUGR, suggesting that these placental transport changes are a cause, rather than a consequence, of IUGR. Reduced maternal levels of insulin, leptin and IGF-1 may link maternal protein malnutrition to reduced fetal growth by down-regulation of key placental amino acid transporters.

Topics: Amino Acid Transport System A; Amino Acid Transport Systems; Amino Acids; Animals; beta-Alanine; Biological Transport; Diet, Protein-Restricted; Down-Regulation; Female; Fetal Growth Retardation; Gene Expression Regulation; Glucose; Insulin; Insulin-Like Growth Factor I; Leptin; Placenta; Pregnancy; Protein Kinases; Rats; Rats, Sprague-Dawley; Signal Transduction; TOR Serine-Threonine Kinases

Singleton infants with intrauterine growth restriction have an adaptive hormonal profile characterized by decreased levels of IGF-1, IGF-2, IGFBP-3 and insulin and elevated levels of IGFBP-1 and IGFBP-2. This study examined the association between cord serum levels of six growth factors and anthropometric features at birth in twins in order to determine the intrauterine growth factor interactions and to characterize the specific hormonal profile of small discordant twins.. Prevalent case-control study.. Twenty pairs of discordant twins (5 monozygotic, 15 dizygotic) and 20 pairs of concordant twins (6 monozygotic, 14 dizygotic) matched for gestational age.. Cord blood levels of IGF-1, IGF-2, IGFBP-1, IGFBP-3, insulin, leptin and anthropometric measurements at birth. Intra- and inter-pair differences and correlation coefficients were calculated, and the data were fitted to multivariate regression models.. In both discordant and concordant groups, the smaller twins had a significantly lower level of IGF-1 (P < 0.03) and significantly higher level of IGFBP-1 (P < 0.02) than their larger cotwins. IGFBP-1 was inversely correlated with IGF-1 (P < 0.05). Insulin levels were significantly higher in the smaller discordant than the smaller concordant twins (P < 0.001) and in the larger discordant than the larger concordant twins (P < 0.004). Among the monozygotic twins, the leptin level was significantly higher in the larger discordant than the larger concordant twins (P < 0.025). Percentage birth weight discordancy was statistically correlated with twin-pair differences in IGF-1 and IGFBP-1.. Of the six factors studied, IGF-1 appears to be the main indicator of intrauterine growth. Twin discordancy may involve compensatory rather than adaptive mechanisms or a multihormone relative resistance syndrome.

Topics: Birth Weight; Case-Control Studies; Diseases in Twins; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Immunoradiometric Assay; Infant, Newborn; Insulin; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Pregnancy; Radioimmunoassay; Regression Analysis; Twins, Dizygotic; Twins, Monozygotic

Topics: Biomarkers; Biomarkers, Tumor; Chorionic Gonadotropin; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Inflammation; Interleukin-10; Killer Cells, Natural; Leptin; Luteinizing Hormone; Neoplasms; Pre-Eclampsia; Pregnancy; Pregnancy Proteins

To determine the relation between weight deficit at birth and IGF-I, IGFBP-I, Leptin, and AFP levels in amniotic fluid after 14-18 weeks; to assess the diagnostic usefulness of these biochemical markers.. Longitudinal, prospective study. Amniocentesis was performed in pregnant women after 14-18 weeks of gestation.. 86 controls, 18 IUGR <10 percentile, and 17 IUGR <5 percentile.. No significant correlation was found between severity of IUGR and IGF-I, IGFBP-I, or Leptin. AFP was inversely correlated with severity of IUGR; results for the IUGR <10 percentile were: S: 65.7%, SP: 56.9%, PPV: 38.3%, NPV: 80.3%, and an overall diagnostic capacity of 65.6%. Results for the IUGR <5 percentile were: S: 76.4%, SP: 54.8%, PPV: 21.6%, NPV: 93.4% were obtained, and an overall capacity of 70.6%.. Elevated values of AFP in amniotic fluid may help early detection of populations at risk of developing IUGR.

Topics: alpha-Fetoproteins; Amniocentesis; Amniotic Fluid; Biomarkers; Fetal Growth Retardation; Gestational Age; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Leptin; Longitudinal Studies; Prospective Studies; Sensitivity and Specificity

To investigate the intestine and body development of intrauterine growth retardation (IUGR) rats under early different protein diet and to analyze the correlation between leptin and intestine and body development.. An IUGR rat model was established by food restriction of pregnant female rats. Fifty-six neonatal IUGR rats and 24 neonatal normal rats were randomly divided into normal control group (C group), IUGR model group (SC group), low protein diet IUGR group (SL group), and high protein diet IUGR group (SH group). Eight rats were killed per group at wk 0, 4, and 12. Serum leptin, body weight (BW), body length (BL), intestinal weight (IW), intestinal length (IL), and intestinal disaccharidase (including lactase, maltase, and saccharase) were detected.. BW (4.50+/-0.41 g), BL (5.96+/-0.40 cm), IW (0.05+/-0.01 g), and IL (15.9+/-2.8 cm) in neonatal IUGR rats were much lower than those in C group (6.01+/-0.55 g, 6.26+/-0.44 cm, 0.10+/-0.02 g, 21.8+/-2.7 cm, P<0.05), while intestinal lactase and maltase activities were higher than those in C group. SH group showed the fastest catch up growth and their BW, BL, IW, and IL reached the C group level at wk 4. SC group showed relatively slower catch up growth than SH group, and their BW, BL, IW did not reach the C group level at wk 4. SL group did not show intestine and body catch up growth. Intestinal maltase (344+/-33 micromol/(min.g)) and saccharase activities (138+/-32 micromol/(min.g)) in SL group were both markedly lower than those in C group (751+/-102, 258+/-27 micromol/(min.g), P<0.05). There were no significant differences in lactase activities at wk 4 and disaccharidase activities at wk 12 among all groups (P>0.05). The leptin level in SL group (0.58+/-0.12 ng/mL) was the highest in all groups, and much lower in SH group (0.21+/-0.03 ng/mL) than that in any other IUGR groups at wk 4 (P<0.05). Leptin was negatively related to BW (r = -0.556, P = 0.001), IW (r = -0.692, P = 0.001) and IL (r = -0.738, P = 0.000) at wk 4, while no correlation was found at wk 12.. High protein diet is a reasonable early nutritional mode to IUGR rats in promoting intestine and body catch up growth.

Topics: Animals; Dietary Proteins; Disease Models, Animal; Female; Fetal Growth Retardation; Fetal Nutrition Disorders; Intestines; Leptin; Male; Pregnancy; Rats; Rats, Sprague-Dawley

To evaluate the relationship of endothelin 1 (ET-1) and leptin concentrations in women and newborns following a pregnancy complicated with intrauterine growth restriction (IUGR).. Twenty-five women with a pregnancy complicated with IUGR at 19 different gestational ages were matched with women with uncomplicated pregnancies. Blood samples from the umbilical artery and maternal peripheral venous circulation were collected at delivery, and ET-1 and leptin levels were determined from the blood samples. Data relating to obstetric complications (e.g., pregnancy-induced hypertension), delivery (e.g. mode, birth weight, signs of intrapartum fetal distress, and Apgar scores) were also recorded.. Mean maternal ET-1 (13.4+/-6.2-9.9+/-2.9 pmol/l) and mean fetal ET-1 (14.5+/-4.2-11.7+/-3.1 pmol/l) concentrations were significantly higher when women had experienced pregnancies complicated with IUGR than when they had had normal pregnancies. Mean fetal leptin concentration was significantly lower in the study group (6.8+/-2.2 ng/ml) than in the control group (10.6+/-3.6 ng/ml (P<0.05). However, fetal leptin per kilogram of fetal weight was not significantly different in the study group (3.16+/-1.18 ng/ml) than in the control group (3.23+/-0.96 ng/ml) (P>0.05, paired t-test). However, a statistically significant correlation was observed between fetal leptin concentrations per kilogram of fetal weight and fetal endothelin concentrations in pregnancies complicated with IUGR (r=0.546; P<0.05).. These results suggest the intertwined roles of ET-1 and leptin in the pathophysiology of IUGR. Further studies concerning interaction between these peptides in different pregnancy conditions may provide important information about the actions of ET-1 and leptin on fetal growth.

Topics: Adult; Birth Weight; Body Mass Index; Case-Control Studies; Endothelin-1; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Pre-Eclampsia; Pregnancy; Regression Analysis

Leptin takes part in fat regulation and can also take part in regulation of prenatal fetal weight.. The aim of the study was to find correlation between leptin concentration in healthy women and intrauterine growth restriction.. The study was done in Medical University in Lodz in 2000-2002. The study group consisted of 50 women with IUGR, the control group of 50 healthy pregnant women. Elisa immunoenzymatic IBL test was used. The results were expressed in microgram/l.. In group of normal pregnancy leptin concentration was 5.347 +/- 1.098 micrograms/l. In group of intrauterine growth restriction leptin concentration was 4.617 +/- 0.949 micrograms/l. The difference between groups was statistically significant but the mean values in both groups were normal for nonpregnant women.. Low concentration of leptin can play role in intrauterine growth restriction.

Topics: Adult; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Fetal Blood; Fetal Growth Retardation; Humans; Leptin; Pregnancy; Retrospective Studies; Statistics, Nonparametric; Time Factors

There is growing evidence that prenatal adversities could be implicated in foetal programming of adult chronic diseases. Since maternal stress is known to disturb the foetal glucocorticoid environment, we examined the consequences of prenatal stress on foetal growth, on glucose-insulin metabolism and on feeding behaviour in the aged male rat. In foetuses at term, maternal stress reduced body, adrenal and pancreas weight as well as plasma corticosterone and glucose levels. In aged male rats (24 months of age), prenatal stress induced hyperglycaemia and glucose intolerance and decreased basal leptin levels. Moreover, after a fasting period, they showed an increased food intake. These data suggest that maternal stress induces a long-lasting disturbance in feeding behaviour and dysfunctions related to type 2 diabetes mellitus. This programming could be linked to the early restricted foetal growth and to the adverse glucocorticoid environment in utero.

Topics: Adrenal Glands; Aging; Animals; Birth Weight; Blood Glucose; Corticosterone; Feeding Behavior; Female; Fetal Growth Retardation; Glucose Intolerance; Leptin; Male; Organ Size; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Stress, Psychological

To investigate different factors related to fetal growth restriction (FGR) and to find out the possible causes of FGR with unclear etiologies.. Sixty-three women who were suspected of FGR during pregnancy between March 2002 and March 2003 were included in this study. Their age, body mass index (BMI) before pregnancy, and gestational weeks were recorded at the time when they were first diagnosed. Haemoglobin levels, haematocrit (HCT), TORCH, anticardiolipin antibody (ACA), 50 gram glucose challenge test (50g GCT), 75 gram oral glucose tolerance test (75g OGTT), leptin levels, systolic/diastolic (S/D) ratio by color doppler monitor and chlamydia trachomatis (CT) were detected and urine culture was done in these groups during the same period. The gestational week, birth weight, body length and the gender were recorded at the delivery period. The FGR group was then divided into two subgroups according to the birth weights: study A group whose birth weights were lower than 10th% of the birth weights at the given gestational weeks (29 cases) and study B group whose birth weights were beyond 10th% (34 cases). The chromosome, leptin, C-peptide, insulin and TORCH of umbilical blood were measured at delivery. The other 25 normal pregnant women were included as control and the same tests were performed accordingly.. The fasting glucose and the third hour's glucose of 75 gram oral glucose tolerance test of study A were (3.8 +/- 0.6) mmol/L and (4.5 +/- 1.1) mmol/L. The fetal leptin, C-peptide, and insulin were (7.3 +/- 5.2) ng/ml, (0.5 +/- 0.3) nmol/L and (2.3 +/- 1.3) mU/L. The S/D ratio of umbilical artery, maternal and fetal infection rate of CMV, positive rate of ACA-IgM and the rate of asymptomatic bacteriuria were 3.06, 20.7%, 24.1%, 44.8% and 62.1% respectively. The fasting glucose and the third hour's glucose of 75 gram oral glucose tolerance test of study B were (4.4 +/- 0.7) mmol/L and (4.6 +/- 1.1) mmol/L. The fetal leptin, C-peptide, and insulin were (13.2 +/- 11.3) ng/ml, (0.7 +/- 0.4) nmol/L and (4.3 +/- 3.3) mU/L. The S/D ratio of umbilical artery, maternal and fetal infection rate of CMV, positive rate of ACA-IgM and the rate of asymptomatic bacteriuria were 2.63, 2.9%, 0%, 5.9% and 44.1% respectively. The fasting glucose and the third hour's glucose of 75 gram oral glucose tolerance test in control were (4.3 +/- 0.7) mmol/L and (5.3 +/- 1.2) mmol/L. The fetal leptin, C-peptide, and insulin were (20.5 +/- 12.0) ng/ml, (1.0 +/- 0.4) nmol/L and (6.3 +/- 4.0) mU/L. The S/D ratio of umbilical artery, maternal and fetal infection rate of CMV, positive rate of ACA-IgM and the rate of the asymptomatic bacteriuria were 2.80, 0, 0, 0 and 24.0% respectively. All these items were significantly higher in study A than those in the control (P < 0.05). There was no significant difference between the study B and the control in all the items.. Many factors may play a role in the pathogenesis of FGR, including the maternal blood glucose level, the ability for fetus to use the glucose, the infection of some microorganisms, insufficiency of the blood supply and the autoimmunity of the mother. Finding out the possible causes of FGR and managing them accordingly may improve the outcomes of the fetus.

Topics: Adult; Birth Weight; C-Peptide; Cytomegalovirus Infections; Female; Fetal Growth Retardation; Glucose Metabolism Disorders; Glucose Tolerance Test; Humans; Insulin; Leptin; Pregnancy; Pregnancy Outcome; Risk Factors

Altered Doppler flow velocimetry of the uterine arteries during the second trimester is correlated with the risk of developing pre-eclampsia. Serum levels of leptin, a protein regulating body weight and secreted by the placenta, are higher in women with severe pre-eclampsia. We investigated whether alterations of uterine arteries' Doppler flow velocimetry during the early second-trimester scan were accompanied by changes in leptin levels, and whether these changes might be an early risk factor for pre-eclampsia. We retrospectively selected 50 women with altered uterine artery velocimetry at the second-trimester scan who subsequently developed pre-eclampsia (group A) and 100 women who did not develop pre-eclampsia, divided into two groups: 50 women with normal velocimetry at the second-trimester scan (group B) and 50 women with altered velocimetry at the second-trimester scan (group C). Serum leptin levels during the second and third trimesters and bilateral uterine artery resistance index during the second trimester were evaluated. No differences were observed in serum leptin levels in the second trimester among the three groups. During the third trimester, women in group A showed significantly higher serum leptin levels in comparison with women in groups B and C (p < 0.01). Serum leptin levels do not seem to be a useful early marker for the development of pre-eclampsia in the presence of altered uterine blood flow, and may be a late compensatory mechanism or reflect a generalized response of the trophoblast to hypoxic stimuli.

Topics: Adult; Arteries; Biomarkers; Birth Weight; Blood Flow Velocity; Body Mass Index; Female; Fetal Growth Retardation; Gestational Age; Humans; Laser-Doppler Flowmetry; Leptin; Parity; Pre-Eclampsia; Pregnancy; Retrospective Studies; Uterus; Vascular Resistance

Low birth weight in humans predisposes to obesity, cardiovascular diseases, and type 2 diabetes in adult life. Alcohol exposure during pregnancy has been associated with fetal growth restriction. We investigated the effects of prenatal exposure to alcohol on glucose metabolism later in the offspring. Female Sprague Dawley rats were given ethanol (ETOH), 4 g/kg/day by gavage throughout pregnancy. Compared with controls, newborn ETOH rats had decreased body size (5.1 +/- 0.1 v 6.3 +/- 0.1 g, P <.001), plasma insulin (0.44 +/- 0.4 v 0.67 +/- 0.1 ng/mL, P <.05), and leptin mRNA (P <.05), but they had normal beta-cell mass and elevated adipose resistin mRNA and plasma glucose (5.0 +/- 0.5 v 3.6 +/- 0.3 mmol/L, P <.01). Food intake was decreased in ETOH rats during the fourth week of life, and body weight remained decreased compared with controls until a catch-up growth occurred by 7 weeks of life. At 13 weeks of age, body weight and beta-cell mass of ETOH offspring were normal, but plasma glucose and insulin after a glucose challenge were increased compared with controls (P <.05). Adipose leptin and hypothalamic Ob-R mRNA were not different from controls, but resistin was increased (P <.05), and muscle GLUT4 content was decreased (P <.05) in ETOH offspring compared with controls. The data suggest that prenatal alcohol exposure impairs glucose tolerance in the offspring by both inducing insulin resistance and beta-cell dysfunction. The prevailing mechanism in 3-month-old rat offspring appears to be insulin resistance, manifested by glucose intolerance and decreased GLUT4 despite hyperinsulinemia.

Topics: Animals; Body Weight; Central Nervous System Depressants; Eating; Ethanol; Female; Fetal Growth Retardation; Glucose Intolerance; Glucose Transporter Type 4; Hormones, Ectopic; Insulin; Leptin; Monosaccharide Transport Proteins; Muscle Proteins; Nerve Growth Factor; Pancreas; Pregnancy; Prenatal Exposure Delayed Effects; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, Leptin; Resistin

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

Ghrelin is a GH secretagog isolated recently from rat stomach and involved in the stimulation of food intake and adiposity in rodents and humans. Moreover, subsequent studies showed that ghrelin is expressed in rat and human placenta, suggesting a possible influence of the peptide on fetal growth. The aim of this study was to evaluate circulating levels of ghrelin in appropriate for gestational age (AGA) or intrauterine growth-restricted (IUGR) fetuses.. Ghrelin levels between 20 and 39 weeks of gestation were measured in 16 AGA and nine IUGR fetuses in whom blood was collected by cordocentesis performed for prenatal diagnosis of different diseases or during elective cesarean section. In most samples, GH, cortisol and leptin levels were also evaluated. Results are expressed as means+/-S.D. Differences were tested using the Student's t-test with Welch correction. P<0.05 was considered significant.. All fetuses showed levels of ghrelin in the umbilical venous blood (100+/-99 pmol/l) that did not correlate with the gestational age or the maternal ghrelin levels. No difference was found between umbilical venous and arterial concentrations, suggesting that fetal tIssues are a source of ghrelin. Ghrelin levels in IUGR fetuses were significantly higher than those found in AGA fetuses (176+/-125 vs 58+/-44 pmol/l; P<0.005). Moreover, in samples obtained at birth, ghrelin concentrations correlated negatively with birth weight (P<0.05). In IUGR fetuses, GH and cortisol concentrations were higher and leptin levels lower than in AGA fetuses, although no significant correlation between these parameters and ghrelin levels was found.. The presence of ghrelin in the fetal circulation as well as its increase in IUGR fetuses suggest a role of this peptide during intrauterine development.

Topics: Adult; Cesarean Section; Female; Fetal Growth Retardation; Fetal Weight; Fetus; Gestational Age; Ghrelin; Human Growth Hormone; Humans; Hydrocortisone; Leptin; Male; Peptide Hormones; Pregnancy; Sex Characteristics

To ascertain whether fetal growth restriction is associated with alterations of leptin concentrations in umbilical cord blood and maternal serum.. Maternal serum and umbilical cord blood leptin concentrations were determined by immunoradiometric assay at term in 43 women with uncomplicated singleton pregnancies (group A) and in 27 women with singleton pregnancies complicated by fetal growth restriction (group B), all with normal pregravid body mass index (BMI).. Maternal serum leptin concentrations were significantly higher in group B compared with group A (45.0 ng/mL [range 34.2-54.9] versus 29.0 ng/mL [range 24.7-33.3]; P<.01). Umbilical cord blood leptin levels were significantly lower in group B compared with group A (8.4 ng/mL [range 3.6-13.2] versus 13.1 ng/mL [9.7-16.5]; P<.01). Maternal serum leptin levels were not significantly correlated with maternal BMI or with neonatal birth weight in either group. Umbilical cord blood leptin concentrations were significantly correlated with neonatal birth weight in both groups.. Growth restricted fetuses at term show umbilical cord blood leptin concentrations significantly lower than those in normal fetuses, suggesting that fetal adipose tissue is a major source of leptin. Maternal serum leptin concentrations are higher in the presence of a growth restricted fetus. This increase might be due to an intrinsic placental mechanism, by which small placentas produce more leptin as a compensatory mechanism, or to early hypoxia.

Topics: Adult; Biomarkers; Birth Weight; Body Mass Index; Case-Control Studies; Cohort Studies; Embryonic and Fetal Development; Female; Fetal Blood; Fetal Growth Retardation; Follow-Up Studies; Gestational Age; Humans; Infant, Newborn; Leptin; Parity; Pregnancy; Probability; Reference Values; Risk Assessment; Sensitivity and Specificity; Ultrasonography, Prenatal

Many adult diseases, including type 2 diabetes, hypertension and cardiovascular disease, are related to low birth weight. The mechanistic basis of this relationship is not known. To investigate the role of fetal undernutrition, we used a rat model of maternal protein restriction in which dams were fed a diet containing 80 g protein/kg (v. 200 g/kg in the control group) throughout gestation and lactation. Offspring were born smaller than controls and in adulthood developed diabetes, hyperinsulinaemia and tissue insulin resistance. To determine possible mechanisms of fetal programming, circulating levels of several hormones were measured in maternal plasma at gestational days 14, 17 and 21 and fetal plasma at gestational day 21. Several differences were noted at day 14, when glucose concentrations in maternal and feto-placental blood were raised significantly (P=0.04 and P=0.0001 respectively); insulin levels in the low-protein (LP) dams were raised (P=0.04), prolactin levels were raised (P=0.047) and progesterone levels were reduced (P=0.02). Circulating 17beta-oestradiol in the LP dams was raised by 35 % over those of the controls from day 17 to day 21 (P=0.008). A significant decrease in maternal leptin levels (P=0.004) was observed at gestation on day 21. Neither oestradiol nor leptin levels were altered in the fetal circulation at day 21. Maternal and fetal corticosterone levels were comparable with control levels, suggesting that they do not initiate the programming effects in this model. Our present results suggest that maternal protein restriction imposes changes in maternal levels of glucose, insulin, prolactin, progesterone, oestradiol and leptin; these changes could influence the programming of eventual adult disease in the developing fetus.

Topics: Animals; Blood Glucose; Body Weight; Corticosterone; Diet, Protein-Restricted; Disease Models, Animal; Eating; Estradiol; Fatty Acids, Nonesterified; Female; Fetal Growth Retardation; Insulin; Leptin; Organ Size; Placenta; Pregnancy; Progesterone; Prolactin; Rats; Rats, Wistar; Triglycerides; Weight Gain

Leptin, the hormone product of the ob gene, has recently been implicated as an important player in the complex hormonal control of fetal growth. Leptin actions are mediated via the long isoform of its receptor (Ob-Rb), while shorter isoforms may serve as transporters of leptin through physiological barriers (Ob-Ra) or as leptin-binding proteins in plasma (Ob-Re). Placental expression of these receptor isoforms could thus mediate leptin actions within the placenta or regulate transport of maternal, placental, and fetal leptin. In the present study, we show by real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) that Ob-Ra, Ob-Rb, and Ob-Re mRNAs are dynamically expressed in the functionally distinct basal and labyrinth zones of the rat placenta during the period of maximal fetal growth (i.e., from Day 16 to Day 22 of pregnancy; term = Day 23). Western blot analyses confirmed placental expression of the Ob-Rb protein, and immunolocalization was most prominent in trophoblast and vascular tissues of the labyrinth zone. Ob-Ra and Ob-Re mRNA expression increased markedly (P < 0.01) from Day 16 to Day 22 in the labyrinth but not in the basal zone, whereas Ob-Rb mRNA and protein remained relatively stable. Because glucocorticoids inhibit feto-placental growth, placental leptin receptor (Ob-R) expression was also measured after manipulation of feto-placental glucocorticoid exposure. Maternal treatment with dexamethasone reduced (P < 0.05) placental expression of Ob-Rb mRNA and protein, whereas metyrapone (an inhibitor of glucocorticoid synthesis) stimulated (P < 0.01) placental expression of mRNAs encoding all three Ob-R isoforms. Dexamethasone and carbenoxolone (an inhibitor of the enzyme 11beta-hydroxysteroid dehydrogenase) also markedly reduced (P < 0.01) fetal but not maternal plasma leptin concentrations, consistent with inhibition of transplacental passage of maternal leptin. In conclusion, our data indicate that placental expression of Ob-Ra, Ob-Rb, and Ob-Re is likely to mediate leptin action and transport in the fetus and placenta. The effects of glucocorticoid manipulations on placental expression of these isoforms suggest that glucocorticoid-induced feto-placental growth retardation could be mediated, in part, via inhibition of leptin action or transport in the placenta.

Topics: Animals; Carbenoxolone; Dexamethasone; Enzyme Inhibitors; Female; Fetal Growth Retardation; Gene Expression; Gestational Age; Glucocorticoids; Immunohistochemistry; Leptin; Metyrapone; Placenta; Pregnancy; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Steroid 11-beta-Hydroxylase

Leptin, the ob gene product, plays an important role in the regulation of body fat mass and weight. In previous studies, it was demonstrated that leptin is detectable in human fetal cord blood as early as at 18 weeks of gestation and that serum leptin concentrations are significantly reduced in small gestational age newborns. In the present study, we investigated whether umbilical and maternal serum leptin concentrations correlate with intrauterine growth retardation (IUGR). In addition, we aimed to determine the relationships between leptin concentration in the maternal and cord blood. We studied 40 newborn infants (21 female and 19 male; gestational age, 38-42 weeks) and their mothers. Of the infants studied, 10 had IUGR. Serum leptin concentrations were measured by radioimmunoassay. All newborns had detectable leptin concentrations. Leptin concentrations were significantly lower in newborns with IUGR and in their mothers (n = 10; 3.53 +/- 1.42 ng/ml, 6.75 +/- 1.47 ng/ml, respectively) than in infants experiencing normal growth and their mothers (n = 30; 5.58 +/- 2.98 ng/ml, 9.85 +/- 6.50 ng/ml, respectively) (p < 0.01 for newborns, p < 0.05 for mothers). There was no significant correlation between umbilical leptin concentration and maternal leptin concentration (r = 0.229; p = 0.155) in all study groups but, significantly, a correlation was observed in the group with IUGR (r = 0.736; p = 0.015). There were no significant correlations between both umbilical and maternal leptin concentrations and parity, delivery type and gestational age. There was a correlation between umbilical leptin concentration and birth weight of newborns (r = 0.383; p = 0.015) but no correlation with body mass index (BMI) of the newborns (r = 0.034; p = 0.834). Maternal leptin concentrations correlated with maternal weight and BMI (r=0.606; p=0.000, r=0.535; p=0.000, respectively). There was no correlation between maternal leptin concentrations and birth weight of the newborns (r=0.179; p=0.269) and with BMI of the newborns (r = 0.146; p = 0.367). There was no gender difference in leptin concentrations in the newborns (n=21; 5.50 +/- 3.37 ng/ml, for females; n = 19; 4.58 +/- 1.98 ng/ml for males) (p = 0.296). In summary, we have shown that IUGR is associated with a decreased leptin concentration in newborns and their mothers. The association between umbilical serum leptin and birth weight in this and other studies suggests a pivotal role of fetal leptin in regulating fetal growt

Topics: Birth Weight; Body Mass Index; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Male; Pregnancy; Pregnancy Complications, Hematologic; Statistics as Topic

In-utero under-nutrition dramatically alters the development of adipose tissue, during the fetal and the neonatal period.. To investigate whether adults born with intra-uterine growth retardation (IUGR) show evidence of impaired adipose tissue development and leptin regulation.. Serum leptin concentrations were measured in 26 healthy adults born with IUGR and 25 controls aged 24 y who have been studied previously, 3 y ago.. The IUGR group demonstrated a significant increase of body mass index (BMI) in comparison to controls between 21 and 24 y of age (4.8+/-7.7%, P=0.004 vs 0.8+/-6.7%, P=0.70). Percentage of total body fat mass was significantly higher in IUGR-born subjects than in controls (27.2+/-7.6 vs 22.0+/-7.3%, P=0.02). Fasting insulin was significantly higher in the IUGR group (7.5+/-3.8 vs 5.3+/-2.3 miccroU/ml, P=0.03). Surprisingly, crude serum leptin concentrations did not significantly differ between the two groups. Moreover, adjusted means of serum leptin levels were significantly lower in IUGR-born subjects than in controls when corrected for body fat mass, gender and fasting insulin (11.3 vs 13.8 ng/ml, P=0.02).. Adults born with IUGR developed an excess of adipose tissue associated with relatively low serum leptin levels suggestive of an altered adipocyte function. Considering the close relationship between adipose tissue and insulin-sensitivity, these observations point to the potential implication of abnormal adipose tissue development in the long-term metabolic consequences associated with in-utero undernutrition.

Topics: Adipocytes; Adipose Tissue; Adult; Aging; Body Constitution; Body Mass Index; Body Weight; Case-Control Studies; Female; Fetal Growth Retardation; Humans; Insulin; Insulin Resistance; Leptin; Male; Nutritional Status

The objective of this study was to determine the plasma leptin concentrations in twin pregnancies in relation to chorionicity and discordant fetal growth. We studied 53 twin pregnancies of which 26 had growth discordance of > or =20% and 27 were concordant for growth (discordance of < or =10%). Paired maternal and fetal blood samples were obtained at birth. Plasma leptin concentrations were measured by RIA. In discordant monochorionic pregnancies, fetal plasma leptin concentrations in the intrauterine growth-restricted twins were lower than the co-twins with normal growth (mean difference, 3 ng/mL; 95% CI, 2.2 to 3.3 ng/mL; p < 0.001), whereas no such differences were present between concordant monochorionic twin pairs (mean difference, 0.1 ng/mL; 95% CI, -0.2 to 0.5 ng/mL; NS). Similarly, fetal plasma leptin concentrations in appropriate-for-gestational-age twins were higher than in the intrauterine growth-restricted twins of the discordant dichorionic pregnancies (mean difference, 2.4 ng/mL; 95% CI, 1.8 to 3.1 ng/mL; p < 0.001). No such differences were present between the concordant dichorionic twin pairs (mean difference, 0.2 ng/mL; 95% CI, -0.1 to 0.5 ng/mL; NS). Maternal plasma leptin concentrations were comparable among all four groups and were higher than the fetal levels. Fetal plasma leptin concentrations of the intrauterine growth-restricted twins of discordant monochorionic and dichorionic pregnancies were comparable. There was a positive association between cord plasma leptin concentrations and the birth weight of twin pairs (y = 0.002x - 0.32; r = 0.63; p < 0.001; n = 106). A significant positive association was also found between percent differences in birth weight and fetal delta plasma leptin concentrations of the discordant monochorionic and dichorionic twin pairs (y = 0.057x + 0.93; r = 0.60; p < 0.001, n = 26). In conclusion, irrespective of chorionicity, plasma leptin concentrations in intrauterine growth-restricted twins were 2-fold lower than their co-twins with normal growth. These differences may be attributed to placental factors.

Topics: Birth Weight; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Fetus; Humans; Leptin; Male; Pregnancy; Twins, Dizygotic; Twins, Monozygotic

In this study we examined the body composition at onset of puberty in intrauterine growth retarded (IUGR), postnatal food restricted (FR), and control male and female rats. IUGR was induced by ligation of the uterine artery on d 17 of gestation and FR by litter enlargement to 20 pups per mother from d 2 after birth until weaning (d 24). We defined onset of puberty as balanopreputial separation in male rats and vaginal opening in female rats. We calculated body mass index, measured body composition with dual-energy x-ray absorptiometry, and measured leptin concentrations in serum. It was reported previously that early malnutrition, either during late gestation or immediately postnatally, results in a delayed onset of puberty in IUGR and FR male rats and in IUGR female rats, but not in FR female rats. In IUGR male rats at balanopreputial separation and in IUGR female rats at vaginal opening no differences were found in body mass index, body composition, and leptin levels compared with controls. FR male rats had a significantly lower percentage of fat and serum leptin concentrations at balanopreputial separation. FR female rats had a significantly lower body mass index, percentage of fat, and serum leptin concentrations at vaginal opening. We conclude that the onset of puberty in the rat is not dependent on a certain percentage of body fat or a certain threshold of circulating levels of leptin and that food deprivation during different "critical" time periods around birth results in different effects in later life.

Topics: Animals; Body Composition; Body Mass Index; Energy Intake; Female; Fetal Growth Retardation; Leptin; Male; Pregnancy; Rats; Rats, Wistar; Sexual Maturation

Leptin concentrations are increased during late pregnancy, and leptin receptors are expressed in placental and fetal tissues, suggesting a role for leptin in placental and/or fetal growth, or both. In humans, leptin concentrations in adulthood are inversely related to body weight at birth, independent of adult adiposity, and correlate with fasting insulin. Glucocorticoids and insulin regulate leptin secretion. Excessive exposure to glucocorticoids during late fetal development in the rat causes intrauterine growth retardation (IUGR), together with hypertension and hyperinsulinaemia in adulthood. Leptin may have a role in the development of some forms of hypertension.. To determine whether IUGR induced by maternal glucocorticoid treatment during the last third of pregnancy in the rat is associated with modulation of either maternal or fetal leptin concentrations, the placental expression of leptin or the short form of the leptin receptor (ObR-S), or combinations thereof, and to evaluate whether hypertension or hyperinsulinaemia in the early-growth-retarded adult progeny of dexamethasone-treated dams is associated with altered leptin concentrations.. Dexamethasone was administered to pregnant rats from day 15 to day 21 of gestation via a chronically implanted subcutaneous osmotic minipump. Protein expression of leptin and ObR-S in the placenta at day 21 of pregnancy was measured by western blotting. Plasma leptin and insulin concentrations were determined by radioimmunoassay and ELISA respectively. Systolic hypertension was measured by tail cuff plethysmography.. Dexamethasone administration during the last third of pregnancy decreased placental mass and fetal body weight at day 21 of gestation, caused maternal hyperleptinaemia but fetal hypoleptinaemia, and suppressed placental leptin protein expression whilst up-regulating placental protein expression of ObR-S. The male and female offspring of dexamethasone-treated dams were hypertensive from 12 weeks of age. One-year-old offspring of dexamethasone-treated dams exhibited significant hyperleptinaemia compared with age-matched controls, an effect associated with hyperinsulinaemia in the male, but not female, offspring.. The rat model of maternal dexamethasone treatment is established as a paradigm of 'programmed' hypertension in man. Our data show modification of placental leptin and leptin receptor protein expression by dexamethasone treatment during the last third of pregnancy. We also show that leptin concentrations are suppressed during fetal life but increased in adulthood in this rat model of programmed hypertension. Our data do not necessarily establish a causal relationship between fetal hypoleptinaemia and impaired fetal growth during early life, or between hyperleptinaemia and hypertension in adulthood. Nevertheless, they suggest that hyperleptinaemia may be a component of the cluster of metabolic abnormalities seen in the insulin resistance syndrome in man. They also suggest that excessive fetal exposure to glucocorticoids could be a common early-life stimulus to the association between hyperinsulinaemia, hypertension and hyperleptinaemia often seen in individuals of low birthweight.

Topics: Animals; Body Weight; Carrier Proteins; Dexamethasone; Dose-Response Relationship, Drug; Eating; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Fetus; Glucocorticoids; Hypertension; Insulin; Leptin; Male; Organ Size; Placenta; Pregnancy; Pregnancy, Animal; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; Time Factors

The purpose of this study was to detect the presence of leptin and its receptor in ovine fetal tissues and to examine the relationship between circulating leptin concentrations and fetal and placental weights on gestational day 138 (GD138) of ovine pregnancy (term, 145 days).. Pregnant sheep (n = 18) were instrumented on GD 110 to facilitate measurement and chronic reduction of uterine blood flow and produce intrauterine growth restriction. Four animals that served as controls were euthanized on GD 138 to obtain fetal tissues to determine the presence of ovine leptin and its receptor by reverse transcriptase-polymerase chain reaction. Seven instrumented animals were randomized into the control group, and 7 instrumented animals were randomized into the uterine blood flow restricted group (reduction equaled approximately 50% on GD 138). Maternal and fetal blood samples were obtained on day 138 to measure plasma leptin concentrations, and animals were euthanized for the determination of fetal morphometrics and placental weight.. Expression of RNA for ovine leptin and its receptor were observed in fetal liver, skeletal muscle, kidney, heart, and placenta. Fetal body weight, ponderal index, and placental weight were significantly decreased by approximately 40% in the blood flow restricted group as compared with controls. Fetal leptin concentrations were increased by 45% in the uteroplacental blood flow restricted group (P =.01). Maternal leptin concentrations were not significantly different between the 2 groups and did not correlate with fetal concentrations. Fetal leptin concentrations had an inverse relationship with uterine blood flow (r = -0.73; P =.004), fetal body weight (r = -0.78; P =.002), and placental weight (r = -0.68; P =.01).. Ovine fetal tissues express RNA for leptin and its receptor. Circulating leptin concentrations in the ovine intrauterine growth restriction fetus were significantly elevated on gestational day 138 compared with controls. Fetal leptin concentrations were inversely related to uterine blood flow and fetal and placental weight. These findings suggest that fetal leptin may be involved in an adaptive response to intrauterine growth restriction.

Topics: Animals; Disease Models, Animal; Embryonic and Fetal Development; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Leptin; Placenta; Placentation; Polymerase Chain Reaction; Pregnancy; Pregnancy, Animal; Radioimmunoassay; Random Allocation; Reference Values; Regional Blood Flow; RNA, Messenger; Sensitivity and Specificity; Sheep; Statistics, Nonparametric; Uterus

The study used a rat model of moderate protein restriction exclusively during fetal and early neonatal life, which has been established to cause intrauterine early growth retardation, to investigate possible association between adipocyte glucose utilisation and leptin secretion in vivo.. These rats, termed early protein restricted, were transferred to a diet containing the standard amount of protein at weaning and remained on this diet til adulthood, at which time adipocyte glucose utilisation and leptin secretion was compared with that of age-matched controls. Insulin status was modulated by acute (2 h) insulin infusion at a constant rate (4.2 mU/min per kg) to elevate insulin to the high physiological range. Euglycaemia was maintained by variable glucose infusion.. Glucose utilisation was measured in vivo in conscious unrestrained rats using 2-deoxy[1-3H] glucose. Leptin concentrations (measured by radioimmunoassay) and whole-body glucose kinetics (measured using [3-3H] glucose) were studied in the postabsorptive state and after acute insulin stimulation.. Adipose-tissue glucose utilisation rates in vivo tended to be higher in the post-absorptive state and were consistently 1.8-3.0-fold higher after insulin stimulation in the early-protein-restricted group compared with the control group. Both the absolute increase in leptin concentration elicited by hyperinsulinaemia and the magnitude of the effect of insulin to elevate plasma leptin levels were greater in the early-protein-restricted group compared with the control group (by 2.2-fold and 1.6-fold, respectively). The effect of insulin to stimulate R(d) was much greater in the early-protein-restricted group (4.1-fold) than in the control group (2.2-fold) and the absolute increase in R(d) elicited by insulin was 43% higher in the early-protein-restricted group than in the control group.. It is concluded that poor early growth enhances the acute leptin response to changes in insulin status through programmed changes in adipocyte glucose handling.

Topics: Adipocytes; Adipose Tissue; Animals; Diet, Protein-Restricted; Female; Fetal Growth Retardation; Food Deprivation; Glucose; Infusions, Intravenous; Insulin; Leptin; Models, Animal; Radioimmunoassay; Rats; Rats, Wistar

To study the effect of maternal pre-eclampsia on cord plasma leptin concentrations in preterm infants.. Leptin concentration was analysed in cord plasma of 74 preterm infants, gestational age 24 to 32 weeks. Of these, 14 were born to pre-eclamptic mothers, in 10 intrauterine growth retardation (IUGR) was present, and 59 had been exposed antenatally to corticosteroids.. The mean (SD) concentration of cord plasma leptin was 1.31 (0.88) microg/l. A significant correlation was found between leptin concentration and gestational age (r = 0.336; p = 0.0037). Leptin levels were higher in infants of pre-eclamptic mothers (p = 0.0007), in those with IUGR (p = 0.0005), and in infants exposed antenatally to corticosteroids (p = 0.02). In multiple regression analysis, leptin was associated with gestational age and maternal pre-eclampsia (both p < 0.05), but not with antenatal corticosteroids.. Increased fetal leptin in maternal pre-eclampsia may reflect a physiological adaptation to fetal stress such as hypoxia.

Topics: Birth Weight; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Glucocorticoids; Humans; Infant, Newborn; Infant, Premature; Leptin; Male; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy

Leptin expression in third trimester placenta (p) and leptin concentrations in umbilical cord blood (cb) were investigated in normal pregnancies [n = 10 (p), 31 (cb)] and abnormal pregnancies complicated with (i) maternal insulin-dependent diabetes [IDDM: n = 3 (p), 13 (cb)], (ii) gestational diabetes [GD: n = 2 (p), 10 (cb)] and (iii) fetal growth retardation [FGR: n = 5 (p), 5 (cb)]. By in-situ hybridization and immunohistochemistry, placental leptin mRNA and protein were co-localized to the syncytiotrophoblast and villous vascular endothelial cells. Leptin receptor was immunolocalized to the syncytiotrophoblast. Relative to controls, the FGR group was characterized by low concentrations of placental and cord blood leptin. In a twin pregnancy, the normal-sized infant exhibited more placental and cord blood leptin than its growth-retarded twin. In contrast, both diabetic groups exhibited high concentrations of placental leptin mRNA and protein. The IDDM group exhibited the highest concentrations of leptin in cord blood. No change was observed in the expression of the leptin receptor in either the growth-retarded or diabetic pregnancies. In conclusion, the localization of placental leptin suggests that it may be released into both maternal and fetal blood. Furthermore, in fetal growth-retarded and diabetic pregnancies, the changes in leptin expression in the placenta and in leptin concentrations in umbilical cord blood appear to be related.

Topics: Carrier Proteins; Diabetes Mellitus, Type 1; Female; Fetal Blood; Fetal Growth Retardation; Humans; Insulin; Leptin; Placenta; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, First; Pregnancy Trimester, Third; Receptors, Cell Surface; Receptors, Leptin; Reference Values

The relationship between in utero fetal growth and fetal leptin concentrations was investigated between 19 and 41 wk in 40 normal (appropriate for gestational age, AGA) fetuses, in 25 intrauterine growth-restricted (IUGR) fetuses, and in 18 fetuses from gestational diabetic mothers (GDM), representing different intrauterine growth patterns. Umbilical venous plasma leptin concentrations were determined at the time of either in utero fetal blood sampling or delivery. Plasma leptin was measurable as early as 19 wk of gestation. A significant difference was observed between umbilical venous and arterial plasma leptin concentrations (0.6+/-0.6 ng/mL; p<0.01). In AGA and in IUGR fetuses, significant positive relationships were found between fetal leptin concentrations and both gestational age (p<0.001) and fetal weight (p<0.001). Leptin concentrations were significantly higher in AGA than IUGR only after 34 wk (p<0.05), but leptin per kilogram fetal weight (leptin/kg) was not significantly different. In IUGR with abnormal umbilical arterial Doppler velocimetry and fetal heart rate, leptin/kg significantly higher than in IUGR with normal biophysical and biochemical parameters was found (p<0.05). Both circulating plasma leptin and leptin/kg were significantly higher in GDM than in normal fetuses (p<0.001) and correlated with abdominal fat mass measured by ultrasound. No gender differences were observed in any group of fetuses. These findings indicate a clear relationship between fetal leptin concentrations and fetal fat mass. Data in severe IUGR suggest the presence of increased leptin concentrations associated with in utero signs of fetal distress.

Topics: Diabetes, Gestational; Embryonic and Fetal Development; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Male; Pregnancy; Reference Values

The aim of the study was to investigate how leptin could be involved in catch-up growth of children born with intrauterine growth retardation (IUGR). The study population was made up of 70 newborns with IUGR longitudinally studied during the first 2 yr of life and 35 newborns and 32, 66, and 61 children with normal birth weight aged 3 days, 12 months, and 24 months, respectively. Postnatal patterns of body mass index (BMI) were similar in the 2 groups, but BMI remained significantly lower in IUGR over the study period. In contrast, children born with IUGR aged 1 yr had significantly higher serum leptin levels than normal children (P < 0.0001) independently of BMI. The correlation observed between BMI and serum leptin at birth in both groups and in the control group thereafter disappeared in children born with IUGR. Similarly, sexual dimorphism observed in normal children over the study period was not observed in the IUGR group during the first 2 yr of life. In summary, serum leptin is effective and regulated during the first years of life as it is in older children. Children born with IUGR demonstrate high serum leptin values during the first year of life, with a loss of the regulatory effect of BMI and gender. We suggest that these children develop an adaptative leptin resistance beneficial for their catch-up growth. An alternative hypothesis is that these observations could reflect an adipocyte dysfunction, a consequence of the special time course of adipose tissue development in children born with IUGR.

Topics: Aging; Body Mass Index; Female; Fetal Growth Retardation; Growth; Humans; Infant; Infant, Newborn; Leptin; Longitudinal Studies; Male; Proteins; Sex Characteristics

Serum leptin concentrations reflect the fat mass of an individual. Fetal growth is rapid and it might be expected that major changes in circulating leptin concentrations in the fetus and neonate take place. We have studied the ontogeny of serum leptin concentrations in cord blood samples obtained by cordocentesis between 14 and 32 weeks of gestation and in samples obtained at term.. Cordocentesis samples from 10 appropriately grown for gestational age (AGA) and 10 intrauterine growth restricted (IUGR) fetuses. The results were compared with cord serum leptin concentrations obtained in 39 term healthy pregnancies.. In the AGA and term pregnancies serum leptin concentrations changed little up until 38 weeks of gestation when there was an increase in concentration (Pre 38 weeks 3.5 microg/l (SEM 0.3); Post 38 weeks 5. 6 microg/l (SEM 0.7): Mann Whitney P = 0.03). Serum leptin concentrations were similar in the AGA and IUGR fetuses (AGA 5.9 microg/l (SEM 3.0); IUGR 4.2 microg/l (SEM 1.5): Mann-Whitney P = ns). Serum leptin was strongly related to birth weight (r = 0.58; P < 0.001) and birth length (r = 0.32; P = 0.05) in the term babies but not in the AGA or IUGR groups.. Serum leptin concentrations in the fetus appear to be independent of gestational age and only rise towards the end of gestation. This late change probably reflects the changes in the accretion of body fat. There appears to be little difference in serum leptin concentrations between AGA and IUGR fetuses.

Topics: Female; Fetal Blood; Fetal Growth Retardation; Humans; Infant, Newborn; Leptin; Pregnancy; Pregnancy Trimester, Second; Statistics, Nonparametric

To test the hypothesis that maternal and cord serum leptin concentrations correlate with birth weight of infants.. Pregnant women (n = 135) of low socioeconomic status who delivered full-term infants were selected from more than 1500 women who participated in a study to identify factors related to fetal growth restriction (FGR). They were divided into two groups based on their infants being classified as having FGR (n = 66) or not (n = 69), and each group was divided further into three subgroups based on prepregnancy body mass index (BMI): less than 19.8, 19.8-28.9, and 29 or more. Sample estimations indicated that 20 subjects per subgroup would be adequate to detect 50% difference in leptin concentrations.. Mean maternal serum leptin concentrations adjusted for BMI were highest at approximately 22-27 weeks' gestation (29.8 ng/mL) and declined thereafter until term (25.2 ng/mL). Leptin concentration and prepregnancy BMI correlated significantly. We found neither significant difference in leptin concentrations between the subjects with and without FGR infants nor significant correlation between maternal leptin concentrations and birth weight of infants. Mean cord serum leptin concentration (10.8 ng/mL) was lower than maternal concentrations and correlated significantly with birth weight (r = .61, P < .001).. Our findings suggest that maternal leptin concentration during pregnancy is not an accurate indicator of fetal growth. Cord serum leptin concentrations were lower than maternal serum concentrations and correlated significantly with birth weight.

Topics: Adult; Embryonic and Fetal Development; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Leptin; Pregnancy; Proteins

Leptin is a 16-kD protein encoded by the ob/ob (obesity) gene. In rodents it plays a role in obesity, diabetes, fertility, and neuroendocrine function. In humans serum concentrations of leptin correlate with total body fat in both adults and children. We measured cord blood leptin in 186 neonates that included 82 appropriate for gestational age (AGA), 47 large for gestational age (LGA), 20 infants of diabetic mothers, 52 preterm infants, and 15 intrauterine growth-retarded (IUGR) infants. There were 16 pairs of twins. The mothers of 17 preterm infants were treated with steroids before delivery. Leptin (mean +/- SD) concentration in term, AGA infants (39.4 +/- 1.1 wk) with birth weight (BW) of 3.2 +/- 0.3 kg, body mass index (BMI) of 12.6 +/- 1.1 was 4.01 +/- 3.5 ng/mL. BW correlated with cord leptin (p = 0.002) in a multivariate analysis controlling for potential confounders. Both LGA infants and infants of diabetic mothers had higher cord leptin concentration 7.3 +/- 3.8 and 6.1 +/- 4.8 ng/mL, respectively, compared with AGA infants (p < 0.05). Preterm infants had a mean leptin level of 1.8 +/- 0.97 ng/mL and a 3-fold elevation was seen if mothers received steroids antenatally (p = 0.006). IUGR infants had increased leptin (6.5 +/- 3.9 ng/mL, p = 0.03). Concerning the twin pairs, the smaller had a higher leptin level compared with larger twin (4.1 +/- 9.51 versus 2.8 +/- 5.14, p = NS). Neonatal cord leptin concentrations correlate well with BW and BMI. No gender differences were found in cord blood leptin. Maternal obesity had no effect on cord leptin, whereas exogenous maternal steroids increased neonatal leptin concentrations.

Topics: Adult; Birth Weight; Body Mass Index; Child; Diabetes, Gestational; Female; Fetal Blood; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Premature; Leptin; Maternal-Fetal Exchange; Obesity; Pregnancy; Proteins; Steroids

The aim of this study was to investigate the ontogeny of serum leptin concentrations during the second half of gestation and at birth in small for gestational age and normal fetuses and newborns. Serum leptin concentrations were measured in arterial cord blood of fetuses (n = 79) and newborns (n = 132), with or without intrauterine growth retardation, at 18-42 weeks gestation. Serum leptin was detectable in fetal cord blood in all subjects as early as 18 weeks gestation. Leptin levels dramatically increased after 34 weeks gestation. In newborns, serum leptin concentrations were positively correlated with body weight (P < 0.001) and body mass index (P < 0.001). Newborns with intrauterine growth retardation had significantly lower serum leptin values (P < 0.001) than those with normal growth, and leptin levels were only positively correlated with body mass index (P < 0.001). These results suggest that the development of adipose tissue and the accumulation of fat mass are the major determinants of fetal and neonatal serum leptin levels. In addition, a gender difference, with higher leptin concentrations in female fetuses, was observed during the last weeks of gestation and was confirmed at birth regardless of growth status, suggesting that a sexual dimorphism already exists in utero.

Topics: Adolescent; Adult; Case-Control Studies; Embryonic and Fetal Development; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Leptin; Male; Multivariate Analysis; Obesity; Organ Size; Placentation; Proteins; Reference Values; Sex Characteristics